What does it actually mean to have a “healthy” gut microbiome? One of the earliest attempts to answer this question was inspired by the world of invertebrates, where it is possible to identify a common, key set of bacterial species that is consistently found within members of the same species. If such a pattern exists in invertebrates, perhaps humans also have a similar, shared set of key species that define a healthy gut? Dysbiosis would then simply be a deviation from this pattern.

However, this concept ran into a major problem: in humans, there is no common set of key bacterial species. Unlike invertebrates, the gut microbiota of different individuals varies so extensively that it is impossible to identify a group of species that could be considered a shared core across all humans.

That does not mean the question is settled. But it does raise another question: are we looking for the answer at the wrong level? What if, instead of looking for specific species shared by all humans, we should look at something else: functional groups of bacteria, known as ecological guilds, that are connected not by their relatedness but by the way they use the resources available in the gut?

This brings us to the concept of oxygen-driven dysbiosis.

Why Some Bacteria Win the Race for Dominance in the Colon

What exactly are ecological guilds? To understand this, we first need to look at what determines which bacteria will dominate a given environment.

The answer is energy. Microorganisms that can produce the most energy divide the fastest. Over time, they take control of the microbial community (1, 2).

Energy is generated through reactions in which electrons “jump” from one molecule (such as glucose) to another, the so-called electron acceptor. The stronger the electron acceptor, the more energy a bacterium can extract from the same “fuel.” And oxygen is the strongest electron acceptor.

That is why, in environments where oxygen is available, bacteria capable of using it gain an advantage. Some bacteria are aerobic and need oxygen to grow. Others are facultatively anaerobic, meaning that they can use oxygen but can also grow without it.

In an anaerobic environment, the situation is different. There, the dominant group is the so-called primary fermenters: bacteria that break down organic compounds without oxygen or an external electron acceptor. They use endogenous electron acceptors, such as pyruvate or phosphoenolpyruvate, and the products of fermentation include short-chain fatty acids such as butyrate.

Which bacteria gain the upper hand therefore depends not only on the availability of nutrients, but also on how they can obtain energy in a given environment.

The Same Mechanism, Different Bacteria — What the Colons of Infants and Adults Can Teach Us

Take two very different colons: that of a breastfed infant and that of a healthy adult. At the species level, they look completely different. In infants, bacteria from the class Actinomycetia dominate, specifically Bifidobacterium longum subsp. infantis, specialized in breaking down oligosaccharides from breast milk that are not absorbed in the small intestine and reach the colon intact. In adults, after weaning and the introduction of solid foods, the picture changes. Different primary fermenters become important, including members of the Bacteroides genus and butyrate-producing bacteria such as Faecalibacterium. Bacteroides specialize in breaking down dietary fiber and other carbohydrates that escape digestion, while some primary fermenters produce metabolites such as butyrate.

At the species level, this would look like two completely different, unrelated ecosystems.

At the functional level, however, both colons have the same structure: in both, the primary fermenter guild dominates. The “supplier” has changed (bacteria adapted to the current diet), but the role remains the same. Homeostasis therefore does not depend on a specific species composition, but on maintaining the dominance of primary fermenters, regardless of which bacteria happen to perform this function (1).

In a healthy gut, facultatively anaerobic bacteria remain relatively scarce. In a disrupted microbiome, however, their abundance can increase substantially, challenging the dominance of primary fermenters. They are most commonly bacteria from the phylum Proteobacteria, which includes familiar bacteria such as E. coli, Salmonella, and Klebsiella (1, 3). An increased abundance of this group has been observed in, among others, inflammatory bowel disease (4, 5), irritable bowel syndrome (6), and histamine intolerance (7). A study involving people with obesity also found an increased abundance of a specific E. coli strain. Interestingly, when this strain was administered to mice, its colonization led to obesity, liver steatosis, and systemic inflammation (8).

Oxygen-driven dysbiosis involves two related phenomena: the expansion of facultatively anaerobic bacteria and a decline in primary fermenters. For the latter, an interesting example comes from a study published this year comparing the microbiota of people with Parkinson’s disease and Alzheimer’s disease. While the changes in the microbiota associated with Alzheimer’s were relatively subtle and inconclusive, Parkinson’s disease was characterized by a clear and consistent decline in butyrate-producing bacterial genera, such as Faecalibacterium and Roseburia (9). I wrote more about what this means for the gut–brain axis in my article: New Insights on the Gut–Brain Axis in Parkinson’s Disease.

A similar decline in butyrate-producing bacteria is also observed in metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease, NAFLD). A systematic review published in 2026, including seven studies and 1,185 participants, found that people with MASLD often had lower butyrate levels in stool or blood, as well as lower abundance of butyrate-producing bacteria such as Faecalibacterium prausnitzii and members of the genus Eubacterium (10).

Moreover, lower butyrate levels and lower abundance of butyrate-producing bacteria were associated with more severe liver steatosis and fibrosis, greater inflammation, and less favorable metabolic parameters, including higher BMI, greater insulin resistance, and impaired lipid metabolism. I wrote more about the role of butyrate in MASLD and the mechanisms linking its metabolism to liver health here: Butyrate and Fatty Liver Disease: A Bioenergetic Perspective.

Who Keeps Oxygen Out of the Colon?

From this point on, when I simply write “gut,” I mean the colon. This distinction matters because the small intestine is more oxygenated, and different factors play a key role in shaping its microbial composition.

If homeostasis depends on maintaining the dominance of primary fermenters, a key question becomes: who actually keeps the colon’s environment anaerobic?

It turns out that the gut itself actively limits the amount of oxygen reaching its interior. A key role is played by the very high oxygen consumption of the mitochondria in the colonic epithelium. As a result, the mucosal surface remains hypoxic, with oxygen levels below 1% O₂. This limits the diffusion of oxygen into the intestinal lumen. An interesting confirmation of the importance of this mechanism came from comparing the intestines of conventional and germ-free mice: in both cases, the intestinal lumen remained anaerobic, despite the complete absence of microbiota in the latter group (11). This means that the basic maintenance of this anaerobic environment does not require the presence of bacteria.

The anaerobic environment of the colon therefore benefits both sides. The host limits oxygen availability, creating conditions that favor primary fermenters, while these bacteria break down components of food that our enzymes cannot digest and produce metabolites that the body can use. This relationship is one of the factors supporting intestinal homeostasis (1, 2).

This system can, however, change quite easily. The way epithelial cells obtain energy is particularly important. When they shift away from mitochondrial respiration toward aerobic glycolysis, they produce lactate despite the presence of oxygen. Their oxygen consumption then decreases. More oxygen can then reach the intestinal lumen. This changes the competitive landscape: facultatively anaerobic bacteria can begin using the available oxygen as an electron acceptor, obtaining more energy than bacteria relying on fermentation.

Oxygen is not the only factor that gives facultatively anaerobic bacteria an advantage. Another, almost equally powerful electron acceptor is nitrate, which appears in the gut under very different circumstances than oxygen.

When inflammation develops in the gut, immune cells increase production of the enzyme iNOS, which produces nitric oxide. Nitric oxide then reacts with superoxide radicals, byproducts of the inflammatory response, and this reaction produces nitrate, generated by the host itself as a kind of side effect of inflammation.

This is an important difference from oxygen: oxygen availability increases as a result of metabolic changes in the epithelium, whereas nitrate availability increases directly as a consequence of inflammation. Elevated nitrate concentrations in the intestinal lumen allow facultatively anaerobic bacteria to gain a growth advantage through nitrate respiration.

In other words, inflammation and oxygen-driven dysbiosis can reinforce each other. Inflammation increases the availability of both oxygen (through changes in epithelial metabolism) and nitrate (through iNOS production), and both factors favor the growth of facultatively anaerobic bacteria, which in turn may further fuel inflammation, creating a vicious cycle (1, 12).

Increasing oxygen availability in the gut can shift the microbial balance in favor of bacteria that are able to use oxygen. A similar shift can also favor fungi, specifically Candida albicans, an opportunistic fungal pathogen that can use oxygen for growth. Increased oxygen availability at the epithelium, observed for example after antibiotic treatment, creates conditions that favor Candida proliferation in the colon (13).

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Butyrate and Pathogens — Two Sides of the Same Story

Butyrate as Fuel and Signal

Butyrate is a short-chain fatty acid produced by primary fermenters. It is not merely a byproduct of fermentation. It is the preferred “fuel” for cells of the colonic epithelium, while also acting as a molecular signal. Butyrate activates the PPAR-γ receptor in colonocytes, which maintains high oxygen consumption by epithelial mitochondria and therefore directly reinforces the same mechanism of hypoxia we discussed earlier (14).

Biochemical studies have shown that butyrate can also directly inhibit prolyl hydroxylases (PHD), stabilizing hypoxia-inducible factor (HIF). This means that butyrate can strengthen the cellular response to hypoxia not only by increasing oxygen consumption, but also by influencing the mechanism through which oxygen is sensed (15).

Primary fermenters produce butyrate → butyrate maintains epithelial hypoxia → hypoxia protects the environment needed by primary fermenters. This creates a self-sustaining mechanism of intestinal homeostasis.

If microbiota-produced butyrate helps maintain oxygen consumption by the epithelium, why does the intestine of germ-free mice remain anaerobic despite the absence of a microbiota? One possible explanation is that, in this model, the absence of butyrate is compensated for by other mechanisms that maintain low oxygen levels.

When Pathogens Disrupt This Mechanism

Some microorganisms can actively disrupt colonocyte metabolism to their own advantage: Salmonella enterica serotype Typhimurium is one example of this phenomenon (16).

S. Typhimurium invades the intestinal mucosa and triggers a strong inflammatory response. Inflammation leads to two changes here.

First, it depletes the population of Clostridia, the same bacteria that produce butyrate. Fewer Clostridia means less butyrate, and less butyrate means weaker PPAR-γ signaling and reduced oxygen consumption by the epithelium.

Second, inflammation recruits neutrophils into the intestinal lumen, where they produce reactive oxygen and nitrogen species in response to the infection. These react with each other to generate additional powerful electron acceptors: nitrate and tetrathionate. Primary fermenters cannot use these compounds as electron acceptors, whereas Salmonella and other bacteria from the Proteobacteria group can use them for anaerobic respiration. The inflammation caused by such a pathogen therefore creates an environment that favors its further expansion, as well as the growth of other bacteria capable of using the same electron acceptors.

What’s more, in response to infection, the host itself begins releasing antimicrobial compounds such as hydrogen peroxide into the intestinal lumen to fight the pathogen. The problem is that many pathogenic bacteria possess the enzyme catalase, which breaks hydrogen peroxide down directly into water and oxygen. The host’s defense mechanism may therefore further increase oxygen availability, which facultatively anaerobic bacteria can exploit.

This does not necessarily mean an acute infection. What matters is the ability of certain microorganisms to disrupt epithelial metabolism and transform the intestinal environment into conditions that favor their expansion.

What’s Next?

In upcoming articles, I’ll look at how we can specifically support epithelial hypoxia and limit oxygen-driven dysbiosis, including dietary strategies and specific compounds and substances that may strengthen this mechanism.

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References:

1. Lee JY, et al. 2024. The human gut microbiome in health and disease: time for a new chapter? Infect Immun. 92:e0030224.

2. Litvak Y, et al. 2018. Colonocyte metabolism shapes the gut microbiota. Science. 362:eaat9076.

3. Litvak Y, et al. 2017. Dysbiotic Proteobacteria expansion: a microbial signature of epithelial dysfunction. Curr Opin Microbiol. 39:1-6.

4. Aceto GM, et al. 2026. Deciphering the Implications of Escherichia coli in Inflammatory Bowel Disease: From Symbiont to Pathogen. Pathogens. 15:548.

5. Arroyo-Mendoza M, et al. 2026. Escherichia coli pathobionts and Crohn’s disease: varied genetic paths leading to similar phenotypes. J Bacteriol. 208:e0001626.

6. Aggeletopoulou J, and Triantos Ch. 2024. Microbiome Shifts and Their Impact on Gut Physiology in Irritable Bowel Syndrome. Int J Mol Sci. 25:12395.

7. Sánchez-Pérez S, et al. 2022. Intestinal Dysbiosis in Patients with Histamine Intolerance. Nutrients. 14:1774.

8. Singh A, et al. 2025. High alcohol-producing Escherichia coli causes obesity and steatotic liver disease in a non-alcoholic cohort -a preclinical study. BMC Microbiol. 25:809.

9. Jaegher SD, et al. 2026. Identifying microbial biomarkers of neurodegeneration: a comparative study in Alzheimer’s and Parkinson’s disease. Front Microbiomes. 5:1831956.

10. González-González A, et al. 2026. The Role of Butyrate in People with Metabolic Dysfunction-Associated Steatotic Liver Disease and Related Metabolic Comorbidities: A Systematic Review. Curr Obes Rep. 15:17.

11. Friedman ES, et al. 2018. Microbes vs. chemistry in the origin of the anaerobic gut lumen. Proc Natl Acad Sci U S A. 115:4170-4175.

12. Winter SE, and Bäumler AJ. 2023. Gut dysbiosis: Ecological causes and causative effects on human disease. Proc Natl Acad Sci U S A. 120:e2316579120.

13. Savage HP, et al. 2024. Epithelial hypoxia maintains colonization resistance against Candida albicans. Cell Host Microbe. 32:1103-1113.e6.

14. Byndloss MX, et al. 2017. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science. 357:570-575.

15. Zhang F, et al. 2026. Butyrate-Producing Bacteria in Intestinal Disease Therapy: Potential and Challenges. Biotechnol J. 21:e70260.

16. Rivera-Chávez F, et al. 2016. Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella. Cell Host Microbe. 19:443-54.

Histamine is most commonly associated with allergic reactions. In recent years, however, it has become the focus of intensive research in the context of irritable bowel syndrome (IBS). Current evidence indicates that histamine may be involved in mechanisms contributing to IBS symptom severity. Some of these findings may also have practical implications for the management of IBS.

The Role of Histamine in IBS

Several independent observations point to a role for histamine in IBS. In some patients with IBS, particularly those with diarrhea-predominant IBS (IBS-D), increased numbers of activated mast cells in the intestinal mucosa and higher histamine concentrations have been observed compared with healthy individuals. Moreover, the greater the activity of these cells, the more severe the abdominal pain (1).

Mast cells are one of the main sources of histamine in the gut. When activated, they undergo degranulation, releasing numerous biologically active compounds, including histamine, tryptase, prostaglandin E₂, and cytokines. A growing body of research indicates that these mediators may not only increase pain perception but also impair intestinal barrier function.

However, this is not the only reason why mast cells play such an important role in the gut. They can respond directly to dietary components as well as indirectly to changes in the gut microbiome. In this way, they link the effects of diet, the gut microbiome, and the intestinal immune response.

Some gut bacteria are capable of producing histamine (2). I discuss histamine production within the gut, as well as the effects of SIBO, methanogen overgrowth, and fungal overgrowth on this process, in greater detail in the first two parts of my histamine intolerance series: Histamine Intolerance (Part 1): When Histamine Is Produced Inside the Gut and Histamine Intolerance (Part 2): SIBO, Methane and Fungal Overgrowth.

Since mast cells respond both to dietary components and to changes in the gut microbiome, it is worth taking a closer look at how these mechanisms are influenced by the low FODMAP diet (low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols).

How the Low FODMAP Diet Works

The low FODMAP diet has long been one of the best-studied dietary approaches for patients with IBS. Its effectiveness is most commonly attributed to reduced bacterial fermentation, lower gas production, and decreased water influx into the intestinal lumen. In recent years, however, studies have suggested that the mechanisms underlying the effects of the low FODMAP diet are more complex.

One study found that after just 3 weeks on a low FODMAP diet, people with IBS experienced not only a marked improvement in symptoms but also an approximately 8-fold reduction in urinary histamine concentrations (3). This observation indicates that reducing the histamine burden may be be one of the mechanisms responsible for the beneficial effects of this diet.

This raises an important question: what accounts for such a marked reduction in histamine concentrations? Another study provides part of the answer by examining how the low FODMAP diet affects mast cell activation and intestinal barrier function (4). It combined experiments in animal models with clinical studies in patients and additional experiments using mast cells. The clinical part of the study included patients with IBS-D because the effectiveness of the low FODMAP diet has been best established for this IBS subtype in randomized clinical trials.

The results showed that a diet high in FODMAPs led to mast cell activation and impaired intestinal barrier function in mice, whereas the low FODMAP diet reduced mast cell activation and improved barrier integrity. In patients with IBS-D who responded to the low FODMAP diet, the authors also observed increased expression of the tight junction proteins JAM-A and ZO-1, which play a key role in maintaining intestinal barrier integrity. At the same time, blood concentrations of histamine and tryptase decreased, consistent with the earlier observation of an approximately 8-fold reduction in urinary histamine concentrations following the low FODMAP diet. Additional experiments indicated that one of the mechanisms underlying these changes was mast cell activation by lipopolysaccharide (LPS) through the TLR4 receptor.

According to the authors, this is the first study indicating that mast cell activation is one of the key mechanisms contributing to intestinal barrier damage induced by a diet high in FODMAPs.

What Are the Most Common Symptoms of Histamine Intolerance?

Interesting insights come from a study involving individuals who met the diagnostic criteria for histamine intolerance. These included, among others, low activity of diamine oxidase (DAO)—the enzyme responsible for breaking down histamine in the gut (<10 U/mL), symptom improvement following a low-histamine diet, and the exclusion of other common causes of similar symptoms, such as celiac disease, Helicobacter pylori infection, lactose intolerance, and fructose malabsorption (5).

Although histamine intolerance is most commonly associated with skin symptoms or a runny nose, the findings of this study indicate that gastrointestinal symptoms were the predominant complaints. The most commonly reported symptoms were:

• abdominal bloating (92%),

• postprandial fullness (73%),

• diarrhea (71%),

• abdominal pain (68%),

• constipation (55%).

Moreover, patients rated gastrointestinal symptoms as the most severe.

The study also shows how diverse the clinical presentation of histamine intolerance can be. In addition to gastrointestinal symptoms, some participants reported itching, skin flushing, dizziness, headaches, heart palpitations, a runny nose, and nasal congestion. On average, each participant reported 11 different symptoms, and nearly 97% experienced more than three complaints.

From the perspective of IBS, what is particularly important is that gastrointestinal symptoms were the predominant complaints.

Why Can DAO Activity Be Reduced?

DAO activity is not constant and can decrease for a variety of reasons. One of them is damage to the intestinal lining, where this enzyme is produced.

This is supported by studies indicating that DAO activity is closely linked to the activity of other enzymes produced by enterocytes, such as lactase, maltase, and sucrase. This means that when the intestinal lining is damaged, the activity of several enzymes involved in digestion and the metabolism of different compounds may decline simultaneously (1).

This may partly explain why lactose intolerance and histamine-related symptoms coexist in some patients.

Moreover, one study found that more than 50% of patients with both lactose intolerance and fructose malabsorption also met the criteria for histamine intolerance (6). The authors noted that, in some of these individuals, a low-histamine diet combined with DAO supplementation was associated with an improvement in symptoms.

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DAO Supplementation in a Patient with IBS – A Case Report

To date, no randomized clinical trials have evaluated the effectiveness of DAO supplementation in patients with IBS. However, a published case report provides a compelling illustration of the hypothesis regarding the role of histamine in IBS.

The report describes a 46-year-old woman with constipation-predominant irritable bowel syndrome (IBS-C) who had experienced abdominal pain, bloating, excessive gas, and constipation for many years (7). The structured elimination and reintroduction process used in the low FODMAP diet identified onion and wheat as the main foods triggering her symptoms. After implementing the dietary recommendations, she experienced a marked reduction in bloating (by approximately 71%) along with a substantial improvement in quality of life. However, the diet alone had no effect on either the severity or frequency of her abdominal pain, which remained unchanged.

She then began taking one tablet of a porcine-derived DAO supplement (20,000 HDU) before meals that might contain onion or wheat. She did this primarily when eating at restaurants or at friends’ homes, where she did not have full control over the ingredients in her meals. After introducing DAO, her abdominal pain and constipation resolved completely, while bloating improved even further (from 20 to 10 points on the IBS Symptom Severity Score [IBS-SSS], a validated questionnaire used to assess IBS symptom severity).

She emphasized that although the low FODMAP diet had produced a clear improvement, it was the addition of DAO that gave her more complete control over her symptoms. From that point on, symptom flare-ups became infrequent and were usually limited to mild bloating after meals that might contain onion or wheat. No adverse effects were reported during DAO supplementation. From the start of dietary treatment to the period following the introduction of DAO, her total IBS-SSS score decreased from 330 to 10 points, corresponding to a transition from severe IBS to remission.

What Can We Learn from Research on Histamine and IBS?

The studies presented here indicate that histamine is one component of the complex interactions among diet, the gut microbiome, mast cells, and the intestinal barrier.

The findings also indicate that the low FODMAP diet, whose effectiveness in patients with IBS has been confirmed in numerous clinical trials, may exert at least part of its beneficial effects through its influence on LPS production, mast cell activation, and intestinal barrier integrity.

The case report highlights another interesting possibility. The patient took DAO primarily before meals containing onion or wheat—foods rich in FODMAPs rather than histamine. This may indicate that, in some patients, the benefits of DAO supplementation are not solely due to the breakdown of histamine present in food. It is possible that DAO also reduces the burden of histamine released by activated mast cells as well as histamine produced by gut bacteria. This hypothesis represents an interesting direction for future research.

One approach I consider in selected patients with IBS is a short-term reduction of foods particularly high in histamine, together with DAO supplementation for approximately 7–14 days. This approach makes it possible to evaluate whether histamine may play an important role in symptom severity. However, this does not mean that simply reducing dietary histamine or taking DAO resolves the underlying problem. In Histamine Intolerance (Part 3): Rebalancing the Gut Environment and Histamine Intolerance (Part 4): Stabilizing the Histamine Regulatory System, I discuss strategies aimed at reducing histamine production within the gut and improving the mechanisms that regulate histamine metabolism. These approaches may also be helpful for some patients with IBS.

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References:

1. Alemany-Fornés M, et al. 2025. Diamine oxidase deficiency implications for health, current management, and future directions in the treatment of histamine intolerance: A review. Int J Biol Macromol. 327:147130.

2. Sánchez-Pérez S, et al. 2022. Intestinal Dysbiosis in Patients with Histamine Intolerance. Nutrients. 14:1774.

3. McIntosh K, et al. 2017. FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. Gut. 66:1241-1251.

4. Singh P, et al. 2021. High FODMAP diet causes barrier loss via lipopolysaccharide-mediated mast cell activation. JCI Insight. 6:e146529.

5. Schnedl WJ, et al. 2019. Evaluation of symptoms and symptom combinations in histamine intolerance. Intest Res. 17:427-433.

6. Schnedl WJ, et al. 2020. Increasing Expiratory Hydrogen in Lactose Intolerance Is Associated with Additional Food Intolerance/Malabsorption. Nutrients. 12:3690.

7. Pierce C, and Coetzee O. 2026. Diamine Oxidase Supplementation for Histamine Regulation in Constipation-Predominant Irritable Bowel Syndrome: A Case. Report. Integr Med (Encinitas). 25:22-26.

Most people associate Parkinson’s disease with tremors and difficulty moving. However, for many patients, the first symptoms appear years—sometimes more than a decade—before movement problems develop. Chronic constipation and other gastrointestinal symptoms are among the most common early signs.

These observations gave rise to the gut-origin hypothesis of Parkinson’s disease. According to this hypothesis, the disease process may begin in the gut before gradually spreading to the brain.

The Gut-Origin Hypothesis of Parkinson’s Disease

According to the gut-origin hypothesis proposed by Braak, misfolded α-synuclein may first appear in the enteric nervous system in some individuals before gradually traveling to the brain via the vagus nerve (1). α-Synuclein is a protein found in both the central nervous system and the enteric nervous system. Under normal conditions, it plays an important role in communication between neurons. In Parkinson’s disease, however, it can become misfolded and form aggregates that progressively damage the dopamine-producing neurons responsible for controlling movement.

Animal studies have provided substantial evidence supporting this hypothesis. More recently, human studies have also found that abnormal forms of α-synuclein may already be present in gastrointestinal tissues during the early stages of the disease.

The gut-origin hypothesis has significantly reshaped the direction of Parkinson’s disease research. Increasing attention is now being given to the gut microbiome, the intestinal barrier, and bacterial metabolites that may influence the gut–brain axis.

One condition that may also fit within this framework is small intestinal bacterial overgrowth (SIBO). Studies indicate that SIBO may increase intestinal permeability and promote inflammation. These changes may contribute to the misfolding of α-synuclein and the activation of microglia, potentially linking gut dysfunction to the neurodegenerative processes seen in Parkinson’s disease.

Butyrate: Far More Than Fuel for the Gut

One of the most important metabolites produced by gut bacteria is butyrate—a short-chain fatty acid generated during the fermentation of certain types of dietary fiber. While it serves as the primary energy source for the cells lining the colon, its effects extend far beyond the digestive tract.

Butyrate helps maintain the integrity of the intestinal barrier, reduces inflammation, and supports immune function. It may also influence several biological processes involved in the development of Parkinson’s disease, including microglial activation, mitochondrial function, autophagy, and α-synuclein aggregation (1). In animal models, both butyrate supplementation and strategies that increase its availability have been associated with protection of dopaminergic neurons and improvements in motor function.

Since butyrate is produced by gut bacteria that ferment dietary fiber, the solution might seem straightforward: simply eat more fiber-rich foods. In reality, however, butyrate production depends on many factors, including the type of fiber consumed, the composition of the gut microbiome, and the overall health of the gastrointestinal tract.

Parkinson’s disease illustrates why this seemingly simple recommendation can be misleading. Numerous studies have reported a reduced abundance of butyrate-producing bacteria in people with Parkinson’s disease. Particularly compelling findings came from a study published in 2026 that compared the gut microbiomes of individuals with Parkinson’s disease, Alzheimer’s disease, and healthy controls (2). The authors found that a marked depletion of butyrate-producing bacteria was much more pronounced in Parkinson's disease than in Alzheimer's disease. Among the affected species were Faecalibacterium prausnitzii, Agathobacter rectalis, Roseburia intestinalis, and Faecalicatena fissicatena. In contrast, changes in the gut microbiome were considerably less pronounced in individuals with Alzheimer's disease.

However, this is only part of the picture. A meta-analysis including 11 studies found that approximately 46% of people with Parkinson’s disease tested positive for small intestinal bacterial overgrowth (SIBO) (3).

In this situation, increasing the intake of foods rich in rapidly fermentable carbohydrates (FODMAPs) may worsen bloating, abdominal pain, and other gastrointestinal symptoms in some individuals.

This highlights why increasing butyrate production cannot be reduced to the simple advice to “eat more fiber.” Diet remains the cornerstone of treatment, but dietary recommendations should also take gastrointestinal symptoms and individual food tolerance into account.

Short-Chain Fatty Acids: The First Randomized Clinical Trial

Butyrate is the best-studied member of the short-chain fatty acid family. Another member is propionate, which, like butyrate, may support intestinal barrier function, help regulate immune responses, and reduce inflammation. Although propionate shares several biological functions with butyrate, it has been studied much less extensively in humans, and its effects appear to be more context- and dose-dependent.

A randomized, double-blind clinical trial published last year evaluated butyrate, propionate, and 2'-fucosyllactose in people with Parkinson's disease (4). The study included 72 participants who received either delayed-release capsules containing butyrate (2,400 mg) and propionate (1,200 mg), 3,900 mg of the prebiotic 2’-fucosyllactose, or a combination of both interventions for six months. 2’-Fucosyllactose is a prebiotic that may increase the production of short-chain fatty acids by gut bacteria. It's also worth noting that butyrate and propionate were administered together in this trial, making it impossible to determine the specific contribution of each short-chain fatty acid to the observed effects. The authors emphasized that this was the first study to show that short-chain fatty acid supplementation in people with Parkinson’s disease was associated with improvements in both motor and non-motor symptoms beyond those achieved with standard pharmacological treatment alone.

Across all intervention groups, improvements in motor function reached or exceeded the threshold considered clinically meaningful. These improvements were accompanied by a reduction of more than 15% in levodopa dosage, along with benefits in selected measures of cognitive function and olfaction.

The authors also performed additional analyses to better understand the mechanisms underlying these findings. Taken together, the results indicate that supplementation may improve intestinal barrier function, promote a more balanced immune response, and enhance mitochondrial activity in immune cells.

Interestingly, neither direct supplementation with butyrate and propionate nor supplementation with the prebiotic 2’-fucosyllactose produced significant changes in the overall composition of the gut microbiome, despite the clinical improvements observed across all groups. However, the absence of major changes in microbiome composition does not rule out changes in how gut bacteria function, which may have contributed to the observed benefits.

The authors also noted that supplementation led to only a modest and transient increase in serum short-chain fatty acid levels. At the same time, no significant changes in fecal short-chain fatty acid levels were observed. Based on these findings, the authors suggest that the observed benefits may primarily reflect the local actions of short-chain fatty acids within the gut, including improved intestinal barrier function and modulation of immune responses.

However, this is unlikely to be the only explanation. As discussed in the next section, a clinical trial using tributyrin shows that butyrate can also reach other organs—including the brain. It is therefore possible that some of the observed benefits result from a combination of local effects within the gut and systemic effects throughout the body. At the same time, it is important to remember that the two studies used different strategies to increase butyrate availability, so their mechanisms of action should not be expected to be identical.

Tributyrin: The First Clinical Trial

The previously discussed study used direct supplementation with butyrate and propionate. Another way to increase butyrate availability is through tributyrin—a compound that gradually releases three butyrate molecules during digestion.

This year, the first clinical trial evaluating tributyrin in people with Parkinson's disease was published (5). Fourteen participants received 500 mg of tributyrin three times daily for approximately 30 days. The primary objective was to evaluate safety and determine whether oral tributyrin supplementation could increase butyrate availability in the brain and other organs.

To answer this question, a subset of participants underwent PET imaging using labeled butyrate. The results confirmed that tributyrin supplementation increased butyrate availability in the brain, heart muscle, liver, and spleen. This finding is particularly intriguing because butyrate may influence the function of these organs not only as an energy source, but also as a signaling molecule involved in numerous biological processes.

The authors also observed improvements in selected aspects of cognitive function, including memory, visuospatial function, and overall cognitive function. Improvements were also reported in selected motor outcomes, including bradykinesia, motor coordination, and balance. In addition, supplementation was associated with lower hs-CRP levels and was well tolerated. This finding is consistent with the anti-inflammatory effects attributed to butyrate.

Although this was a pilot study that needs to be confirmed in larger clinical trials, it indicates that tributyrin may be a promising strategy for increasing butyrate availability in people with Parkinson's disease.

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Lactiplantibacillus plantarum in Parkinson’s Disease

One of the best-studied bacterial species in the context of probiotic therapy for Parkinson’s disease is Lactiplantibacillus plantarum. Experimental studies indicate that selected strains of this species may influence several biological mechanisms involved in Parkinson's disease, including the composition of the gut microbiome, bile acid metabolism, and inflammatory processes (1).

One of these mechanisms involves bacteria that have repeatedly been found in increased abundance in people with Parkinson’s disease. These include Escherichia coli and bacteria belonging to the Desulfovibrio genus. Animal studies have shown that Escherichia coli may promote α-synuclein aggregation in the gut through proteins known as curli. Likewise, a higher abundance of Desulfovibrio has been associated with more severe disease and increased inflammatory activity.

Studies have shown that selected L. plantarum strains can inhibit the growth of both Escherichia coli and Desulfovibrio. One mechanism underlying this effect is the production of bacteriocins known as plantaricins. These are naturally occurring antimicrobial compounds produced by selected L. plantarum strains that can suppress the growth of certain microorganisms by disrupting their cell membranes.

Selected L. plantarum strains may also influence bile acid metabolism. Some bile acids, such as tauroursodeoxycholic acid (TUDCA), may reduce α-synuclein aggregation and exert neuroprotective effects. Others, including lithocholic acid (LCA), may promote inflammation and contribute to neuronal damage. Experimental studies have shown that supplementation with selected L. plantarum strains increases TUDCA levels while simultaneously reducing LCA concentrations.

Research also indicates that selected L. plantarum strains may indirectly increase butyrate availability. Although these bacteria do not produce butyrate themselves, they generate lactate, which can be used by butyrate-producing bacteria as a substrate for butyrate synthesis. In this way, L. plantarum may indirectly support butyrate production by other members of the gut microbiome.

Experimental studies have also reported beneficial effects of selected L. plantarum strains on mitochondrial function and cellular defense mechanisms against oxidative stress. These findings provide another potential explanation for their observed neuroprotective effects.

It is important to emphasize that these mechanisms are not unique to L. plantarum. Selected strains of other bacterial species may also exhibit antimicrobial properties, influence bile acid metabolism, or indirectly increase butyrate availability. However, L. plantarum stands out because it has been the subject of numerous experimental studies in Parkinson’s disease, making it one of the most extensively investigated probiotic species in this field.

Lactiplantibacillus plantarum PS128: A Clinical Trial

Readers of my previous article on psychobiotics may already be familiar with Lactiplantibacillus plantarum PS128. In that article, I discussed studies examining its effects on stress, sleep, and mood. Interestingly, the same strain has also been evaluated in a clinical trial involving people with Parkinson’s disease.

Participants received L. plantarum PS128 alongside their standard Parkinson’s medication for 12 weeks (6). In people taking levodopa, symptoms typically fluctuate throughout the day. During periods when the medication is working (the ON state), movement becomes easier. As its effects wear off (the OFF state), symptoms become more pronounced again.

After 12 weeks of supplementation, participants showed improvements in motor function during both ON and OFF periods. Time spent in the OFF state was reduced by an average of approximately 48 minutes per day, while the duration of the ON state increased by about 50 minutes.

Improvements were also observed in selected aspects of quality of life, including mobility, activities of daily living, and cognitive function. Moreover, approximately 68% of participants reported feeling better after 12 weeks of supplementation.

Although additional clinical trials are still needed, L. plantarum PS128 is currently one of the best-studied individual probiotic strains in the context of Parkinson's disease. The evidence available so far indicates that it may become a valuable component of strategies that support the treatment of Parkinson's disease.

What Does This Mean in Practice?

The studies discussed in this article are still preliminary and do not justify considering tributyrin, butyrate and propionate, 2’-fucosyllactose, or L. plantarum PS128 as standard treatments for Parkinson’s disease. Nevertheless, each of these strategies has the potential to support biological processes that are essential for a healthy gut–brain axis, including maintaining intestinal barrier integrity, promoting balanced immune regulation, and supporting a healthy gut microbiome.

For this reason, their potential applications extend beyond Parkinson’s disease itself. They may also be considered as part of a broader strategy to support gut health and overall physiological function.

One final point is worth keeping in mind. The clinical trials discussed here used high doses of the tested compounds. That does not necessarily mean supplementation should begin at those doses. Individual responses—particularly to higher doses of butyrate or tributyrin—can vary considerably. In some people, bowel habits improve, while in others constipation may actually worsen. In practice, a more sensible approach is to introduce these strategies gradually, starting with lower doses and adjusting them based on individual response.

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References:

1. Chen WL, et al. 2025. Lactiplantibacillus plantarum as a Psychobiotic Strategy Targeting Parkinson’s Disease: A Review and Mechanistic Insights. Nutrients. 17:3047.

2. Li X, et al. 2021. Association of small intestinal bacterial overgrowth with Parkinson’s disease: a systematic review and meta-analysis. Gut Pathog. 13:25.

3. Jaegher SD, et al. 2026. Identifying microbial biomarkers of neurodegeneration: a comparative study in Alzheimer’s and Parkinson’s disease. Front Microbiomes. 5:1831956.

4. Hegelmaier T, et al. 2025. Supplementation with short-chain fatty acids and a prebiotic improves clinical outcome in Parkinson’s disease: a randomized double-blind prospective study. Sci Rep. 16:315.

5. Bohnen JLB, et al. 2026. Dietary tributyrin supplementation in Parkinson’s disease: An open-label target engagement study. Neurotherapeutics. 23:e00791.

6. Lu CS, 2021. et al. The Add-On Effect of Lactobacillus plantarum PS128 in Patients With Parkinson’s Disease: A Pilot Study. Front Nutr. 8:650053.

Gastroesophageal reflux disease (GERD) is one of the most common digestive disorders. For some people, symptoms remain a persistent problem despite attempts to address them. Against this background, the results of the first clinical trial investigating Manuka honey for GERD are particularly interesting.

The most common symptoms of GERD are heartburn and the backflow of stomach contents into the esophagus (acid regurgitation). However, some patients also experience less typical symptoms, such as hoarseness, chronic cough, sore throat, or chest pain.

The First Clinical Trial of Manuka Honey in GERD

The study included 30 patients with gastroesophageal reflux disease (GERD), more than 77% of whom had been experiencing symptoms for at least one year.

Participants were randomly assigned to one of two groups. For four weeks, they received either:

• 15 g of Manuka honey per day, divided into three servings taken in the morning, on an empty stomach, and between meals,

or

• a placebo in the form of artificial honey.

The Manuka honey used in the study contained at least 400 mg of methylglyoxal (MGO) per kilogram. MGO content is one of the most commonly used indicators of Manuka honey quality and one of its most distinctive bioactive compounds.

Researchers assessed both patients’ reported symptoms and the results of endoscopic and histopathological examinations. They also analyzed participants’ dietary habits, allowing potential dietary changes to be taken into account when interpreting the results.

What Were the Results?

The first beneficial effects were observed after just two weeks. In the Manuka honey group, 9 of 15 patients experienced a marked improvement in GERD symptoms. In the placebo group, only 4 of 15 patients reported mild improvement, and none experienced a marked improvement.

After four weeks, all patients receiving Manuka honey reported improvement. In 11 of the 15 participants, the improvement was marked, while the remaining 4 reported mild improvement. By comparison, in the placebo group, marked improvement was observed in 3 of 15 patients, while another 3 reported only mild improvement.

Just as importantly, these improvements were also confirmed by endoscopic and histopathological examinations. Favorable changes were observed in 73.3% of patients receiving Manuka honey, compared with 33.3% in the placebo group.

Before the study began, about 90% of participants regularly consumed foods that could worsen GERD symptoms. After four weeks, despite receiving dietary advice, 66.7% of participants were still consuming these foods in substantial amounts. Interestingly, among eight patients receiving Manuka honey, favorable endoscopic and histopathological changes were observed despite the absence of meaningful dietary changes.

Another noteworthy finding was that 80% of participants continued taking acid-suppressing medications throughout the study. The Manuka honey group included four patients who were not taking these medications. Every one of them experienced either mild or marked symptom improvement after both two and four weeks. By comparison, the placebo group included two participants who were not taking acid-suppressing medications, and neither experienced any improvement.

Why Manuka Honey?

Manuka honey is produced by bees that collect nectar from the Manuka shrub (Leptospermum scoparium), which grows primarily in New Zealand and Australia.

Compared with most other honeys, it contains particularly high amounts of methylglyoxal (MGO), along with a rich variety of polyphenols, including flavonoids and phenolic acids.

Manuka honey has well-documented antibacterial and bacteriostatic properties. Its biological activity is likely the result of multiple bioactive compounds working together, including methylglyoxal (MGO), polyphenols, and hydrogen peroxide. It also exhibits anti-inflammatory and antioxidant effects.

For many years, Manuka honey has been used to support the treatment of chronic wounds and difficult-to-heal postoperative wounds. Research indicates that it may promote tissue repair, reduce inflammation, and help limit the formation of bacterial biofilms (2).

Its high viscosity may also play an important role. Because of its thick consistency, Manuka honey may remain on the surface of the esophageal lining for longer, forming a protective coating.

How to Use Manuka Honey for GERD

A growing body of research suggests that several other types of honey also possess valuable biological properties. However, the first clinical data in patients with GERD are currently available only for Manuka honey containing at least 400 mg of MGO per kilogram. For this reason, this is the product I use in my clinical practice with selected patients experiencing gastroesophageal reflux disease.

In my opinion, a sensible starting point is about 5 g (one level teaspoon) of Manuka honey containing at least 400 mg MGO/kg, taken 30–40 minutes before breakfast or before one of the main meals. If it is well tolerated, adding another one or two teaspoons per day after one to two weeks can be considered.

At the same time, it is worth viewing Manuka honey as one component of a broader strategy. The best results can be expected when it is incorporated into a well-designed, individualized plan that addresses the underlying causes of symptoms.

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References:

1. Gośliński M, et al. 2023. Application of Manuka honey in treatment patients with GERD. Food Sci Nutr. 12:172-179.

2. Alhabsi AN, et al. 2026. Clinical and Postoperative Applications of Manuka Honey in Wound Healing: An Evidence-Based Review. Int Wound J. 23:e70939.

For years, inositol has been one of the most extensively studied compounds in polycystic ovary syndrome (PCOS). This is where the largest body of clinical research has been conducted, with available evidence suggesting benefits for both metabolic and hormonal health. Inositol is widely used in women with insulin resistance, ovulatory dysfunction, or fertility problems.

In recent years, however, the scientific literature has expanded well beyond PCOS. New studies have begun exploring its potential role in Hashimoto’s disease, subclinical hypothyroidism, and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD).

What makes this particularly interesting is that the same molecule keeps appearing in conditions that, at first glance, seem largely unrelated. PCOS, Hashimoto’s disease, and MASLD are usually discussed as separate disorders. Yet an increasing body of evidence suggests that inositol may play an important role in each of them.

PCOS: Why Did Inositol Become So Interesting?

The human body synthesizes approximately 4 grams of inositol per day, primarily in the kidneys. Additional amounts are obtained through the diet.

Most research has focused on two forms: myo-inositol and D-chiro-inositol.

The ratio between these two forms is not the same throughout the body. In the plasma of healthy women, the average myo-inositol-to-D-chiro-inositol ratio is approximately 40:1. In the follicular fluid surrounding the developing oocyte, however, this ratio increases to roughly 100:1.

This suggests that the ovary maintains a particularly high concentration of myo-inositol. That is unlikely to be a coincidence, as myo-inositol is involved in ovarian follicle maturation, the response to follicle-stimulating hormone (FSH), and oocyte development.

Against this background, findings from PCOS become particularly compelling. Some studies suggest that within the ovary, the myo-inositol-to-D-chiro-inositol ratio may change dramatically, falling to values as low as approximately 0.2:1 (1).

This is not a minor deviation from normal physiology. It represents a shift from an environment in which myo-inositol predominates at roughly 100:1 to one characterized by a profound relative deficiency of myo-inositol.

Such a shift may contribute both to impaired FSH signaling and to increased androgen production.

These observations provide a biological rationale for using inositol in PCOS. The key question, however, is whether this translates into meaningful clinical outcomes.

Inositol in PCOS: What Do Clinical Studies Show?

An umbrella review published this year included 13 meta-analyses of randomized clinical trials, providing one of the most comprehensive summaries of the available evidence on inositol supplementation in PCOS (1).

The strongest findings relate to insulin resistance. Across the analyzed meta-analyses, inositol supplementation reduced both the HOMA-IR index and fasting insulin levels. This is hardly surprising, as impaired insulin signaling is one of the central features of PCOS.

The available meta-analyses also reported reductions in total testosterone, free testosterone, and androstenedione, along with an increase in sex hormone-binding globulin (SHBG). In addition, inositol supplementation was associated with improved ovulation rates and favorable effects on fertility-related outcomes.

The authors of the umbrella review also evaluated studies comparing inositol with metformin. Across most of the assessed outcomes, no significant differences were found between the two interventions.

It is worth noting that effective doses of inositol most commonly ranged from 2 to 4 grams per day. Well-designed clinical trials typically lasted at least 12 weeks, making it difficult to expect the full benefits of supplementation after only a few weeks of use.

Based on the evidence currently available, I do not see sufficient reason to routinely choose myo-inositol and D-chiro-inositol formulations in a 40:1 ratio for women with PCOS. In my own clinical practice, I most often use supplements containing myo-inositol alone.

Hashimoto’s Disease and Hypothyroidism: What Do We Know About Myo-Inositol?

In most clinical studies, myo-inositol has been investigated in combination with selenium. This combination has a strong biological rationale.

Myo-inositol functions as a second messenger for TSH in the IP3/Ca²⁺ signaling pathway. When TSH binds to its receptor on the surface of thyroid cells, one of the downstream events is the release of intracellular calcium, an essential step in thyroid hormone synthesis.

Selenium acts at a different level. It is essential for the proper function of numerous selenoproteins, including the deiodinases responsible for converting T4 into biologically active T3. Selenium also supports antioxidant enzymes such as glutathione peroxidases (GPx) and thioredoxin reductases (Trx), which help limit oxidative stress within the thyroid gland.

Viewed as a whole, the two compounds appear remarkably complementary. Myo-inositol participates in TSH signaling, while selenium supports downstream intracellular processes and helps protect thyroid tissue from damage associated with chronic inflammation and oxidative stress (2).

But how do these mechanisms translate into clinical outcomes?

One randomized clinical trial included 168 individuals with Hashimoto’s disease and TSH levels between 3 and 6 mIU/L (3). Participants were assigned to receive either selenium alone or a combination of 600 mg of myo-inositol and 83 μg of selenium daily for six months.

Both groups showed improvements in some outcomes, but the benefits were consistently greater in the group receiving myo-inositol plus selenium. The most pronounced change was a reduction in TSH, whereas no meaningful change was observed in the selenium-only group. At the same time, FT4 levels increased only in the group receiving the combination of myo-inositol and selenium.

The findings on thyroid antibodies were also noteworthy. Anti-thyroid peroxidase antibodies (TPOAb) decreased significantly in the myo-inositol plus selenium group, whereas no significant change was observed in the control group. Anti-thyroglobulin antibodies (TgAb) also declined in the treatment group, although the reduction did not reach statistical significance. Even so, the overall differences between the groups favored the combination of myo-inositol and selenium.

Interestingly, overall well-being improved in both groups, but the improvement was more pronounced among participants receiving both myo-inositol and selenium.

Equally intriguing are the findings on thyroid nodules. In one study, six months of supplementation with 600 mg of myo-inositol and 83 μg of selenium was associated not only with lower TSH levels but also with reductions in the number of thyroid nodules, their size, and several ultrasound parameters (4).

One possible explanation is the reduction in TSH, which can stimulate thyroid tissue growth. Reduced oxidative stress and signaling pathways involved in regulating cell growth may also contribute. One pathway that has attracted particular interest is PI3K/AKT, as myo-inositol and its derivatives participate in its regulation.

Another interesting study was published just last month.

It included 163 individuals with both Hashimoto’s disease and migraine (5). Participants received a combination of myo-inositol and selenium for six months, while researchers evaluated both thyroid function and migraine severity.

As in previous studies, TSH levels declined, with the median decreasing from 3.6 to 2.8 mIU/L. At the same time, the number of monthly migraine days fell from 14 to 11, and participants relied less frequently on rescue medications during migraine attacks.

The authors also observed a relationship between changes in TSH and migraine severity. The greater the reduction in TSH, the greater the improvement in monthly migraine days.

Interestingly, changes in TSH showed the strongest association with migraine improvement. No similar relationship was observed for FT3, FT4, participants’ age, or disease duration.

Most of the available studies on Hashimoto’s disease and other thyroid disorders have used a very similar supplementation protocol:

• 600–1200 mg of myo-inositol per day,

• 83 μg of selenium per day,

• 3–12 months of supplementation.

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MASLD, the Gut Microbiome, and Myo-Inositol

I first discussed myo-inositol in a previous article about butyrate and fatty liver disease.

That was prompted by discoveries involving Dysosmobacter welbionis, a gut bacterium capable of using myo-inositol to produce butyrate. This was the first experimental evidence showing that a bacterium residing in the human gut can directly convert myo-inositol into butyrate (6).

Interestingly, two studies found that D. welbionis was less abundant in individuals with fatty liver disease than in healthy controls. A third study did not find an association with MASLD itself, but lower levels of this bacterium were linked to more advanced liver fibrosis.

These are not the only observations connecting inositol with liver health.

A systematic review of studies on fatty liver disease found that inositol deficiency promoted hepatic steatosis in animal models (7). In the same studies, inositol supplementation reduced the accumulation of triglycerides and cholesterol in the liver while also improving liver histology.

Interestingly, butyrate and other short-chain fatty acids have also begun to appear in studies on PCOS and Hashimoto’s disease. It is possible that some of the effects attributed to myo-inositol in these conditions are mediated by its conversion into butyrate by D. welbionis.

Last month, another interesting study was published, this time focusing on acne in individuals with PCOS and metabolic syndrome (8). After 12 weeks of supplementation with myo-inositol and D-chiro-inositol, the investigators observed increased FOXO1 expression along with reduced MTOR and IGF1 expression in acne-affected skin. The direction of these changes is consistent with the current model in which impaired insulin signaling plays an important role in the development of acne.

More than 80% of participants experienced an improvement in their acne, while nearly 30% achieved what was classified as a marked clinical improvement.

Importantly, similar findings were observed across all study groups, including women with PCOS as well as women and men with metabolic syndrome. This applied both to changes in gene expression and to improvements in acne severity.

PCOS, Hashimoto’s disease, thyroid nodules, migraine, and MASLD do not represent the full scope of inositol research. The scientific literature also includes studies on mental health, pregnancy, and nervous system function, illustrating just how broad the field of inositol research has become.

Note: In 2026, an international consensus proposed changing the name PCOS to polyendocrine metabolic ovarian syndrome (PMOS) to better reflect the metabolic and endocrine nature of the condition and move away from a name focused primarily on ovarian morphology. However, because virtually the entire scientific literature published to date still uses the term PCOS, I have chosen to retain that terminology throughout this article.

Note: The acne study discussed above used a myo-inositol-to-D-chiro-inositol ratio of 3.6:1. At present, it is not known whether this is the optimal ratio for people with acne. Answering that question will require studies directly comparing different myo-inositol-to-D-chiro-inositol ratios. It is also worth remembering that different tissues maintain different myo-inositol-to-D-chiro-inositol ratios and utilize the two inositol isomers somewhat differently. For that reason, it is difficult to expect that a single ratio would be optimal across all clinical applications.

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References:

1. Duan M, et al. 2026. Effects of inositol in women with polycystic ovary syndrome: an umbrella review of meta-analyses from randomized controlled trials. Front Endocrinol (Lausanne). 17:1741509.

2. Samuel CG, et al. 2025. Unlocking the Therapeutic Potential: Selenium and Myo-Inositol Supplementation in Thyroid Disorders-Efficacy and Future Directions. Life (Basel). 15:1500.

3. Nordio M, Basciani S. 2017. Myo-inositol plus selenium supplementation restores euthyroid state in Hashimoto’s patients with subclinical hypothyroidism. Eur Rev Med Pharmacol Sci. 21:51-59.

4. Nordio M, Basciani S. 2018. Evaluation of thyroid nodule characteristics in subclinical hypothyroid patients under a myo-inositol plus selenium treatment. Eur Rev Med Pharmacol Sci. 22:2153-2159.

5. Lorenzo CD, et al. 2026, Myoinositol and Selenium (MYSE) Supplementation Is Associated with Favorable Changes in Thyroid Parameters and Migraine Outcomes in Patients with Migraine and Hashimoto’s Thyroiditis: A Retrospective Cohort Study. Nutrients. 18:1554.

6. Lee CH, et al. 2026. Novel myo-inositol to butyrate fermentation pathway in the prevalent human gut species Dysosmobacter welbionis, a bacterium associated with improved metabolic and liver health. Gut. 75:1338-1352.

7. Pani A, et al. 2020. Inositol and Non-Alcoholic Fatty Liver Disease: A Systematic Review on Deficiencies and Supplementation. Nutrients. 12:3379.

8. Vaccaro M, et al. 2026. Oral myo-inositol plus D-chiro-inositol (3.6:1) reduces insulin resistance pathway biomarkers in acne-involved skin among subjects with metabolic comorbidities: A gene expression study. Neuro Endocrinol Lett. 47:127-134.

In my previous article, I discussed carbohydrate sources that may be particularly useful for individuals with metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) and coexisting disturbances of the gut–liver axis. The recommendations I presented were largely consistent with the bioenergetic perspective, which emphasizes well-tolerated carbohydrate sources while minimizing factors that may promote endotoxemia.

I also pointed out that some strategies commonly used to reduce gastrointestinal symptoms—including the low FODMAP diet—may be associated with reduced production of short-chain fatty acids by the gut microbiota. At the time, I briefly mentioned microencapsulated sodium butyrate as one potential way to address this issue.

However, this topic deserves a much closer look.

A growing body of evidence suggests that butyrate plays an important role in both gut and liver health. At the same time, new strategies are emerging that may increase butyrate availability without relying solely on increasing the intake of highly fermentable foods.

In this article, we will take a closer look at what is currently known about butyrate, its relevance to MASLD, and several particularly interesting ways to increase its availability.

Why Is Butyrate Important for Gut and Liver Health?

Over the past several years, increasing attention has been directed toward the role of the gut–liver axis in the development and progression of MASLD. Because the intestines are directly connected to the liver through the portal circulation, compounds produced by the gut microbiota can significantly influence liver function.

One of the most important metabolites produced by gut bacteria is butyrate (butyric acid)—a short-chain fatty acid generated primarily through the fermentation of undigested dietary components.

Butyrate serves as the primary fuel source for colonocytes, the cells lining the large intestine. As a result, it helps maintain intestinal barrier integrity and supports the normal function of the intestinal epithelium.

Butyrate also influences:

• immune function,

• gut hormone production,

• intestinal barrier integrity,

• glucose and lipid metabolism,

• inflammatory processes (1).

From the perspective of fatty liver disease, its effects on the intestinal barrier may be particularly important. Impaired barrier function can promote the translocation of bacterial endotoxins such as lipopolysaccharide (LPS) into the portal circulation. Once these compounds reach the liver, they may contribute to inflammation, oxidative stress, and processes involved in liver steatosis and fibrosis.

Additional evidence comes from a systematic review published in 2026 that included seven studies and 1,185 participants (2). Individuals with MASLD frequently exhibited lower levels of butyrate in stool or blood, as well as lower abundance of butyrate-producing bacteria such as Faecalibacterium prausnitzii and members of the genus Eubacterium.

Moreover, lower butyrate levels and reduced abundance of butyrate-producing bacteria were associated with more severe liver steatosis, fibrosis, and inflammation, as well as less favorable metabolic parameters, including higher BMI, greater insulin resistance, and impaired lipid metabolism.

Which Bacteria Produce Butyrate?

Since butyrate is one of the key metabolites involved in the gut–liver axis, it is worth asking: which bacteria are responsible for producing it?

Among the best-known butyrate producers are:

• Faecalibacterium prausnitzii

• Roseburia intestinalis

• certain Eubacterium species

Important contributions also come from bacteria belonging to the genera Anaerobutyricum and Anaerostipes, which can use lactate and acetate to produce butyrate (3).

In recent years, increasing attention has also been directed toward Dysosmobacter welbionis, a relatively recently described gut bacterium. Unlike many other butyrate producers, it uses myo-inositol as a substrate for butyrate production.

This discovery is interesting not only because of butyrate production itself. A growing body of evidence suggests that D. welbionis may also be linked to metabolic health and liver function. We will return to this topic later in the article.

SIBO and MASLD: Why Increasing Butyrate Production Is Not Always Straightforward

A growing body of evidence suggests that individuals with fatty liver disease frequently exhibit disturbances of the gut–liver axis, including changes in gut microbiota composition, increased intestinal permeability, and small intestinal bacterial overgrowth (SIBO).

In a meta-analysis including 18 studies and 1,263 patients, SIBO was identified in approximately 35% of individuals with chronic non-alcoholic liver diseases (4).

Even more interesting findings emerged from a study published this year involving 2,549 patients with MASLD and gastrointestinal symptoms (5).

Key findings included:

• 66.3% of participants had a positive breath test consistent with SIBO,

• SIBO prevalence increased with disease severity, reaching nearly 79% among patients with cirrhosis.

The investigators also observed a progressive increase in the prevalence of intestinal methanogen overgrowth (IMO) as liver disease advanced. This is particularly interesting because IMO is commonly associated with constipation and slowed intestinal transit.

In the remainder of this article, we will explore several strategies that may increase butyrate availability without relying on large amounts of highly fermentable foods.

Microencapsulated Sodium Butyrate in SIBO, IBS, and MASLD

Different countries have adopted somewhat different approaches to increasing butyrate availability. In the United States, interest in tributyrin has been growing rapidly, whereas in Poland and Italy, products containing microencapsulated sodium butyrate have become particularly popular. Polish and Italian research groups have published numerous studies examining the use of this approach in gastrointestinal and metabolic disorders.

As a dietitian based in Poland, I have followed the research on microencapsulated sodium butyrate with great interest. Products using this technology are readily available on the Polish market, which further increases their practical relevance.

The goal of microencapsulation is to protect butyrate from being released too early and to improve its delivery to more distal regions of the gastrointestinal tract.

This raises an important question: does this translate into meaningful clinical effects?

One particularly interesting study published in 2024 found that 12 weeks of supplementation with microencapsulated sodium butyrate was associated with:

• lower prevalence of SIBO,

• improvement in gastrointestinal symptoms,

• lower HbA1c,

• improved BMI (6).

Additional studies in patients with inflammatory bowel disease reported increases in short-chain fatty acid–producing bacteria, including members of the genus Butyricicoccus and the family Lachnospiraceae (7).

In a large observational study involving approximately 3,000 patients with irritable bowel syndrome (IBS), sodium butyrate supplementation was associated with improvements in gastrointestinal symptoms and quality of life (8).

These findings are one reason why I regularly use microencapsulated sodium butyrate in my work with patients affected by MASLD, IBS, and SIBO.

Readers living in the United States may also wish to consider tributyrin, which is widely available there. In a recently published study using the SHIME model, approximately half of the administered tributyrin remained stable during simulated passage through the upper gastrointestinal tract and was available to reach the colon (9). The same study reported increased butyrate levels, higher abundance of bacteria such as Bifidobacterium spp. and Akkermansia muciniphila, and beneficial effects on markers related to intestinal barrier function and immune activity.

Myo-Inositol, Dysosmobacter welbionis, and Butyrate Production

Myo-inositol is a naturally occurring compound found in many foods. Particularly rich sources include cantaloupe melon, oranges, grapefruit, and kiwi fruit. Interestingly, these foods also fit well within a bioenergetic approach to nutrition.

Most people associate myo-inositol primarily with insulin resistance, blood sugar control, and polycystic ovary syndrome (PCOS). It plays an important role in insulin signaling, and supplementation has been shown to improve insulin sensitivity and lower blood glucose levels in clinical studies.

However, myo-inositol may influence not only host metabolism but also the gut microbiota. Animal studies suggest that myo-inositol and phytic acid can increase the abundance of Lactobacillus species and enhance short-chain fatty acid production (3).

Particularly intriguing are the findings related to D. welbionis. Researchers recently demonstrated that this bacterium possesses a previously undescribed metabolic pathway allowing it to convert myo-inositol into butyrate. This was the first experimental confirmation that a human gut bacterium can produce butyrate from myo-inositol (3).

Further studies suggest that D. welbionis is less abundant in individuals with obesity and type 2 diabetes, while higher abundance has been associated with lower fasting glucose and HbA1c levels. Animal studies have reported improvements in glucose tolerance and fasting blood glucose, and one study even found effects greater than those observed with metformin. This bacterium has also been shown to metabolize cholesterol.

Additional research has linked D. welbionis with higher levels of several bioactive lipids, some of which exhibit anti-inflammatory properties. Experimental studies have also reported reduced intestinal inflammation following administration of this bacterium.

Another interesting observation was that D. welbionis was the most frequently detected Dysosmobacter species in children aged 3–6 years. The authors suggest that this may be related to the relatively high myo-inositol content of breast milk and dairy products commonly consumed during early childhood.

More recently, lower abundance of D. welbionis was observed in two independent cohorts of individuals with MASLD. In a third cohort, no association was found with MASLD diagnosis itself; however, lower abundance of this bacterium was associated with more advanced liver fibrosis (3).

Taken together, current evidence suggests that myo-inositol supplementation and regular consumption of foods naturally rich in myo-inositol may be worth considering, particularly in individuals with MASLD and those following a low FODMAP diet.

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Clostridium butyricum: A Butyrate-Producing Probiotic

Clostridium butyricum is a butyrate-producing bacterium naturally found in both the environment and the human gastrointestinal tract. However, it is estimated to be present in only about 20% of adults (10).

Interestingly, C. butyricum has been used as a probiotic for many years in Japan, Korea, and China. The best-studied strain is Clostridium butyricum MIYAIRI 588.

Research suggests that this strain may support intestinal barrier function through several mechanisms:

• increasing mucin production,

• strengthening tight junctions,

• supporting immune function within the gut,

• reducing inflammatory activity (10).

Particularly interesting are studies involving irritable bowel syndrome. In one study, supplementation with C. butyricum MIYAIRI 588 reduced visceral hypersensitivity and decreased inflammation within the colonic mucosa (11). In another trial involving 200 patients with IBS-D, participants experienced improvements in symptoms, quality of life, and bowel habits compared with placebo (12).

The strain also appears to influence gut microbiota composition. Studies have reported increases in beneficial bacteria such as Bifidobacterium and Lactobacillus, accompanied by reductions in certain potentially unfavorable microorganisms (10).

Unlike many commonly used probiotics, C. butyricum MIYAIRI 588 combines butyrate production with documented effects on intestinal barrier function, inflammation, and IBS symptoms.

Most of the data discussed above relate specifically to the MIYAIRI 588 strain. This is important because not all products containing C. butyricum use the same strain. Another limitation is availability, as MIYAIRI 588 remains difficult to obtain outside selected Asian countries, although products containing this strain can also be found in parts of Europe, including Italy.

What Does This Mean in Practice?

Although part of the questions regarding the role of butyrate in MASLD remain unanswered, the available evidence is compelling enough that I routinely incorporate many of the strategies discussed in this article into my work with patients.

In the context of the low FODMAP diet discussed in my previous article, these strategies appear particularly interesting because they may help support the production or availability of short-chain fatty acids—including butyrate—in individuals following this dietary approach.

It is also worth mentioning that cranberry extract and pomegranate husk extract, which I briefly touched on in the previous article, may support butyrate-producing bacteria and other beneficial members of the gut microbiota. For this reason, I would also consider them worth exploring in individuals following a low FODMAP approach.

At the same time, the strategies discussed in this article—including microencapsulated sodium butyrate, myo-inositol, and C. butyricum MIYAIRI 588—should be viewed as components of a broader strategy rather than standalone solutions. Depending on the situation, they may complement an appropriately designed diet and other interventions aimed at supporting gut and liver health.

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References:

1. Krauze W, et al. 2025. Effect of Sodium Butyrate Supplementation on Type 2 Diabetes-Literature Review. Nutrients. 17:1753.

2. González-González A, et al. 2026. The Role of Butyrate in People with Metabolic Dysfunction-Associated Steatotic Liver Disease and Related Metabolic Comorbidities: A Systematic Review. Curr Obes Rep. 15:17.

3. Lee CH, et al. 2026. Novel myo-inositol to butyrate fermentation pathway in the prevalent human gut species Dysosmobacter welbionis, a bacterium associated with improved metabolic and liver health. Gut. 75:1338-1352.

4. Gudan A, et al. 2022. The Prevalence of Small Intestinal Bacterial Overgrowth in Patients with Non-Alcoholic Liver Diseases: NAFLD, NASH, Fibrosis, Cirrhosis-A Systematic Review, Meta-Analysis and Meta-Regression. Nutrients. 14:5261.

5. Li Y, et al. 2026. Small Intestinal Bacterial Overgrowth in Metabolic Dysfunction-Associated Steatotic Liver Disease: Prevalence, Subtypes, and Risk Factors Across Disease Spectrum and Comorbidity Profiles. Biomedicines. 14:1042.

6. Panufnik P, et al. 2024. Effect of Butyrate on GI Signs, SIBO, and Diabetes Control—Randomized, Placebo-Controlled Study in Patients with Type 2 Diabetes. Diabetes. 73:610-P.

7. Facchin S, et al. 2020. Microbiota changes induced by microencapsulated sodium butyrate in patients with inflammatory bowel disease. Neurogastroenterol Motil. 32:e13914.

8. Lewandowski K, et al. 2022. The effectiveness of microencapsulated sodium butyrate at reducing symptoms in patients with irritable bowel syndrome. Prz Gastroenterol. 17:28-34.

9. Duysburgh C, et al. 2025. Tributyrin (CoreBiome®) enhances butyrate levels and modulates the gut microbiota, barrier function, and immune response in vitro. Front Nutr. 12:1712993.

10. Bertuccioli A, et al. 2025. Targeted probiotic therapy in irritable bowel syndrome: a clinical evaluation on Clostridium butyricum CBM588 and Bifidobacterium longum W11. Front Med (Lausanne). 12:1604319.

11. Zhao K, et al. 2018. Clostridium butyricum regulates visceral hypersensitivity of irritable bowel syndrome by inhibiting colonic mucous low grade inflammation through its action on NLRP6. Acta Biochim Biophys Sin (Shanghai). 50:216-223.

12. Sun YY, et al. 2018. The effect of Clostridium butyricum on symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. Sci Rep. 8:2964.

Metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is now one of the most common metabolic disorders in the modern world. Fatty liver disease is usually discussed primarily in the context of excess calories, weight loss, and carbohydrate restriction. In practice, however, the situation is often far more complex.

In some patients with fatty liver disease, metabolic dysfunction coexists not only with insulin resistance or obesity, but also with:

• bloating,

• intestinal discomfort,

• altered bowel habits,

• chronic fatigue.

These symptoms may point toward disturbances in the gut-liver axis.

In this context, it becomes highly relevant how the body responds to specific carbohydrate sources — particularly in terms of gut fermentation and worsening gastrointestinal symptoms.

At the same time, very restrictive approaches to calories and carbohydrates may also have important limitations — especially in relation to thyroid function, the conversion of thyroxine (T4) into active triiodothyronine (T3), and long-term dietary tolerability.

All of this makes the question of optimal carbohydrate sources in fatty liver disease far more complex than it may initially appear.

The Gut-Liver Axis, SIBO, and Gut Fermentation in MASLD

An increasing body of evidence suggests that disturbances in the gut-liver axis — including SIBO, increased intestinal permeability, and endotoxemia — may play an important role in the development and progression of fatty liver disease.

A recently published meta-analysis including 18 studies and 1,263 patients found that SIBO may be present in up to 35% of individuals with chronic non-alcoholic liver disease (1).

The intestines are directly connected to the liver through the portal circulation, which means that substances produced within the gastrointestinal tract can directly affect liver function. In patients with MASLD, disturbances in the composition and function of the gut microbiota are increasingly observed — including overgrowth of Gram-negative bacteria characteristic of SIBO (2).

These disturbances may lead to increased production of lipopolysaccharide (LPS), ethanol, and other bacterial metabolites that reach the liver through portal blood flow and may contribute to inflammation, oxidative stress, hepatic steatosis, and fibrosis.

More and more attention is also being given to the fact that this relationship may work in both directions. Insulin resistance and hyperglycemia, commonly observed in patients with MASLD, may impair gut barrier function and increase intestinal permeability, further worsening endotoxemia and inflammation (2).

These changes may influence not only the progression of fatty liver disease itself, but also how certain foods are tolerated.

Carbohydrate Sources in MASLD: Not All Work the Same Way

Diets commonly recommended for MASLD — including the Mediterranean diet — are often based on foods such as whole-grain rye and wheat bread, legumes, apples, pears, onions, and garlic. These foods contain substantial amounts of fermentable carbohydrates.

In some individuals — especially those with coexisting SIBO, significant gastrointestinal symptoms, or high sensitivity to fermentation — this may lead to:

• worsening bloating,

• abdominal pain,

• diarrhea,

• impaired day-to-day functioning.

These issues were also highlighted by the authors of the review paper “Dysbiosis and nutrition in steatotic liver disease: addressing the unrecognized small intestinal bacterial overgrowth (SIBO) challenge” (3).

In practice, this means that when selecting carbohydrate sources, it may be important to consider not only their nutritional value, but also their impact on gastrointestinal symptoms.

The Low FODMAP Diet: More Than Just IBS Symptom Control?

In this context, growing attention has been directed toward the low FODMAP diet (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols), which involves temporarily restricting fermentable carbohydrates that may worsen gut fermentation and gastrointestinal symptoms in some individuals.

The low FODMAP diet has been studied most extensively in patients with irritable bowel syndrome (IBS), where many studies have shown meaningful improvements in symptoms such as bloating, abdominal pain, and altered bowel habits.

However, increasing attention is being paid to the fact that the effects of a low FODMAP diet may extend beyond symptom control alone. Some studies have observed not only improvements in gastrointestinal symptoms, but also reductions in markers associated with endotoxemia, intestinal permeability, and inflammation (4).

In a 12-week study conducted in patients with IBS-D, the use of a low FODMAP diet was associated with reductions in LPS levels, improvements in markers of intestinal barrier function — including zonulin and intestinal fatty acid-binding protein (I-FBP) — and reductions in inflammatory markers. Improvements were also observed in gastrointestinal symptoms, well-being, and selected mental health-related parameters (5).

Interesting findings also came from a randomized study comparing the low FODMAP diet with rifaximin — an antibiotic commonly used in the treatment of SIBO and IBS (6). After four weeks, both strategies showed comparable effectiveness in improving IBS symptoms, while SIBO eradication was observed both in the rifaximin group (63.6%) and the low FODMAP group (50%).

The biggest differences involved the speed of symptom improvement. Rifaximin led to faster reductions in bloating, abdominal pain, and overall gastrointestinal symptoms within the first two weeks of treatment. After four weeks, however, the effects of both approaches were broadly similar.

The Low FODMAP Diet in Practice

It may be more useful to view the low FODMAP diet as a diagnostic and therapeutic tool rather than a permanent dietary model.

The classic low FODMAP approach generally includes three stages:

• an elimination phase (typically around 2–8 weeks),

• gradual reintroduction of individual food groups (around 6–10 weeks),

• and a stabilization and dietary expansion phase.

The goal is therefore not to return to a “standard” diet or maintain a maximally restrictive eating pattern indefinitely, but rather to identify the broadest possible range of foods that do not worsen symptoms and are well tolerated on a daily basis.

Tolerance to individual groups of fermentable carbohydrates often changes over time as gastrointestinal function and gut microbiota composition improve.

For this reason, the low FODMAP strategy is often worth combining with additional interventions aimed at improving the gut environment and reducing excessive bacterial fermentation.

Among the most interesting options, in my opinion, are:

• Saccharomyces boulardii CNCM I-745,

• cranberry extract,

• pomegranate husk extract,

• microencapsulated sodium butyrate.

These strategies may support long-term dietary tolerance and partially minimize some potential limitations of FODMAP restriction — including reduced production of short-chain fatty acids.

I would also add that a well-designed low FODMAP diet can still provide adequate amounts of nutrients and dietary fiber — including during the elimination phase. In some individuals, transitioning to a well-structured low FODMAP diet may actually improve overall diet quality and nutrient intake, particularly if their previous diet was a typical Western diet based heavily on ultra-processed foods.

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Fruit in MASLD: Should It Really Be Restricted?

It is still common to encounter the idea that fruit should be restricted in fatty liver disease because of its simple sugar content — especially fructose. In practice, however, this perspective often overlooks the important differences between whole fruit and highly processed foods containing added sugars or high-fructose syrups.

Whole fruits provide not only carbohydrates, but also fiber, polyphenols, potassium, and many other biologically active compounds that may positively influence liver metabolism, oxidative stress, and inflammation.

Interesting findings came from a randomized study conducted in patients with MASLD, in which participants consumed either 400 g of whole oranges daily or the same amount of non-citrus fruits for four weeks (7).

Participants were also instructed not to change their diet or physical activity levels, so that any observed effects could be linked primarily to orange consumption rather than weight loss or other lifestyle changes.

After four weeks, the orange group showed a clear reduction in the prevalence of fatty liver as well as lower GGT (gamma-glutamyl transferase) levels, while no such effects were observed in the control group.

Interestingly, these improvements occurred without weight loss, calorie restriction, or improvements in glucose and insulin levels.

Citrus fruits are rich sources of polyphenols, particularly those found in the albedo and membranes separating the fruit segments.

These compounds may influence:

• lipid metabolism,

• oxidative stress,

• inflammation,

• mitochondrial function.

In oranges, particular attention has been given to compounds such as hesperidin, naringenin, and polymethoxyflavones, which are believed to have potential liver-protective and anti-inflammatory effects.

Nutrients such as vitamin C, thiamine, and riboflavin may also play an important role by supporting antioxidant defenses and mitochondrial energy production.

This does not mean, however, that larger amounts of citrus fruits will be beneficial for every patient with fatty liver disease. In some individuals, citrus fruits may worsen symptoms of gastroesophageal reflux disease (GERD), while in others they may aggravate symptoms associated with histamine intolerance, such as headaches or skin itching.

It is also worth mentioning that the study was conducted in Italy and used organic Navelina oranges from the Calabria region, which may be relevant in terms of polyphenol content and fruit ripeness.

Similar findings have also been observed in experimental studies using other polyphenol-rich fruits — including pomegranate and lychee — where improvements in fatty liver and selected metabolic parameters were reported (7).

Some fruit juices — particularly pomegranate juice and red grape juice — are also very rich sources of polyphenols and may have a place in the diets of individuals with fatty liver disease. In my opinion, however, patients with fatty liver disease should preferentially choose whole fruits, while fruit juices — especially pomegranate, red grape, or orange juice — tend to work best in moderate amounts during the post-workout period.

In practice, whole fruits rich in polyphenols may represent a far more interesting component of a nutritional strategy for MASLD than is often assumed.

Carbohydrates, Thyroid Hormones, and Liver Metabolism

In discussions surrounding fatty liver disease, there is often an assumption that the fewer carbohydrates, the better. In practice, however, liver metabolism is also closely connected to thyroid function and energy availability.

Thyroid hormones — especially T3 — play an important role in regulating glucose and lipid metabolism.

They influence, among other things:

• mitochondrial function,

• fatty acid β-oxidation,

• triglyceride metabolism,

• insulin sensitivity (8).

Interestingly, one study identified subclinical hypothyroidism as an independent predictor of advanced fibrosis in patients with fatty liver disease (9).

In some cases, ketogenic diets may be effective tools for supporting weight loss and reducing fatty liver. In certain individuals, however, they may also lead to marked reductions in T3 levels, impaired cold tolerance (e.g., cold hands and feet), and substantial increases in total cholesterol and LDL cholesterol — often associated with reduced T3 levels (10).

Because thyroid hormones play such an important role in regulating metabolism and liver function, I generally prefer diets containing more than around 150 g of carbohydrates per day combined with a moderate caloric deficit. In patients with obesity, this most often means a deficit closer to 800–1000 kcal per day, while in patients with lower levels of body fat, a deficit closer to 500 kcal per day is usually more appropriate.

The Bioenergetic Perspective and Practical Takeaways

For a significant proportion of patients with fatty liver disease — especially those with coexisting IBS, SIBO, or pronounced gastrointestinal symptoms — minimally processed low FODMAP foods such as basmati rice, potatoes, and selected polyphenol-rich fruits including kiwi, honeydew melon, blueberries, and oranges may represent particularly useful carbohydrate sources.

It is also worth noting that the approach presented here is largely consistent with the bioenergetic (or pro-metabolic) perspective, which favors easily digestible carbohydrate sources — especially fruits and fruit juices — that help support healthy thyroid hormone levels and T4-to-T3 conversion while minimizing endotoxemia and gastrointestinal symptoms.

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References:

1. Gudan A, et al. 2022. The Prevalence of Small Intestinal Bacterial Overgrowth in Patients with Non-Alcoholic Liver Diseases: NAFLD, NASH, Fibrosis, Cirrhosis-A Systematic Review, Meta-Analysis and Meta-Regression. Nutrients. 14:5261.

2. Gudan A, et al. 2023. Small Intestinal Bacterial Overgrowth and Non-Alcoholic Fatty Liver Disease: What Do We Know in 2023? Nutrients. 15:1323.

3. Stachowska E, et al. 2024. Dysbiosis and nutrition in steatotic liver disease: addressing the unrecognized small intestinal bacterial overgrowth (SIBO) challenge. Intern Emerg Med. 19:1229-1234.

4. Ribichini E, et al. 2024. Gut–Brain Axis and Psychopathology: Exploring the Impact of Diet with a Focus on the Low-FODMAP Approach. Nutrients. 16, 3515

5. Prospero L, et al. 2021. Psychological and Gastrointestinal Symptoms of Patients with Irritable Bowel Syndrome Undergoing a Low-FODMAP Diet: The Role of the Intestinal Barrier. Nutrients. 13, 2469.

6. Chuah KH, et al. 2026. Clinical Trial: Rifaximin Versus Low FODMAP Diet in Irritable Bowel Syndrome. Aliment Pharmacol Ther. 63:210-221.

7. Notarnicola M, et al. 2024. Daily Orange Consumption Reduces Hepatic Steatosis Prevalence in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: Exploratory Outcomes of a Randomized Clinical Trial. Nutrients. 16:3191.

8. Bian L, et al. 2026. Correlation Between the Thyroid Hormone Levels and Type 2 Diabetes Mellitus in Non-Alcoholic Fatty Liver Disease. Diabetes Metab Syndr Obes. 19:577491.

9. Kim D, et al. 2018. Subclinical hypothyroidism and low-Normal thyroid function are associated with nonalcoholic Steatohepatitis and fibrosis. Clin Gastroenterol Hepatol. 16:123–131.

10. Cooper ID, et al. 2023. Thyroid markers and body composition predict LDL-cholesterol change in lean healthy women on a ketogenic diet: experimental support for the lipid energy model. Front Endocrinol (Lausanne). 14:1326768.

In Part 1, I covered selected single-strain probiotics and their potential applications in the context of mood, stress, and sleep.

In practice, however, some of the research focuses not on individual strains, but on specific multi-strain formulations.

In this part, we’ll take a closer look at several of these formulations — and where they may be useful in the context of mood regulation, stress, and sleep.

Lactobacillus helveticus R0052 + Bifidobacterium longum R0175: Probiotics for Stress and Depression

One of the formulations studied in the context of the gut–brain axis is the combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175. In animal models, it has been shown to influence stress- and anxiety-related behaviors, as well as how the body responds to chronic stress. Observed effects included:

• changes in stress hormone levels,

• effects on processes related to neurogenesis and factors such as brain-derived neurotrophic factor (BDNF), a protein involved in brain function and adaptability (1).

One of the more important studies using this formulation was conducted in patients with depression. In a randomized, double-blind trial, participants received either the combination of these two strains at a dose of at least 10 billion colony-forming units (CFU) per day, a prebiotic (galactooligosaccharides, GOS, 4 g per day), or placebo for 8 weeks (2).

After 8 weeks, the probiotic group showed a significant reduction in depressive symptoms (measured by the BDI scale) compared to placebo. No meaningful improvement was observed in the prebiotic group.

BDNF levels were also assessed. In the probiotic group, BDNF increased, and these changes were associated with a reduction in depressive symptoms (1). This may represent one of the mechanisms through which this formulation influences mood.

In another study, the same formulation was evaluated in healthy individuals exposed to stress. In a randomized, double-blind trial, participants received either the combination of L. helveticus R0052 and B. longum R0175 at a dose of 3 billion CFU per day or placebo for 30 days (3).

At the end of the study, the following were observed:

• a reduction in overall psychological stress (measured by the HSCL-90 scale),

• reduced anxiety symptoms,

• improved coping with stress.

Additionally, urinary free cortisol levels were reduced, suggesting an effect on the body’s stress response.

In practice, this is a formulation I most often use in individuals with depressive symptoms or chronic stress — especially when gut symptoms are not dominant. When IBS symptoms are present, I more often reach for other strains, such as Bacillus coagulans MTCC 5856, which have better-documented effects on gastrointestinal symptoms.

De Simone Formulation (CDS22): Probiotics for Gut Health, Inflammation, and Depression

Another formulation worth considering in the context of the gut–brain axis is the De Simone Formulation. It was developed by Professor Claudio De Simone. This is a high-potency, multi-strain probiotic containing eight strains from the Lactobacillus, Bifidobacterium, and Streptococcus genera.

This formulation has been well studied in gastrointestinal conditions — including irritable bowel syndrome (IBS), pouchitis, ulcerative colitis, and Crohn’s disease — where it has been associated with:

• improvement in symptoms,

• reduction in inflammation,

• improved gut barrier function.

In studies on non-alcoholic fatty liver disease (NAFLD), improvements in liver function markers and reduced liver damage have also been observed (4).

Until 2016, the name VSL#3 referred to the original De Simone Formulation. Since then, the product sold under that name has a different composition, meaning that studies conducted before 2016 refer to the De Simone Formulation, not the current version of VSL#3.

Today, the original De Simone Formulation is available as Visbiome in the United States and Canada, and as CDS22-formula in Europe and the United Kingdom (5).

In recent years, studies have also examined its effects in patients with depression.

In one randomized clinical trial, the De Simone Formulation was evaluated in patients with depressive symptoms who were receiving standard treatment. The study lasted 31 days, and participants received the probiotic at a dose of 900 billion CFU per day. Changes in depressive symptoms were assessed using the HAM-D scale (6).

Both groups improved, but the reduction in symptoms was more pronounced in the probiotic group. At the same time, changes in the gut microbiota were observed — including an increase in Lactobacillus species, which was associated with symptom improvement.

Additionally, brain imaging showed changes in brain activity (including in the striatum), suggesting that this formulation may influence emotional processing.

In practice, this is a formulation worth considering in patients with inflammatory bowel diseases (IBD), IBS, or NAFLD. It may be particularly useful when depressive symptoms are also present.

Lab4 Probiotic: IBS, Anxiety, and Quality of Life

Another formulation studied in the context of the gut–brain axis is Lab4 — a combination of Lactobacillus and Bifidobacterium strains (Lactobacillus acidophilus CUL60 and CUL21, Bifidobacterium bifidum CUL20, and Bifidobacterium animalis subsp. lactis CUL34).

In one randomized, double-blind study, its effects were evaluated in women with irritable bowel syndrome (IBS) (7). Participants received either the probiotic or placebo for 8 weeks, with the primary outcome being changes in symptom severity measured by the IBS-SSS scale.

In the probiotic group, the following were observed:

• a significant reduction in IBS symptoms,

• improvements in psychological symptoms — including reduced anxiety and depressive symptoms,

• improved stool consistency and fewer loose bowel movements.

In practice, this is a formulation to consider in patients with IBS who also experience anxiety or elevated stress.

It is also worth noting that this formulation is available in a product certified by Informed Sport. This program tests individual product batches for substances banned in sports, making it one of the options I consider when working with athletes.

How to Choose the Right Probiotic: Practical Applications

These data show that multi-strain formulations — much like single strains — differ in both their mechanisms of action and the contexts in which they are most useful.

In practice, several scenarios stand out where choosing a specific formulation may be most appropriate:

• depressive symptoms and chronic stress without prominent gastrointestinal complaints
  → in this case, one of the more reasonable options is the combination of L. helveticus R0052 and B. longum R0175

• gastrointestinal conditions (IBD, IBS, NAFLD) coexisting with low mood
  → in such cases, the De Simone Formulation (CDS22) may be particularly relevant, given the available data in both gastrointestinal disorders and depression

• IBS with accompanying anxiety, low mood, or reduced quality of life
  → in this context, the Lab4 formulation is worth considering, as there is evidence supporting improvements in both IBS symptoms and selected psychological outcomes

The boundaries between these applications are not rigid. Each of these formulations may influence multiple systems at once — from the microbiota and gut barrier to the immune and hormonal systems.

This article focused on multi-strain formulations. If you want to understand how individual strains compare, Part 1 may be a useful starting point:
Probiotics for Mood (Part 1): 4 Evidence-Based Strains for Stress, Sleep, and Depression

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References:

1. Heidarzadeh-Rad N, et al. 2020. Effects of a Psychobiotic Supplement on Serum Brain-derived Neurotrophic Factor Levels in Depressive Patients: A Post Hoc Analysis of a Randomized Clinical Trial. J Neurogastroenterol Motil. 26:486-495.

2. Kazemi A, et al. 2019. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial. Clin Nutr. 38:522-528.

3. Messaoudi M, et al. 2011. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 105:755-764.

4. Cheng FS, et al. 2022. Probiotic mixture VSL#3: An overview of basic and clinical studies in chronic diseases. World J Clin Cases. 8:1361-1384.

5. https://cds22.com/en/about-us/there-is-one-de-simone-formulation/

6. Schaub, AC, et al. 2022. Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: a randomized controlled trial. Transl Psychiatry. 12:227.

7. Mullish BH, et al. 2024. A double-blind, randomized, placebo-controlled study assessing the impact of probiotic supplementation on the symptoms of irritable bowel syndrome in females. Neurogastroenterol Motil. 36:e14751.

The Gut–Brain Axis: How the Microbiome Influences Mood

More and more evidence suggests that communication between the gut and the brain does not follow a single pathway — it operates across multiple interconnected systems.

The most commonly discussed include the vagus nerve, the immune system, short-chain fatty acids, and tryptophan metabolism. But we now know the system is far more complex.

The way the gut influences the brain is also shaped by:

• the integrity of the intestinal barrier,

• the composition and diversity of the microbiota,

• the production of neurotransmitters, hormones, and signaling molecules by gut bacteria (1).

In practice, this means the microbiota is not just a passive component of digestion — it actively participates in processes related to mood and behavior.

Studies show clear differences in microbiota composition between healthy individuals and patients with irritable bowel syndrome (IBS). Importantly, these changes may also be associated with depressive symptoms — such as low mood, reduced energy, sleep disturbances, and difficulty concentrating.

Disruptions in the gut–brain axis may also be relevant in other contexts — for example in acne, where the psychological burden can be substantial.

I explore this in more detail in the context of acne here.

It’s also worth noting that gut bacteria produce signaling molecules — including compounds involved in tryptophan metabolism — that can influence brain function and behavior. On the other hand, certain bacterial products, such as endotoxins from Gram-negative bacteria, may negatively affect mood and cognitive function.

In this context, modulating the microbiota becomes one potential way to influence mood.

One of the most promising approaches is the use of probiotics — live microorganisms that, when administered in adequate amounts, can confer health benefits.

Probiotics can influence the gut–brain axis on multiple levels — from modulating immune responses, to supporting the intestinal barrier, to producing signaling compounds that affect the brain.

This multi-layered activity is why certain probiotic strains are increasingly being explored as tools for supporting mood and depressive symptoms.

In the following sections, we’ll look at specific strains — and the contexts in which they may be most relevant.

Bacillus coagulans MTCC 5856 in Practice: IBS and Mood

One strain that stands out in this context is Bacillus coagulans MTCC 5856 — also known as LactoSpore®.

Its defining feature is exceptional stability.

Studies show that B. coagulans MTCC 5856 is resistant to both gastric acid and high temperatures. Interestingly, it retains high viability even under conditions that would destroy most probiotics — for example, after being exposed to hot coffee (~90°C) (2).

Similar stability has been observed in baked goods and products stored for extended periods under varying conditions.

Clinically, it has been studied in patients with IBS, where it was well tolerated and helped alleviate symptoms — particularly in diarrhea-predominant cases (3). Other studies have reported improvements in bloating, gas, and overall gastrointestinal discomfort (4).

From a gut–brain perspective, particularly relevant is a study involving patients with IBS and coexisting depression.

In a randomized, double-blind trial, participants with irritable bowel syndrome (IBS) and depression received Bacillus coagulans MTCC 5856 at a dose of 2 billion CFU daily for 90 days, compared to placebo (1).

At the end of the study, researchers observed:

• significant improvements in depressive symptoms — measured using HAM-D, MADRS, and CES-D scales,

• improved IBS-related quality of life,

• reductions in inflammatory markers (including myeloperoxidase).

The effects were consistent across different assessment tools, and supplementation was well tolerated with no serious adverse effects.

In practice, B. coagulans MTCC 5856 may be particularly useful in individuals where gastrointestinal symptoms coexist with mood disturbances — especially in IBS, SIBO, bloating, and irregular bowel habits.

From my experience, its effects are not limited to a single IBS subtype — it can be helpful in both diarrhea- and constipation-predominant cases.

Clostridium butyricum CBM588: Butyrate, Gut Health, and Mood

Another strain of interest in the gut–brain axis is Clostridium butyricum CBM588.

This bacterium produces butyrate — a short-chain fatty acid that plays a key role in maintaining the intestinal barrier, regulating inflammation, and supporting gut–brain communication.

Unlike direct butyrate supplementation, which leads to short-term increases, C. butyricum CBM588 enables continuous production within the gut — which may be more physiologically relevant.

Clinically, it has been well studied in gastrointestinal disorders, particularly IBS with predominant diarrhea (5).

Randomized trials show that its use can lead to meaningful improvements in symptoms such as diarrhea, bowel frequency, and overall quality of life.

These effects may be explained by several mechanisms:

• increased mucus production and barrier support,

• improved tight junction integrity,

• modulation of immune responses and reduction of inflammation,

• support for beneficial bacteria such as Bifidobacterium and Lactobacillus.

It may also influence immune function by activating T cells and increasing immunoglobulin A (IgA), further supporting gut barrier integrity.

Long-term studies have also shown that supplementation may reduce the recurrence of colorectal adenomas — highlighting its broader impact on the gut environment.

In one study involving treatment-resistant depression, C. butyricum CBM588 was used for 8 weeks with a gradual dosing protocol (up to 60 mg/day) (6).

Response rates reached approximately 70%, with remission in 35% of participants, without serious adverse effects.

In practice, I use it in similar contexts as B. coagulans — particularly in IBS, SIBO, bloating, and irregular bowel habits.

When gut symptoms coexist with mood disturbances, it may be especially useful.

Lactiplantibacillus plantarum PS128: Stress, Sleep, and Mood

In a slightly different context, Lactiplantibacillus plantarum PS128 is worth highlighting.

This strain originates from traditionally fermented foods in Taiwan.

Preclinical studies suggest it may influence the nervous system — including increasing neurotransmitters such as dopamine and serotonin, and modulating the stress response (7).

Reductions in anxiety-like and depressive behaviors have been observed, along with decreased visceral hypersensitivity.

Clinically, L. plantarum PS128 has been studied in stress, sleep disturbances, and depression — though the results are not entirely consistent.

Importantly, its effects appear to span multiple levels — from neurotransmitters, to inflammation, to autonomic nervous system balance.

One notable study involved individuals working in the IT sector — a population characterized by high levels of stress (7).

Participants with elevated stress levels received L. plantarum PS128 at a dose of 20 billion CFU daily for 8 weeks.

After 8 weeks, the following were observed:

• significant reductions in perceived stress (measured using the Perceived Stress Scale, PSS),

• improvements in anxiety and depressive symptoms,

• improved sleep quality,

• improved quality of life,

• reduced cortisol levels.

However, this study did not include a placebo group, which requires cautious interpretation.

Another study examined L. plantarum PS128 in individuals with insomnia, in a randomized, double-blind, placebo-controlled design (8).

Participants received 60 billion CFU daily for 30 days, with both subjective and objective measures of sleep assessed.

Compared to placebo, the results included:

• reduced depressive symptoms (measured using the Beck Depression Inventory-II, BDI-II),

• reduced fatigue,

• fewer awakenings during deep sleep,

• changes in brain wave activity related to sleep regulation.

Improvements in mood were linked to changes in sleep architecture and brain activity — suggesting a more direct effect on the nervous system.

In practice, L. plantarum PS128 may be particularly helpful in individuals where mood issues coexist with sleep disturbances and chronic fatigue.

However, results in major depression are less consistent.

While a small pilot study showed improvements, one randomized, placebo-controlled trial did not find a clear advantage over placebo in patients with depression (9, 10).

This suggests that while L. plantarum PS128 may influence certain aspects of the gut–brain axis, its role in established depression remains unclear.

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Lacticaseibacillus paracasei PS23: Stress, Sleep, and the Gut–Brain Axis

A similar but distinct profile is seen with Lacticaseibacillus paracasei PS23.

This strain has been studied in both live and heat-treated (inactivated) forms, particularly in the context of stress and sleep.

Preclinical and early clinical studies suggest it may influence anxiety, low mood, and stress-related biomarkers such as cortisol (11).

In one randomized, placebo-controlled study in highly stressed clinical nurses, supplementation with heat-treated L. paracasei PS23 (300 mg daily, ~10 billion cells) for 8 weeks led to a significant reduction in cortisol levels (12).

Improvements in anxiety were also observed, particularly in individuals with higher baseline anxiety.

The live form of L. paracasei PS23 has also been studied in a randomized, placebo-controlled trial in individuals with elevated stress (11).

Participants received 20 billion CFU daily for 6 weeks.

Observed effects included:

• improved sleep quality (including reduced sleep latency),

• reduced anxiety,

• improvements in selected stress and fatigue markers.

Another study combined L. paracasei PS23 with L. plantarum PS128 (13).

In a randomized, placebo-controlled trial involving highly stressed individuals (including firefighters), participants received:

• 30 billion CFU of L. plantarum PS128,

• 20 billion cells of heat-treated L. paracasei PS23

daily for 8 weeks.

This intervention led to improvements in stress, anxiety, and insomnia, along with changes in neuroendocrine markers such as ACTH and norepinephrine.

However, due to the combined intervention, it is not possible to determine the individual contribution of each strain.

There is also emerging data from other contexts.

In a recent randomized, placebo-controlled study in individuals with long COVID symptoms, heat-treated L. paracasei PS23 (20 billion cells daily for 6 weeks) was associated with:

• reduced cortisol levels,

• improvements in selected cognitive functions,

• reductions in symptoms such as dyspnea and loss of appetite (14).

While this is a different clinical context, it further supports the idea that L. paracasei PS23 may influence stress responses and the gut–brain axis.

In practice, L. paracasei PS23 may be particularly useful in individuals where chronic stress, sleep disturbances, and psychological tension coexist.

How to Choose the Right Probiotic Supplement (In Practice)

When selecting a probiotic, I start by focusing on:

• precise strain identification (e.g., B. coagulans MTCC 5856, L. paracasei PS23),

• dosing aligned with clinical studies,

• formulation — including additional strains, prebiotics, or excipients that may affect tolerance.

Only in the next step, and when possible, do I look for products that meet at least one of the following criteria:

• quality verified by independent certification (e.g., NSF or Informed Sport — still relatively rare in probiotics),

• a declared CFU count not only at manufacture, but also at the end of shelf life,

• use of a product that has been directly tested in clinical trials.

It’s also worth noting that the strains discussed here were selected partly based on real-world availability in Europe and the U.S.

A limited number of additional strains have been studied, though many are not currently accessible in these markets.

Choosing the Right Probiotic Strain for the Right Context

The data clearly show that different strains vary in both mechanisms and clinical effects.

In practice, this means:

• B. coagulans MTCC 5856 and C. butyricum CBM588 may be particularly useful when gastrointestinal symptoms coexist with low mood — especially in IBS, SIBO, and bowel irregularities,

• L. plantarum PS128 and L. paracasei PS23 may play a larger role in stress regulation, sleep quality, and neuroendocrine balance.

That said, these distinctions are not absolute.

Individual responses vary, and the boundaries between use cases are not always clear.

For example, while the strongest evidence for sleep comes from L. plantarum PS128 and L. paracasei PS23, beneficial effects have also been observed with B. coagulans MTCC 5856.

In practice, if a first-line strain does not produce the expected results, it is reasonable to consider alternative options — even if the supporting data are less consistent.

In Part 2, we’ll move beyond individual strains and look at multi-strain formulations — and where they may be useful in the context of stress, IBS, and depression.

Probiotics for Mood (Part 2): Evidence-Based Formulas for Stress, IBS, and Depression

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References:

1. Majeed M, et al. 2018. Bacillus coagulans MTCC 5856 for the management of major depression with irritable bowel syndrome: a randomized, double-blind, placebo-controlled, multicenter pilot clinical study. Food Nutr Res. 62.

2. Majeed M, et al. 2021. Comparative evaluation for thermostability and gastrointestinal survival of probiotic Bacillus coagulans MTCC 5856. Biosci Biotechnol Biochem. 85:962–971.

3. Majeed M, et al. 2016. Bacillus coagulans MTCC 5856 supplementation in the management of diarrhea-predominant irritable bowel syndrome: a double-blind randomized placebo-controlled pilot clinical study. Nutr J. 15:21.

4. Majeed M, et al. 2023. The effects of Bacillus coagulans MTCC 5856 on functional gas and bloating in adults: a randomized, double-blind, placebo-controlled study. Medicine (Baltimore). 102:e33109.

5. Bertuccioli A, et al. 2025. Targeted probiotic therapy in irritable bowel syndrome: a clinical evaluation of Clostridium butyricum CBM588 and Bifidobacterium longum W11. Front Med (Lausanne). 12:1604319.

6. Miyaoka T, et al. 2018. Clostridium butyricum MIYAIRI 588 as adjunctive therapy for treatment-resistant major depressive disorder: a prospective open-label trial. Clin Neuropharmacol. 41:151–155.

7. Wu SI, et al. 2021. Psychobiotic supplementation of PS128 improves stress, anxiety, and insomnia in highly stressed information technology specialists: a pilot study. Front Nutr. 8:614105.

8. Ho YT, et al. 2021. Effects of Lactobacillus plantarum PS128 on depressive symptoms and sleep quality in self-reported insomniacs: a randomized, double-blind, placebo-controlled pilot trial. Nutrients. 13:2820.

9. Chen HM, et al. 2021. Psychophysiological effects of Lactobacillus plantarum PS128 in patients with major depressive disorder: a preliminary 8-week open trial. Nutrients. 13:3731.

10. Lin SKK, et al. 2024. The effects of Lactobacillus plantarum PS128 in patients with major depressive disorder: an 8-week double-blind, placebo-controlled study. Asian J Psychiatr. 101:104210.

11. Wu SI, et al. 2025. Effect of Lacticaseibacillus paracasei PS23 on anxiety and sleep difficulties among office workers: a double-blind randomized controlled pilot trial. Ann Gen Psychiatry. 24:59.

12. Wu SI, et al. 2022. Psychobiotic supplementation of heat-killed PS23 improves anxiety in highly stressed clinical nurses: a double-blind randomized placebo-controlled study. Food Funct. 13:8907–8919.

13. Lee MC, et al. 2025. Dual-strain psychobiotics combining live Lactiplantibacillus plantarum PS128 and heat-treated Lacticaseibacillus paracasei PS23 improve psychological and neuroendocrine outcomes in stressed adults: a randomized, placebo-controlled trial. Foods. 14:4190.

14. Wu SI, et al. 2026. Efficacy of heat-treated Lacticaseibacillus paracasei PS23 in individuals with long COVID: a double-blind randomized controlled pilot study. Sci Rep. 16:5368.

In the previous article, I described acne as a process that goes beyond the skin, involving interactions between the nervous system, the gut, and the immune system.

In this article, we take a step further — moving from a general model to a specific mechanism that may have practical relevance not only in acne, but also more broadly in chronic low-grade inflammation.

That mechanism is endotoxemia — the presence of small amounts of bacterial components in the bloodstream.

This signal may be one of the key links between what happens in the gut and chronic inflammation in other tissues — including the skin.

In the sections that follow, we’ll look at how this mechanism can translate into practical therapeutic decisions — including the use of lactoferrin.

Zonulin and Gut Permeability

The intestinal barrier relies on the coordinated function of several key elements:

• the mucus layer,

• the gut microbiota,

• tight junctions, which regulate permeability between intestinal epithelial cells.

Under normal conditions, this system functions with high precision — allowing selective absorption of nutrients while limiting the passage of bacteria, toxins, and antigens into circulation.

One of the key regulators of this process is zonulin — a protein that can increase intestinal permeability by modulating tight junctions (1).

Zonulin may be released in response to changes in the microbiota and certain dietary factors. This leads to a loosening of the intestinal barrier and increased translocation of molecules from the gut lumen into the bloodstream.

On one hand, this mechanism may serve an adaptive role, helping to eliminate potentially harmful microorganisms. On the other hand, when chronically activated, it may contribute to persistently increased gut permeability.

Notably, in a study comparing 75 adults with acne to 75 healthy controls, patients with acne had higher zonulin levels — suggesting increased intestinal permeability (2).

From Gut Dysbiosis to Endotoxemia

One factor that may disrupt intestinal barrier function is dysbiosis — an imbalance in the composition and function of the gut microbiota.

Although data on the microbiome in acne are still limited, available studies point to several recurring patterns:

• reduced microbial diversity,

• decreased abundance of bacteria with potential anti-inflammatory effects,

• a relative increase in pro-inflammatory bacteria, including members of the Proteobacteria group (3).

A key player here is lipopolysaccharide (LPS) — a component of the outer membrane of Gram-negative bacteria, which can enter the bloodstream when gut permeability is increased.

This can lead to what is often referred to as metabolic endotoxemia — a chronic presence of low levels of endotoxins in the blood. While it does not trigger an acute infection, it may keep the immune system in a state of persistent activation.

How LPS Triggers Chronic Inflammation

When LPS enters the bloodstream, the immune system recognizes it as a signal of bacterial presence.

A central role is played by TLR4 (Toll-like receptor 4), which acts as a sensor for these molecules. Its activation triggers a cascade of responses leading to the production of pro-inflammatory cytokines such as:

• TNF-α,

• IL-6,

• IL-1β.

The problem arises when this signal becomes chronic. At that point, it is no longer a protective response — but a state that begins to disrupt systemic regulation.

The Gut–Liver–Skin Axis: Connecting Endotoxemia and Acne

To better understand what happens next, it helps to look at the relationship between the gut, liver, and immune system as one integrated network.

The gut and liver are closely connected via the portal circulation, which transports not only nutrients but also bacterial components directly from the intestine to the liver.

Under normal conditions, this is part of healthy immune regulation. Small amounts of bacterial signals reaching the liver help maintain immune balance. Kupffer cells play an important role here by capturing and neutralizing these molecules, preventing excessive immune activation.

However, this balance can be disrupted in the presence of dysbiosis and increased gut permeability. In that case, larger amounts of endotoxins and bacterial metabolites reach the liver, potentially driving immune activation and contributing to systemic inflammation.

SIBO in the Gut–Skin Axis: A Missing Amplifier?

Another factor to consider in this context is small intestinal bacterial overgrowth (SIBO).

In SIBO, the microbial environment of the small intestine shifts significantly:

• reduced diversity,

• dominance of specific bacterial groups,

• often including Gram-negative bacteria such as Escherichia coli and Klebsiella (4).

This is not just an increase in bacterial load, but also a shift in composition — potentially leading to greater exposure to endotoxins.

As a result, SIBO may increase exposure to LPS within the small intestine — particularly when the intestinal barrier is compromised.

While direct data linking SIBO to acne vulgaris are limited, studies in rosacea patients show a higher prevalence of SIBO compared to the general population (5).

Moreover, in one study, eradication of SIBO with rifaximin was associated with a significant improvement in rosacea symptoms — suggesting that this pathway may be clinically relevant (6).

This does not mean the same mechanism plays an identical role in acne vulgaris. However, it highlights that the small intestine may be an important source of inflammatory signals affecting the skin.

In this context, SIBO is not a separate mechanism, but rather a factor that may amplify the processes described above — particularly those related to endotoxin exposure and immune activation.

Lactoferrin: A Bridge Between the Gut and Skin

If endotoxemia plays a role in acne, an important question follows: can we directly influence this process?

One compound that may be particularly relevant here is lactoferrin — an iron-binding protein with antimicrobial and immunomodulatory properties.

From a mechanistic perspective, lactoferrin may act at several key points in this pathway:

• limiting the growth of certain Gram-negative bacteria,

• directly binding LPS and reducing its biological activity,

• modulating the immune response and reducing excessive cytokine production,

• supporting intestinal barrier function,

• reducing overactivation of the TLR4 pathway (7).

If these mechanisms are clinically meaningful, we should expect to see their effects reflected in clinical studies.

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Lactoferrin and Acne: What Do Clinical Studies Show?

Available clinical studies provide some support for this.

However, it is important to note that some of these studies used lactoferrin in combination with other compounds, which makes it harder to isolate its individual effect.

In two trials involving young patients with mild to moderate acne, lactoferrin supplementation was associated with a clear improvement in skin condition.

In the first study (39 participants), after 8 weeks of 100 mg lactoferrin per day (chewable tablets), more than 75% of participants showed improvement in acne lesions (8). The total number of lesions decreased by about 22%, with similar reductions in both inflammatory and non-inflammatory lesions.

In the second study, 200 mg of lactoferrin per day was administered in fermented milk (9). After 12 weeks, there was a significant improvement compared to placebo:

• total lesion count decreased by ~23%,

• inflammatory lesions decreased by ~40%,

• overall severity decreased by ~20%.

Additionally, sebum production decreased by over 30%.

Interestingly, while total skin lipids decreased in both groups, triglycerides were reduced only in the lactoferrin group — and this reduction was associated with improvements in acne severity.

Importantly, supplementation was well tolerated and not associated with significant adverse effects.

A more recent clinical study involving a larger group of patients used lactoferrin in combination with zinc and vitamin E (10).

In this randomized, double-blind trial (160+ participants with mild to moderate acne), the intervention included:

• lactoferrin (100 mg/day),

• zinc gluconate (33 mg/day),

• vitamin E (11 IU/day).

The results showed a significant reduction in skin lesions compared to placebo.

Improvements were observed as early as 2 weeks, with the greatest effect at 10 weeks:

• total acne lesions ↓ ~30%,

• comedones ↓ >30%,

• inflammatory lesions ↓ ~40%,

Sebum production also improved after 12 weeks.

How to Use Lactoferrin: Practical Considerations

In clinical studies, lactoferrin has typically been used in doses ranging from 100 to 200 mg per day.

In practice, a gradual approach makes sense:

• start with 50–100 mg per day,

• increase to 100–200 mg after 1–2 weeks (if well tolerated),

• in selected cases — with good tolerance and clear clinical response — consider increasing to 300–400 mg per day (although this range has not been directly studied in acne).

The timing of intake also matters.

In clinical studies, lactoferrin was often taken in divided doses before meals.

This has a practical rationale — taking lactoferrin before meals may reduce its degradation in the acidic environment of the stomach and increase the amount that reaches the intestine intact (11).

In practice, a few key principles are worth considering:

• take approximately 30 minutes before meals,

• use divided doses throughout the day,

• at higher doses (200–400 mg/day), split into 2–4 servings rather than taking a single dose.

Another important factor is the form of lactoferrin.

Depending on iron saturation, lactoferrin exists in different forms with distinct biological properties. Low-iron forms (often labeled as apo-lactoferrin) show strong antimicrobial activity in experimental settings (12).

On the other hand, some clinical data from other contexts suggest that partially iron-saturated lactoferrin (~20–30%) may have stronger anti-inflammatory effects — particularly through reducing IL-6 (11).

In practice, apo-lactoferrin is a reasonable starting point due to its availability.

However, if a product containing partially iron-saturated lactoferrin (20–30%) is available, it may be particularly interesting in individuals with a more pronounced inflammatory component — potentially due to stronger anti-inflammatory effects.

This gradual, adaptive approach reflects how I typically introduce this type of intervention in practice — with an emphasis on tolerance, predictability, and stepwise adjustment.

Conclusion: Targeting Endotoxemia in Acne

From this perspective, endotoxemia can be viewed as one of the mechanisms linking what happens in the gut with changes observed in the skin.

Lactoferrin acts at multiple points within this pathway — influencing the microbiota, intestinal barrier function, and immune response — and in some cases may lead to meaningful improvements in skin condition.

However, this does not mean endotoxemia plays a central role in every case. In practice, it is one of several processes that may contribute to symptoms, and its relevance depends on the individual context.

Within this framework, lactoferrin represents one possible point of intervention — sufficient in some cases, and part of a broader strategy in others.

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References:

1. Andrzejczak, K., et al. 2026. Gut Dysbiosis and the Molecular Landscape of the Gut–Skin Axis: Comparative Insights and Therapeutic Implications for Atopic Dermatitis and Psoriasis. Cells. 15:594.

2. Gürel, R.C., et al. 2025. Measurement of Acne Severity, Dietary Habits, and Blood Zonulin Levels in Acne Patients. J Cosmet Dermatol. 24:e70083.

3. Yan, H.M., et al. 2018. Gut microbiota alterations in moderate to severe acne vulgaris patients. J Dermatol. 45:1166-1171.

4. Leite, G., et al. 2024. Defining Small Intestinal Bacterial Overgrowth by Culture and High Throughput Sequencing. Clin Gastroenterol Hepatol. 22:259-270.

5. Nelson, J.M., et al. 2024. Evaluation of Helicobacter pylori and Small Intestinal Bacterial Overgrowth in Subjects With Rosacea. Cureus. 16:e72363.

6. Parodi, A., et al. 2008. Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 6:759-64.

7. Zong, X., et al. 2025. Role of lactoferrin and its derived peptides in metabolic syndrome treatment. Front Endocrinol (Lausanne). 16:1562653.

8. Mueller, A.E., et al. 2011. Efficacy and tolerability of oral lactoferrin supplementation in mild to moderate acne vulgaris: an exploratory study. Curr Med Res Opin. 27:793-7.

9. Kim, J., et al. 2010. Dietary effect of lactoferrin-enriched fermented milk on skin surface lipid and clinical improvement of acne vulgaris. Nutrition. 26:902-9.

10. Chan, H., et al. 2017. A randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of lactoferrin with vitamin E and zinc as an oral therapy for mild to moderate acne vulgaris. Int J Dermatol. 56:686-690.

11. Lepanto, M.S., et al. 2018. Efficacy of Lactoferrin Oral Administration in the Treatment of Anemia and Anemia of Inflammation in Pregnant and Non-pregnant Women: An Interventional Study. Front Immunol. 9:2123.

12. Kim, J.W., et al. 2025. The Multifaceted Functions of Lactoferrin in Antimicrobial Defense and Inflammation. Biomolecules. 15:1174.

Acne (acne vulgaris) is most often treated as a skin problem.

In practice, this means focusing on what is visible:

• sebum,

• skin bacteria,

• inflammation.

However, this way of thinking may be incomplete. Increasingly, it appears that skin changes are only the final stage of processes occurring much deeper — in the nervous system, the gut, and metabolism.

Interestingly, this idea is not new. As early as the 1930s, dermatologists John H. Stokes and Donald M. Pillsbury proposed that stress and emotional states could influence the function of the gastrointestinal tract, alter the composition of gut microbiota, and increase intestinal permeability (1).

They also pointed to the potential role of:

• reduced gastric acid secretion,

• and the resulting shift of bacteria within the gastrointestinal tract, including their excessive presence in the small intestine, where they are normally found in much lower numbers.

In their view, these changes led to systemic inflammation, which could manifest on the skin — including in the form of acne.

They even proposed approaches that today we would describe as “microbiota-focused,” such as the use of lactic acid bacteria, particularly Lactobacillus acidophilus, as well as fermented dairy products.

Interestingly, even at that time, early observations began to suggest a link between gut microbiota and mental health — including lower levels of Lactobacillus acidophilus in stool samples from individuals with various mental health conditions, as well as reports of potential psychological benefits from supplementation with lactic acid bacteria.

Although many of these hypotheses were developed long before modern microbiome research methods, they align remarkably well with what we now understand about the brain–gut–skin axis.

For many years, this concept remained on the margins, despite occasional publications highlighting its relevance (2). Today, however, it is returning in a new form — as the brain–gut–skin axis (BGSA), supported by advances in research on the gut microbiome, neuroendocrine regulation, and inflammation (3).

It is now becoming increasingly clear that acne can be understood as the result of overlapping processes occurring across multiple interconnected systems.

Stress activates the hypothalamic–pituitary–adrenal (HPA) axis and amplifies inflammatory signaling. At the same time, disruptions in the intestinal barrier may promote the translocation of endotoxins and the persistence of chronic inflammation. These signals do not act independently — they reinforce one another and ultimately shape the skin environment.

From this perspective, acne is no longer just a dermatological issue. It becomes a reflection of what is happening throughout the body — where the brain, gut, and skin form a single, dynamic system.

Importantly, these relationships are bidirectional.

Stress and psychological factors can influence gut function, but disruptions in the microbiota, intestinal barrier, or inflammation can also affect the nervous system — influencing mood, anxiety levels, and the response to stress.

This makes it difficult to clearly identify a single “starting point” — these processes reinforce each other and form a self-perpetuating loop.

It is also important to note that the nervous system and stress are only one part of this system. Gut function, microbiota composition, and intestinal barrier integrity are also influenced by many other factors — such as diet, circadian rhythm, and physical activity.

These factors do not act independently of the stress response — they can modulate it, amplify it, or buffer it, shaping the overall load on the body.

In this article, I focus on the role of the nervous system and stress as one of the mechanisms that integrate these signals and regulate the function of the entire system.

Brain — how stress shapes the brain–gut–skin axis in acne

One layer of this system is the nervous system. It is therefore useful to first clarify what we actually mean by “stress.”

It includes not only psychological factors — such as chronic tension, anxiety, or low mood, which often accompany skin conditions like acne — but also biological stressors, including:

• inflammation,

• metabolic disturbances,

• unstable glucose levels,

• nutrient deficiencies.

These internal factors can activate the same mechanisms as psychological stress, influencing the HPA axis, the nervous system, and immune responses.

It is also worth remembering that the impact of acne on mental health can be significant — studies show increased severity of anxiety and depressive symptoms, and the psychological burden may be higher than in some other chronic conditions, such as diabetes or epilepsy (4).

Regardless of the source, the stress response triggers interconnected biological mechanisms involving the neuroendocrine, immune, and autonomic systems, and their effects can be observed at the level of the skin.

A key component of this response is the HPA axis. Under stress:

• the hypothalamus releases corticotropin-releasing hormone (CRH),

• the pituitary produces adrenocorticotropic hormone (ACTH),

• the adrenal glands release cortisol.

At the same time, the sympathetic nervous system is activated, leading to increased release of catecholamines such as adrenaline and noradrenaline.

These mediators do not act only systemically. The skin itself is an active neuroendocrine organ, capable of producing CRH locally and responding to cortisol via glucocorticoid receptors.

As a result, a complex network of signals emerges, influencing sebaceous gland activity, skin barrier function, and immune responses.

One important mechanism is neurogenic inflammation. Stress increases the release of neuropeptides such as:

• substance P,

• CGRP (calcitonin gene-related peptide).

These act directly on mast cells, triggering their degranulation. As a result, inflammatory mediators are released, vascular permeability increases, and skin reactivity rises.

In individuals with acne, levels of substance P are elevated, suggesting that this mechanism may play a significant role in the development of skin lesions.

At the same time, cortisol and other stress-related molecules can impair skin barrier function — for example by inhibiting collagen synthesis and affecting keratinocyte differentiation — increasing the skin’s susceptibility to inflammatory triggers.

The effects of stress are not limited to the skin. The same signals act on the gastrointestinal tract, increasing intestinal permeability and altering microbiota composition.

In this way, stress acts as one of the factors that can initiate disruptions across the entire brain–gut–skin axis, rather than serving only as a local “trigger” of skin symptoms.

Viewing stress solely as excess cortisol is, however, an oversimplification. It is becoming increasingly clear that the stress response is heterogeneous and involves much broader changes in the nervous system.

Under chronic stress, disruptions may occur in specific neural circuits — including increased reactivity of the amygdala and altered communication with the prefrontal cortex.

At the same time, changes occur in key neurotransmitter systems, including:

• glutamatergic,

• GABAergic,

• orexinergic,

• as well as increased neuroinflammatory activity.

This means that stress can affect the body through multiple pathways — not always through elevated cortisol levels.

In some cases, dysregulation of the HPA axis occurs, including its “flattening,” a state in which the rhythm of cortisol secretion becomes less dynamic and its response to stressors is insufficient.

In such conditions, the body does not simply “switch off” the stress response, but compensates through other mechanisms — primarily increased sympathetic activity and direct neuro–immune signaling, which can sustain inflammation independently of cortisol levels.

As a result, stress is not a single, simple mechanism, but a variable factor that can initiate or amplify disruptions across the entire brain–gut–skin axis through multiple overlapping pathways.

This creates a self-reinforcing loop: stress triggers processes that increase inflammation and impair the intestinal barrier, which in turn increases the skin’s sensitivity to further stimuli.

From this perspective, acne is not an isolated skin problem, but part of a broader process occurring throughout the body.

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Gut — microbiota, metabolism, and inflammation in acne

Another layer of this system is the gut environment, which plays a central role in metabolic, immune, and neuroendocrine processes.

The gut microbiota is not just a collection of bacteria, but an active “metabolic engine” that produces compounds influencing the function of the entire body.

Gut dysbiosis is most often associated with:

• reduced microbial diversity,

• a decrease in anti-inflammatory bacteria — including butyrate producers,

• an increase in potentially pro-inflammatory bacteria, including members of the Proteobacteria group.

In acne, the available data are more limited, but point in a partially similar direction — including reduced levels of bacteria such as Bifidobacterium, Lactobacillus, Butyricicoccus, or members of the Actinobacteria phylum, along with a relative increase in Proteobacteria (5).

Such changes in microbiota composition can disrupt metabolic and immune balance.

A particularly important element is the reduced production of short-chain fatty acids (SCFAs), such as butyrate. SCFAs support the intestinal barrier while also influencing the immune system — for example by promoting the development of regulatory T cells (Treg) and limiting the activity of pro-inflammatory Th17 cells.

In dysbiosis, these mechanisms become less effective. At the same time, increased intestinal permeability (“leaky gut”) facilitates the translocation of lipopolysaccharides (LPS) into the bloodstream.

LPS activate Toll-like receptors (particularly TLR4 — Toll-like receptor 4), triggering a cascade of inflammatory signaling and promoting the persistence of chronic inflammation in the body.

As a result, the gut is no longer just a site of local disturbances — it becomes an important communication hub that integrates metabolic, immune, and neuroendocrine processes.

It is through these mechanisms that the microbiota can influence the skin environment, reinforcing the view of acne as the result of systemic processes rather than a purely local dermatological issue.

Cytokines also play an important role here, acting as signals transmitted between the gut, brain, and skin.

Their production may increase in response to intestinal barrier disruption and activation of the stress response — particularly in the case of pro-inflammatory cytokines such as:

• IL-6,

• TNF-α,

• IL-17.

In practice, this means that they can simultaneously influence both the skin and the function of the central nervous system.

Additionally, immune cells activated in one location can migrate to other tissues, further reinforcing the systemic nature of these processes.

Skin — the point where signals converge in acne

The skin is the place where signals originating from:

• the nervous system,

• the gut,

• the immune system

come together.

Sebaceous glands, the skin microbiota, and immune cells respond to these signals, creating conditions that promote the development of acne lesions.

It is at this level that the effects of processes occurring earlier in other systems become visible.

Conclusion — acne as a systemic condition

In this framework, acne is no longer just a skin problem.

It becomes a signal — a visible reflection of how the body is handling stress, metabolic regulation, and inflammation.

This helps explain why approaches focused solely on the skin often produce limited or short-term results.

If the signal originates in the nervous system and the gut, suppressing it at the level of the skin may improve symptoms, but often has limited impact on the underlying mechanisms.

In practice, this means a shift in perspective.
Instead of asking only “how do we treat the skin?”, it may be more useful to ask:

what within this system is driving the process that ultimately becomes visible on the skin?

In future articles, I will explore this topic further, focusing on selected interventions that have shown potential in clinical studies in the context of acne — placing them within the broader framework of the brain–gut–skin axis.

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References:

1) Bowe, W.P., and Logan, A.C. 2011. Acne vulgaris, probiotics and the gut-brain-skin axis - back to the future? Gut Pathog. 3:1.

2) Bowe, W.P., et al. 2014. Acne vulgaris, probiotics and the gut-brain-skin axis: from anecdote to translational medicine. Benef Microbes. 5:185-99.

3) Guo, Y., et al. 2026. The brain-gut-skin axis in inflammatory and disfiguring skin diseases: mechanistic insights, clinical correlations, and therapeutic strategies. Front Immunol. 17:1737303.

4) Pagliarello, C., et al. 2015. A comprehensive health impact assessment and determinants of quality of life, health and psychological status in acne patients. G Ital Dermatol Venereol. 150:303-8.

5) Yan, H.M., et al. 2018. Gut microbiota alterations in moderate to severe acne vulgaris patients. J Dermatol. 45:1166-1171.

Selenium is a trace element that plays an important role in many biological processes, including the regulation of oxidative stress, immune function, and the maintenance of tissue integrity. It is also well known for its role in thyroid function.

In recent years, however, a growing body of research suggests that selenium may also play a meaningful role in gut health.

At the same time, available data indicate that selenium status may be associated not only with the course of inflammatory bowel disease (IBD), but also with intestinal barrier function, gut microbiota composition, and—potentially—the risk of irritable bowel syndrome (IBS).

In this article, I’ll walk through what current research says about selenium and gut health—from clinical data in IBD and IBS, to underlying biological mechanisms, and finally to practical considerations around intake and supplementation.

Low Selenium Levels in IBD Patients

A recent meta-analysis of 20 studies involving 1,792 patients with IBD found that low serum selenium levels are a common issue in this population, particularly in individuals with Crohn’s disease (1).

Similar findings have also been reported by Polish researchers. In one study, patients with Crohn’s disease and ulcerative colitis had significantly lower serum selenium levels—64.79 µg/L and 68.61 µg/L, respectively—compared to 90.52 µg/L in the control group (2).

Other studies suggest that selenium status may be linked not only to disease severity but also to gut microbiota composition. In a study conducted in China involving 80 patients with Crohn’s disease and 45 healthy controls, serum selenium levels were significantly lower in patients (3).

Higher selenium levels were associated with better nutritional status (including BMI and albumin levels), while lower levels were associated with higher disease activity (CDAI) and elevated CRP.

The study also revealed significant differences in gut microbiota composition depending on selenium status. Patients with selenium deficiency had lower microbial diversity compared to those with adequate levels.

At the phylum level, selenium deficiency was associated with reduced abundance of Firmicutes, Bacteroidetes, and Verrucomicrobia, and increased abundance of Actinobacteria and Proteobacteria.

At the genus level, lower levels of beneficial bacteria such as Bacteroides, Faecalibacterium, Phascolarctobacterium, and members of the Lachnospiraceae family—important butyrate producers—were observed.

At the same time, higher levels of potentially pro-inflammatory bacteria such as Escherichia-Shigella, Fusobacterium, and Morganella were found in individuals with low selenium status.

Why Selenium Levels Are Low in IBD

There are several potential reasons why selenium levels may be reduced in patients with IBD:

• impaired nutrient absorption in the small intestine

• chronic diarrhea

• gastrointestinal blood loss

• insufficient dietary intake

• increased demand during inflammation, particularly for antioxidant nutrients

Importantly, the relationship between selenium and IBD may be bidirectional.

Not only can IBD lead to lower selenium levels, but selenium deficiency itself may contribute to increased intestinal inflammation.

How Selenium Affects the Gut: Key Mechanisms

To understand why selenium may matter in gut health, it’s helpful to look at what happens after it is absorbed.

Once absorbed in the small intestine, selenium is converted into active forms that are used in the liver to synthesize selenoproteins. These specialized proteins contain selenium and are responsible for most of its biological effects (4).

In humans, around 25–26 selenoproteins have been identified. Many play a key role in regulating oxidative processes—that is, the balance between the production and neutralization of reactive oxygen species. Others are involved in thyroid hormone metabolism, energy regulation, and selenium transport.

One particularly important protein is selenoprotein P (SELENOP), which transports selenium to tissues and serves as its main circulating form.

Selenium, Oxidative Stress and Intestinal Damage

One of the key mechanisms linking selenium to gut health is its role in oxidative stress.

In IBD, oxidative stress is increased due to higher production of reactive oxygen and nitrogen species.

This leads to:

• damage to cell membranes

• dysfunction of intestinal epithelial cells

• activation of pro-inflammatory pathways

These processes are central to disease development.

Selenoproteins—especially glutathione peroxidases (GPX)—play a critical role in neutralizing excess reactive oxygen species. They use glutathione to convert hydrogen peroxide into less reactive molecules, helping protect intestinal cells from damage.

Several GPX isoforms are directly expressed in intestinal tissues, suggesting a particularly important role in maintaining local redox balance.

Selenium and Immune Regulation in the Gut

Selenium also influences immune function.

One mechanism involves its effects on immune cells such as macrophages. Altered expression of selenoproteins in these cells can affect their ability to migrate and interact with surrounding tissues, which is important for both inflammation and tissue repair.

In practical terms, selenium deficiency may not only increase oxidative stress but also impair proper immune regulation in the gut.

Selenium and the Gut Microbiome

There is also growing evidence that selenium may influence the composition and function of the gut microbiome.

On one hand, gut microorganisms can utilize selenium for their own metabolic processes. On the other, selenium availability may influence which bacterial species gain a competitive advantage within the intestinal environment.

This may help explain why selenium deficiency has been associated with a shift toward a more pro-inflammatory microbiota profile in clinical studies.

Selenium and Irritable Bowel Syndrome (IBS)

Interestingly, selenium deficiency may also be linked to IBS.

In one prospective study, lower selenium intake was associated with a higher risk of developing IBS (5).

The same research group also conducted an animal study showing that a selenium-deficient diet could lead to IBS-like symptoms, including visceral hypersensitivity. Selenium deficiency was also associated with inflammation and impaired integrity of the colon.

Notably, selenium deficiency also altered the gut microbiota:

• increased abundance of Faecalibaculum and Helicobacter

• decreased abundance of Bifidobacterium and Akkermansia

These changes may affect both barrier function and immune regulation in the gut.

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Can Selenium Supplementation Help?

Clinical data on selenium supplementation in gut disorders are still limited.

However, in one randomized, double-blind clinical trial, supplementation with L-selenomethionine (200 µg/day for 10 weeks) in patients with mild-to-moderate active ulcerative colitis led to significant improvements (6).

In the selenium group, researchers observed:

• a reduction in disease activity (SCCAI)

• clinically meaningful improvement in symptoms in 38% of patients (vs 6% in controls)

• remission (SCCAI ≤ 2) in some patients

• increased serum selenium levels and improved quality of life

Regarding inflammatory markers:

• IL-17 levels decreased

• IL-10 levels did not change significantly

This suggests that selenium’s effects on the immune system may be selective.

Importantly, selenium was used as an adjunct—not a replacement—for standard therapy.

While these findings are promising, more well-designed studies are needed to determine which patients are most likely to benefit.

Optimal Selenium Intake and Status

Although selenium appears to play an important role in gut health, it has a relatively narrow therapeutic window. Both deficiency and excess can be harmful.

From a physiological perspective, what matters is not only total selenium levels, but also its functional availability for selenoprotein synthesis.

Markers such as SELENOP and GPX3 activity can provide additional insight:

• GPX3 activity tends to plateau at serum levels of ~70–90 µg/L

• SELENOP reaches maximal levels at ~100–120 µg/L

• SELENOP declines earlier than GPX3 when intake is insufficient

This suggests that SELENOP may be a more sensitive marker of suboptimal selenium status (7).

In many cases, aiming for serum selenium levels in the range of 100–120 µg/L appears reasonable.

While some experimental data suggest potential benefits of higher levels in specific contexts (e.g., cancer), maintaining such levels is generally not advisable due to associations with increased risk of type 2 diabetes at higher selenium concentrations (8, 9).

The recommended daily intake (RDA) for adults is approximately 55–70 µg/day, which is typically achievable through a well-balanced diet.

Foods such as eggs, dairy products, beef, and poultry can provide meaningful amounts of selenium.

In some cases, I also consider including oysters, which are a good source of both selenium and zinc. Due to variability in selenium content, I generally do not recommend relying on Brazil nuts as a primary source.

It’s also important to note that selenium content in food depends heavily on soil levels, which vary significantly by region. As a result, intake can differ even with similar diets.

Additionally, absorption, metabolism, and overall physiological context influence selenium status.

For this reason, dietary intake alone does not always reflect actual selenium levels in the body. In many cases, measuring serum selenium—especially when adjusting diet or supplementation—can be useful.

Practical Considerations for Supplementation

When it comes to supplementation, both dose and form matter.

Organic forms such as selenomethionine and selenium glycinate tend to have higher bioavailability.

Inorganic forms like sodium selenite generally have lower bioavailability but may still be useful in certain contexts—especially in liquid formulations that allow precise dose adjustment.

Some products contain only sodium selenite and purified water, which may reduce exposure to excipients found in capsules or tablets.

Data on optimal supplementation strategies in IBD and IBS are still limited.

In practice, a reasonable first step is to measure serum selenium before increasing intake or starting supplementation.

For clearly low levels (e.g., ~60–70 µg/L), supplementation around 200 µg/day may be considered.

For levels closer to 100–120 µg/L, lower doses (e.g., ~100 µg/day) or dietary adjustments may be sufficient.

Regardless of the approach, reassessment after 6–8 weeks is important to guide further decisions.

Emerging Research: Selenium Nanoparticles

New approaches to selenium delivery are also being explored, including selenium nanoparticles (4).

These formulations may influence bioavailability, stability, and release dynamics.

Preliminary results—mainly from animal studies—are promising, suggesting potential applications in gut disorders through effects on inflammation, oxidative stress, and barrier function.

However, clinical use remains at an early stage and requires further research.

Key Takeaways

A growing body of evidence suggests that selenium may play an important role in gut health—not only in IBD, but also in barrier function, immune regulation, and microbiota composition. There are also early indications of a possible link with IBS.

On one hand, low selenium levels are common in IBD and may be associated with both disease severity and microbiota imbalance. On the other, biological mechanisms—particularly the role of selenoproteins in oxidative stress and inflammation—suggest that deficiency may actively contribute to gut dysfunction.

Preliminary interventional studies suggest that selenium supplementation may benefit patients with IBD; however, the optimal supplementation strategy remains not fully defined.

At the same time, selenium operates within a relatively narrow range in the body. Both deficiency and excess may be harmful. This means that in many cases it is reasonable to aim for serum selenium levels in the range of approximately 100–120 µg/L.

From a practical standpoint, rather than relying on routine supplementation, a more effective approach is individualized assessment—including measurement of serum selenium—and adjusting intake based on actual needs.

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This is Part 4 of the histamine intolerance series.
If you’d like the full background, you can start with Part 1:
Histamine Intolerance: When Histamine Is Produced Inside the Gut

In the previous part of this series, I emphasized that many of the interventions discussed can be viewed as strategies that help regulate the intestinal environment. In practice, their effects rarely remain confined to a single segment of the digestive tract or to a single mechanism.

A low FODMAP diet (fermentable oligosaccharides, disaccharides, monosaccharides and polyols), Saccharomyces boulardii CNCM I-745, or cranberry extracts influence not only the environment of the small intestine, but also the environment of the colon, patterns of bacterial fermentation, and immune signaling.

Similarly, microencapsulated sodium butyrate — previously discussed in the context of intestinal barrier function — also affects the gut microbiota of the colon, bacterial metabolism, and local inflammatory responses.

For this reason, the boundaries between “eradicating microbial overgrowth,” “supporting the intestinal barrier,” and “stabilizing the colonic environment” are often blurred in practice. Although for clarity I assign individual interventions to specific sections, their real-world effects are multi-layered and frequently complementary.

Stabilizing the Colonic Environment in Histamine Intolerance

Bifidobacterium longum subsp. longum BB536 — one of the best-studied intestinal probiotics

Stabilizing the colonic environment is not only about increasing the production of short-chain fatty acids. Equally important is restoring balance within bacterial populations and supporting the interaction between the microbiota and the immune system. One of the best-studied strains in this context is Bifidobacterium longum subsp. longum BB536 (BB536).

BB536 is a multifunctional probiotic with documented effects in gastrointestinal disorders, immune dysregulation, and certain infectious conditions (1).

The most important effects associated with this strain include:

• improved bowel regularity and improvement of the colonic environment, particularly in individuals with constipation,

• support for populations of beneficial bifidobacteria,

• reduction of activity among potentially pathogenic Gram-negative bacteria,

• influence on bile acid metabolism,

• indirect support for short-chain fatty acid production through cross-feeding mechanisms — cooperation between different gut bacteria.

Particularly noteworthy are studies conducted in Japan on seasonal allergic rhinitis caused by Japanese cedar pollen (Japanese cedar pollinosis). This is a classic IgE-mediated type I allergic reaction. Numerous clinical trials have shown that consumption of BB536 — both in yogurt and freeze-dried powder form — may reduce nasal and ocular symptoms and influence immune responses in sensitized individuals.

Although allergic rhinitis and histamine intolerance are not the same condition, they share certain features — including immune hyperreactivity and dysregulated inflammatory signaling. In this context, the ability of BB536 to modulate IgE-dependent allergic responses and support immune balance may have implications beyond its traditional applications in gastroenterology.

Histamine Production by Bacteria Depends on the Strain, Not the Species

Some bacterial strains produce the enzyme L-histidine decarboxylase, which enables the conversion of histidine into histamine. Importantly, the presence of this enzyme is a property of a specific strain rather than the entire bacterial species. This means that the ability to produce histamine cannot automatically be assumed for all strains belonging to the same species (2).

This distinction has important practical implications. Some recommendations for people with histamine intolerance suggest avoiding entire bacterial species considered potentially histamine-producing. One example frequently mentioned in this context is Limosilactobacillus reuteri, which is sometimes discouraged in individuals with histamine intolerance.

However, such generalizations may overlook significant differences between individual strains.

For example, the widely used probiotic strain Limosilactobacillus reuteri DSM 17938 does not appear to carry genes responsible for histamine production. Similar observations were reported in a study analyzing fifteen strains belonging to species such as Lactobacillus acidophilus, Lacticaseibacillus casei, Lactobacillus delbrueckii ssp. bulgaricus, Lactococcus lactis ssp. lactis, and Lactiplantibacillus plantarum. Among the fifteen strains examined, only two — L. casei TISTR 389 and L. bulgaricus TISTR 895 — showed the potential to produce histamine.

Importantly, the effects of probiotics on the intestinal environment extend far beyond histamine production alone. Some strains influence digestive physiology through additional mechanisms.

For example, L. reuteri DSM 17938 is a well-studied strain that demonstrates several potentially beneficial effects, including:

• modulation of immune responses and reduction of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α),

• support for intestinal barrier integrity,

• production of antimicrobial metabolites such as reuterin,

• improvement of gastrointestinal motility (3).

In one clinical study, four weeks of supplementation with L. reuteri DSM 17938 in patients with functional constipation was associated with both changes in methane production and improved intestinal motility. Average methane levels in breath tests decreased from 21 ppm to 9 ppm, and the number of participants with methane levels below 10 ppm increased from five to ten individuals in the study group (4). At the same time, bowel movement frequency increased from four to six per week.

Although this study did not directly involve patients with histamine intolerance, its findings are relevant for conditions in which slowed intestinal transit may promote the accumulation of biogenic amines. As discussed in the previous part of this series, excessive methane production can prolong the contact time between microorganisms and fermentable substrates, increasing the potential for compounds such as histamine to accumulate.

For this reason, certain probiotic strains — such as L. reuteri DSM 17938 — may also be considered part of a strategy aimed at stabilizing the colonic environment, particularly in individuals with constipation or methane overproduction (intestinal methanogen overgrowth, IMO). It is worth remembering that IMO can involve both the small intestine and the colon.

Why Not All L. reuteri Strains Act the Same

Another important aspect to consider is the functional differences between individual L. reuteri strains.

As mentioned earlier, the strain L. reuteri DSM 17938 does not appear to carry genes encoding histidine decarboxylase, suggesting that it lacks the ability to produce histamine.

However, the situation is different for some other strains of this species. Experimental studies have shown that L. reuteri ATCC PTA 6475 contains genes that enable the conversion of histidine into histamine (5).

This distinction also matters when selecting probiotic products. Some formulations contain only L. reuteri DSM 17938, while others combine it with additional strains, including L. reuteri ATCC PTA 6475.

Long-Fermented L. reuteri Yogurts and Histamine Intolerance

Another factor that has gained popularity in recent years is the preparation of homemade, long-fermented yogurts using L. reuteri strains — most commonly DSM 17938 or ATCC PTA 6475, sometimes combined with other bacteria such as Lactobacillus gasseri.

In these preparations, fermentation is carried out for a much longer period than in standard yogurt production. This promotes intense metabolic activity and results in very high bacterial concentrations in the final product.

In practice, this may also lead to increased formation of biogenic amines during fermentation. For individuals with histamine intolerance, consumption of such long-fermented dairy products may therefore more easily trigger symptoms.

It is also worth emphasizing that conventional fermented dairy products — including standard store-bought yogurts — can contain meaningful amounts of histamine and other biogenic amines produced during fermentation. For many people with histamine intolerance, these foods may also provoke symptoms.

In practice, this means that both the bacterial strain used and the form in which it is applied may influence product tolerance. Even if a particular strain is not known to produce histamine, fermentation conditions and the presence of other microorganisms may alter the profile of metabolites produced during the process.

Mast Cell Stabilization in Histamine Intolerance

Palmitoylethanolamide (PEA) — a natural regulator of mast cell activity

Stabilizing mast cells does not simply mean blocking histamine release. Rather, the goal is to restore local immune balance and limit excessive inflammatory activation without inducing immunosuppression.

Palmitoylethanolamide (PEA) belongs to a group of naturally produced bioactive lipids known as ALIAmides (Autacoid Local Injury Antagonist amides) (6). These compounds are synthesized “on demand” in response to injury, inflammation, or cellular stress in order to limit excessive immune activation and restore tissue homeostasis. PEA is derived from membrane phospholipids, and its levels are regulated by degrading enzymes such as FAAH (fatty acid amide hydrolase) and NAAA (N-acylethanolamine acid amidase), ensuring control over the duration and intensity of its activity.

Among ALIAmides, PEA is one of the best characterized in terms of its biological properties.

Experimental studies show that PEA levels increase locally at sites of inflammation, and supplementation may reduce edema, inflammatory cell infiltration, and cytokine release. PEA acts primarily through activation of the PPAR-α receptor, leading to:

• suppression of pro-inflammatory gene activity dependent on nuclear factor kappa B (NF-κB),

• reduction of VEGF/VEGFR2 signaling (vascular endothelial growth factor and its receptor),

• inhibition of the Akt/mTOR signaling pathway (protein kinase B / mammalian target of rapamycin).

In addition to its direct effects on mast cells, PEA stabilizes epithelial tight junctions, counteracts oxidative stress, and supports restoration of intestinal barrier integrity. In practice, this means that its actions extend both to inflammatory mediators and to the structure of the intestinal environment.

PEA has demonstrated beneficial effects in conditions such as neuropathic pain, fibromyalgia, irritable bowel syndrome, eczema, and atopic dermatitis. Because it is produced physiologically in the body, it acts more as a pro-homeostatic modulator than as a conventional anti-inflammatory drug and does not induce immunosuppression. Clinical and preclinical data indicate very good tolerability and a high safety profile.

Some studies have used micronized or ultramicronized forms of PEA (micronized or ultramicronized PEA), where the reduced particle size may improve the solubility and bioavailability of this lipophilic compound.

In the context of histamine intolerance, PEA does not “block histamine.” Instead, it may reduce mast cell hyperreactivity and dampen inflammatory signal amplification — an important element in stabilizing the broader regulatory system.

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Vitamin C and Histamine Regulation

Vitamin C is one of the classic nutrients used to support individuals with histamine hyperreactivity. Experimental studies suggest that it may stabilize mast cells and reduce histamine release (7).

Its effects, however, are not limited to histamine alone.

Increasing evidence indicates that vitamin C may also influence the composition of the gut microbiota and immune responses. In a study involving healthy young adults with suboptimal serum vitamin C levels, four weeks of supplementation (500 mg twice daily) resulted in significant changes in microbiota composition (8). Among the observed changes were:

• increased relative abundance of Bacillaceae and Anaerotruncus,

• decreased abundance of bacteria belonging to the genus Desulfovibrio.

The reduction in Desulfovibrio was particularly interesting, as its magnitude was associated with improvements in cognitive performance and with changes in neurotrophic and inflammatory markers. At the same time, vitamin C supplementation was associated with reduced serum levels of lipopolysaccharide (LPS) and lower markers of immune activation.

As discussed earlier, bacteria from the genus Desulfovibrio are among the main producers of hydrogen sulfide (H₂S) in the colon. Excessive H₂S production has been associated with diarrhea and abdominal pain.

From this perspective, vitamin C may act at multiple levels:

• stabilizing mast cells and reducing histamine release,

• reducing inflammatory burden and endotoxemia,

• modulating the gut microbiota, including reducing hydrogen sulfide-producing bacteria.

As with other strategies discussed in this series, its effects do not rely on a single mechanism. Rather, they fit within a broader regulatory framework involving the gut–microbiota–immune axis.

It is also worth noting that in some more sensitive individuals, ascorbic acid is occasionally reported to worsen histamine-related symptoms. This may appear paradoxical, as vitamin C is commonly associated with antihistamine effects.

Possible explanations include:

• local irritation caused by low pH within the gastrointestinal tract, particularly in individuals with visceral hypersensitivity or mucosal inflammation,

• transient stimulation of intestinal motility, which may modulate symptoms in some individuals,

• individual differences in mast cell reactivity and receptor sensitivity.

This does not mean that vitamin C itself increases histamine production. Rather, the state of the intestinal environment and the specific formulation used may influence tolerance. In practice, it may be helpful to start with lower doses (200 mg once or twice daily) and adjust gradually while observing individual responses. Some individuals tolerate sodium ascorbate or liposomal vitamin C better than pure ascorbic acid.

Several polyphenols have also been investigated for their potential to modulate mast cell activity (9). Among them, quercetin has attracted particular interest due to its ability to inhibit mast cell degranulation and IgE-mediated signaling in experimental models.

Preliminary clinical studies in allergic rhinitis suggest that bioavailable formulations, such as quercetin phytosome, may reduce nasal symptoms and inflammatory markers. However, available trials remain relatively small and short-term, and further research is needed before firm conclusions can be drawn.

Low-Histamine Diet and DAO in Histamine Regulation

Even when strategies targeting the microbiota, intestinal barrier, and mast cell stabilization are implemented, a low-histamine diet and — in selected cases — DAO supplementation may still be useful.

Some authors have also suggested that supplementation with certain cofactors of the DAO enzyme — such as vitamin C, vitamin B6, or copper — might be helpful in specific situations, although evidence supporting this approach remains limited.

When the body produces more histamine than it can efficiently degrade, reducing foods particularly rich in histamine may lower the overall burden and improve tolerance — especially during periods when regulatory mechanisms are still recovering.

As discussed in the first part of this series, preliminary data suggest that a low-histamine diet may influence not only dietary histamine exposure but also the microbial environment of the gut. In one study examining a nine-month dietary intervention in women with histamine intolerance, researchers evaluated the effects of a low-histamine diet on gut microbiota composition (10). They observed:

• a reduction in several bacteria capable of producing histamine, including members of the family Pseudomonadaceae, species of the genus Proteus (including Proteus mirabilis), and Raoultella,

• an increase in Roseburia — a genus associated with short-chain fatty acid production and improved mucosal environment.

These findings suggest that a low-histamine diet may additionally shift the composition of the gut microbiota toward a profile less favorable for excessive histamine production.

A low-histamine diet and DAO supplementation therefore do not have to be viewed as purely “symptom-based” strategies. They may represent a temporary step that improves comfort while the intestinal environment stabilizes and the body’s ability to handle histamine gradually improves.

Histamine Intolerance as a Multi-Layer Regulatory Disorder of the Gut

Histamine intolerance rarely arises from a single mechanism. Rather, it reflects a shift across several interconnected biological layers — including the microbiota of the small intestine and colon, barrier integrity, fermentation processes, and immune reactivity.

Once histamine enters the circulation, additional regulatory layers may also influence its signaling and clearance in tissues, including cellular uptake and intracellular metabolism. These processes extend beyond the scope of the present series, although they represent an interesting area that may be explored in future articles.

In this context, effective strategies are not aimed at a single target but at gradually restoring balance within the intestinal environment. Dietary adjustments, supporting the microbiota, barrier support, and mast cell stabilization are not competing approaches — they operate at different levels of the same regulatory system.

The goal is therefore not merely to suppress symptoms in the short term, but to rebuild a physiological environment in which histamine can again be produced, metabolized, and tolerated in a more stable and predictable way.

Seen in this light, histamine intolerance becomes less a problem of histamine itself and more a reflection of the regulatory state of the intestinal ecosystem.

Histamine Intolerance Series:

Part 1 — When Histamine Is Produced Inside the Gut
Part 2 — SIBO, Methane and Fungal Overgrowth
Part 3 — Rebalancing the Gut Environment
Part 4 — Stabilizing the Histamine Regulatory System

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This is Part 3 of the histamine intolerance series.
If you’d like the full background, you can start with Part 1:
Histamine Intolerance: When Histamine Is Produced Inside the Gut

In the previous parts of this series, I analyzed the mechanisms underlying histamine intolerance — from bacterial production and microbial overgrowth in the gastrointestinal tract, through intestinal barrier integrity, to the activity of diamine oxidase (DAO). I showed that the small intestine and the large intestine, microorganisms, gut motility, and the immune system form a system that exists in dynamic balance.

In this part, I move from mechanisms to practice. Not in the sense of simplified “protocols,” but rather as an attempt to organize interventions according to regulatory layers that may become disrupted.

In practice, four regulatory layers are key:

• reduction of excessive fermentation and microbial overgrowth in the intestines,

• restoration of the intestinal barrier and support of DAO activity,

• stabilization of the environment in the large intestine,

• modulation of mast cell reactivity.

Each of these layers influences the total histamine burden in a different way — through production, degradation, immune signaling, or barrier integrity.

The goal is not to “silence histamine” in the short term, but to shift the entire regulatory system toward greater stability.

In this article I will focus on the first two layers — reducing excessive fermentation and microbial overgrowth, and restoring the intestinal barrier. In the next part, I will discuss strategies aimed at stabilizing the environment of the large intestine and regulating mast cell activity.

Reducing Microbial Overgrowth in Histamine Intolerance

If in the previous part I analyzed how bacterial, methanogen, and fungal overgrowth modifies the intestinal environment — increasing histamine production, weakening its degradation, and promoting its passage into the circulation — then the first logical step in intervention is to change that environment at its source.

SIBO (small intestinal bacterial overgrowth), IMO (intestinal methanogen overgrowth), and disorders associated with excessive hydrogen sulfide production are not simply problems of “too many bacteria.” They represent a shift in the composition and functioning of the gut microbiota, including among other things:

• dominance of Proteobacteria and proteolytic bacteria,

• increased carbohydrate fermentation and increased hydrogen production,

• increased amino acid metabolism (including histidine — the precursor of histamine),

• slowed intestinal transit (particularly in the context of IMO),

• a shift in acid–base balance toward a more alkaline environment,

• possible coexisting overgrowth of opportunistic fungi.

In this context, histamine becomes part of a broader regulatory disturbance rather than an isolated mediator.

For this reason, eradication of microbial overgrowth should not be understood simply as reducing the number of microorganisms. Its goal is to restore:

• a more balanced microbiota composition,

• more physiological fermentation dynamics,

• an appropriate intestinal pH,

• a more stable interaction between the microbiota and the intestinal barrier.

Low FODMAP Diet and Saccharomyces boulardii: A Strategy for SIBO and Histamine Regulation

An interesting example of this approach comes from a study conducted by Spanish researchers evaluating the effect of the probiotic yeast strain Saccharomyces boulardii CNCM I-745 on SIBO eradication and symptoms of diarrhea-predominant irritable bowel syndrome (IBS) (1). Participants followed a low FODMAP diet (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols) and were assigned either to receive Saccharomyces boulardii CNCM I-745 in addition to the diet or to follow the dietary intervention alone.

Among patients following the low FODMAP diet together with this strain, researchers observed:

• a greater reduction in hydrogen levels in the breath test,

• a more pronounced improvement in the overall IBS symptom severity score

compared with the diet alone.

This study illustrates an important point: modulation of the microbiota — even without classical antibiotic therapy — may influence fermentation dynamics and the intestinal environment, thereby indirectly affecting the total histamine burden.

The mechanisms of action of Saccharomyces boulardii may partly explain these effects. This yeast can limit the activity of certain microorganisms through competition for nutrients, modulation of local intestinal conditions, and effects on immune signaling. Experimental studies have also shown that Saccharomyces boulardii may help reduce the activity of certain opportunistic bacteria, including Escherichia coli, as well as Candida albicans, among other mechanisms through the production of metabolites such as acetic acid and the associated lowering of environmental pH (2).

Similar conclusions come from a randomized study comparing rifaximin with a low FODMAP diet in patients with IBS (3). After four weeks, the effectiveness of both interventions in improving symptoms was comparable (56% vs. 48%). SIBO eradication was observed both in the rifaximin group (63.6%) and in the group following the low FODMAP diet (50%).

The main difference concerned the speed of improvement. Rifaximin produced faster improvement in:

• bloating,

• abdominal pain,

• general intestinal symptoms.

However, over a four-week period both strategies led to similar clinical outcomes.

This means that:

• reducing the availability of fermentable substrates (low FODMAP diet),

• direct modulation of the microbiota (rifaximin)

may lead to comparable symptomatic improvement and partial restoration of balance in the small intestine.

Another interesting study examined the effect of the low FODMAP diet on various metabolic markers in patients with IBS (4). After three weeks of the diet, researchers observed:

• clear improvement in IBS symptoms,

• changes in certain metabolites detected in urine.

One of the most characteristic findings was an approximately eight-fold reduction in urinary histamine levels. This result suggests that reducing fermentable carbohydrates may influence not only intestinal symptoms but also processes involved in histamine regulation.

In practice, the low FODMAP diet is usually applied in a more structured way:

• for a limited period (most often 4–6 weeks),

• followed by gradual reintroduction of selected FODMAP-containing foods,

• in order to determine individual tolerance.

The goal is not permanent elimination of fermentable carbohydrates but adaptation of the diet to individual tolerance.

Long-term data support this approach. In a study assessing patients 12 months after starting a low FODMAP diet — including restriction, reintroduction, and personalization phases — about two-thirds of participants maintained clear symptom improvement (5). Importantly, after one year the abundance of Bifidobacterium was similar to baseline levels, suggesting that the reintroduction phase may mitigate some of the microbiota changes observed during short-term FODMAP restriction.

At the same time, lower levels of short-chain fatty acids — including acetate, propionate, and butyrate — were observed. Because these compounds play a key role in maintaining intestinal barrier integrity and regulating inflammation, their reduction may have implications in the longer term.

For this reason, it may be worth considering combining the low FODMAP diet with interventions that support the large intestinal environment and SCFA production discussed in this and the next article. This may help limit the potential consequences of reduced fermentation while maintaining symptomatic benefits.

From a regulatory perspective, the low FODMAP diet should therefore be seen not as a final solution but as a transitional phase — reducing excessive fermentation during periods of instability and creating conditions for rebuilding a more stable intestinal environment.

Cranberry Extract and Microbiota Modulation in Histamine Intolerance

In cases of SIBO, IMO, or coexisting fungal dysbiosis, strong antimicrobial interventions are often proposed — such as oregano oil, berberine, neem, or olive leaf extract. In certain situations they may have their place.

However, their activity is relatively non-selective. This means that in addition to reducing bacteria responsible for excessive fermentation, they may also reduce populations of protective bacteria — including those producing short-chain fatty acids (SCFAs), such as butyrate. Long-term or repeated use of such interventions may therefore lead to:

• reduced microbiota diversity,

• reduction of acid-producing bacteria (including Bifidobacterium),

• temporary reduction of SCFA production,

• and consequently reduced stability of the intestinal ecosystem.

In the context of histamine regulation this has a double implication: the loss of bacteria producing organic acids favors a shift in intestinal pH toward a more alkaline environment, which may support the growth of proteolytic and amine-producing bacteria. In such a situation, short-term symptom improvement does not always translate into long-term stabilization.

An alternative may be a more selective strategy aimed not at “elimination,” but at regulating the ecosystem. An interesting example is cranberry extract rich in polyphenols and oligosaccharides.

In a study involving 28 participants, after just four days of supplementation researchers observed a clear increase in Bifidobacterium abundance — along with increased numbers of butyrate-producing bacteria (including Clostridium and Anaerobutyricum). At the same time, the proportions of short-chain fatty acids changed: acetate decreased while butyrate increased (6).

In the SHIME fermentation model (Simulator of the Human Intestinal Microbial Ecosystem), cranberry extract supplementation additionally:

• promoted the growth of Bifidobacterium adolescentis in the mucosal layer of the ascending colon,

• reduced adhesion of Proteobacteria,

• shifted fermentation patterns from acetate dominance toward propionate and butyrate,

• supported co-occurrence of butyrate-producing bacteria in the mucus of the transverse colon (7).

Importantly, despite individual differences in the microbiota of participants, the butyrogenic effect was observed consistently.

In practice, this represents more than a simple “probiotic effect.” Increased butyrate production, improvement of the mucosal environment, and reduced overgrowth of Proteobacteria may contribute to:

• strengthening the intestinal barrier,

• reducing inflammatory signaling,

• stabilizing intestinal pH,

• indirectly lowering the tendency toward increased production of biogenic amines, including histamine.

This approach does not completely replace antimicrobial interventions in every case. However, it shows that managing microbial overgrowth may involve not only reducing microbial numbers, but also gradually shifting the intestinal environment toward greater resilience and stability.

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Supporting the Intestinal Barrier in Histamine Intolerance

Butyrate and the Gut Barrier: Why Sodium Butyrate May Support Histamine Regulation

In the context of histamine intolerance, intestinal barrier integrity has a double significance. It determines the degree to which histamine and other biogenic amines enter the circulation, while also influencing local immune signaling that may promote mast cell activation.

One of the most important factors supporting the intestinal barrier is butyrate — a short-chain fatty acid (SCFA) that serves as the primary energy source for colonocytes. It is produced mainly by bacteria from the Clostridium group, including Faecalibacterium, Roseburia, Anaerostipes, Eubacterium, and Anaerobutyricum. The presence of butyrate-producing bacteria helps maintain an anaerobic environment and limits excessive growth of opportunistic bacteria such as Escherichia coli (8).

After absorption, butyrate activates cellular receptors (GPR109A, GPR41, GPR43) present on intestinal epithelial cells. As a result it:

• influences immune responses in the intestinal mucosa,

• stimulates secretion of gut hormones (GLP-1, GLP-2, PYY),

• affects gastrointestinal motility.

Particularly important is its influence on tight junctions. Butyrate:

• reduces expression of claudin-2, decreasing paracellular permeability,

• supports reconstruction of the ZO-1 complex,

• increases structural stability of the epithelium.

At the same time, it inhibits activation of NF-κB and HDAC enzymes, reducing production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. In practice, this means reduced inflammatory signaling that could otherwise promote histamine release.

Both endogenous butyrate and supplementation with sodium butyrate — especially in microencapsulated forms — may support the restoration of the intestinal barrier.

Butyrate does not act in a single dimension. It simultaneously influences the microbial environment, epithelial integrity, and immune signaling — key elements that largely determine the total histamine burden.

It is also worth mentioning a study conducted in patients with inflammatory bowel disease (IBD), in which oral microencapsulated sodium butyrate was administered at a dose of 1800 mg per day for 60 days (9). Compared with placebo, supplementation promoted the growth of short-chain fatty acid-producing bacteria — with increased Lachnospiraceae observed in patients with ulcerative colitis and increased Butyricicoccus in patients with Crohn’s disease.

Although the study involved patients with IBD, its implications extend beyond that condition. It suggests that sodium butyrate supplementation may not only directly influence the intestinal epithelium but also shift the microbiota toward a more butyrogenic, anti-inflammatory profile. In the context of histamine intolerance, this may support the intestinal environment in a way that both strengthens the barrier and reduces inflammatory signaling.

In practice, however, it is worth remembering that in some individuals — particularly those with constipation-predominant symptoms — sodium butyrate supplementation may initially worsen symptoms. In such cases it is often better to start with small doses taken every few days and gradually increase frequency depending on tolerance.

Zinc and Intestinal Barrier Function

The integrity of the intestinal barrier depends not only on microbial metabolites but also on adequate levels of key micronutrients. One of the most important is zinc.

In a review article published this year on the role of zinc in the gut–liver axis, the authors emphasize that this element plays a crucial role in maintaining intestinal barrier integrity, regulating immune responses, and controlling inflammation (10). Zinc supports both defensive mechanisms and repair processes, helping prevent the transition from acute inflammation to chronic inflammatory states.

At the structural level, zinc:

• helps maintain the proper structure and function of epithelial cell membranes,

• supports tight junction integrity,

• influences expression of proteins such as occludin and claudins.

Zinc deficiency is associated with increased nitric oxide production and enhanced oxidative stress, which may lead to increased barrier permeability, a higher risk of bacterial translocation, and greater susceptibility to infections and diarrhea. Both the structure and function of epithelial cells and their intercellular junctions become disrupted.

In the context of histamine intolerance, this becomes particularly important. A weakened barrier facilitates the passage of histamine and other inflammatory mediators into the circulation, while chronic immune activation may further promote histamine release from mast cells. Supporting zinc status therefore becomes part of regulating not only the barrier but the entire gut–liver–immune axis.

It is also worth remembering that high doses of zinc may interfere with the absorption of other minerals, including copper, iron, calcium, magnesium, manganese, and selenium — with the strongest interactions observed for copper and iron. For this reason, in my practice I often begin supplementation with moderate doses, typically around 10–20 mg per day, and only later consider increasing the dose if needed. For many individuals, zinc glycinate is a well-tolerated form.

DAO Activity and Histamine Degradation in the Gut

In this context it is important to remember that DAO activity does not operate in isolation. As discussed in the first part of this series, reduced DAO activity is often secondary — accompanying impaired barrier integrity, chronic inflammatory activation, or changes in microbiota composition.

Reduced mucin synthesis, increased intestinal permeability, or persistent inflammatory signaling may limit the effectiveness of local histamine degradation. Experimental data also suggest that certain bacterial strains may modulate DAO secretion by epithelial cells, further emphasizing that this enzyme functions within a broader regulatory system (11).

From this perspective, DAO supplementation may reduce symptom severity in selected individuals, but it does not replace interventions aimed at restoring the intestinal barrier and stabilizing the microbial environment. These elements largely determine whether the total histamine burden exceeds the body’s capacity for degradation.

Why Histamine Regulation Strategies Often Work Best in Combination

For clarity, the individual elements have been presented separately. In practice, however, they rarely function as completely independent stages of intervention. Many strategies influence several regulatory layers at the same time and in many cases can be implemented in parallel.

In many situations it may be beneficial to apply several strategies simultaneously — for example a low FODMAP diet, Saccharomyces boulardii CNCM I-745, cranberry extract, or sodium butyrate. In some cases this approach may also include strategies aimed at regulating mast cell activity, such as palmitoylethanolamide (PEA), which I will discuss in detail in the next part of the series.

Such an approach may support faster stabilization of the intestinal environment. Using these strategies together may also provide an additional advantage. Some interventions — such as the low FODMAP diet — reduce fermentation and improve symptoms in the short term, but may simultaneously lead to a temporary reduction in short-chain fatty acid production. Introducing parallel strategies that support the intestinal environment — such as butyrate, Saccharomyces boulardii CNCM I-745, or cranberry extract — may help mitigate this effect.

The goal, therefore, is not to follow a rigid sequence of steps but to gradually restore stability across the entire regulatory system.

In the next part of the series, I will present strategies aimed at stabilizing the environment of the large intestine and regulating mast cell activity.

Histamine Intolerance Series:

Part 1 — When Histamine Is Produced Inside the Gut
Part 2 — SIBO, Methane and Fungal Overgrowth
Part 3 — Rebalancing the Gut Environment
Part 4 — Stabilizing the Histamine Regulatory System

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This is Part 2 of the histamine intolerance series.
If you’d like the full background, you can start with Part 1:
Histamine Intolerance: When Histamine Is Produced Inside the Gut

In Part 1, I examined how the intestinal environment — both in the colon and the small intestine — can influence total histamine burden. I discussed bacterial histamine production, intestinal barrier integrity, and diamine oxidase (DAO) activity as components of the same regulatory system.

In this part, I expand that perspective by focusing more closely on the small intestine and on microbial interactions that extend beyond the classical understanding of SIBO. Histamine production is rarely the result of a single factor. More often, it reflects a broader dysbiotic pattern involving fermenting bacteria, methanogens, sulfur-reducing bacteria, and — often overlooked — opportunistic fungi.

Under physiological conditions, the small intestine contains a relatively low density of microorganisms and operates within a tightly regulated environment. This is not accidental but regulatory by design. Digestion and nutrient absorption require controlled microbial density, and disruption of this balance affects both metabolism and immune responses.

Small intestinal bacterial overgrowth (SIBO), intestinal methanogen overgrowth (IMO — excess methane production), and intestinal sulfide overproduction (ISO — excess hydrogen sulfide production) alter the local intestinal environment. In certain contexts, similar shifts may also involve a fungal component.

It is useful to view these phenomena as parts of a single regulatory network influencing both histamine production and histamine handling.

SIBO and Histamine Production — Selective Dominance Rather Than Random Migration

For years, SIBO was described as a simple migration of colonic bacteria into the small intestine. However, a recent study using next-generation sequencing techniques demonstrated that the picture is far more specific.

In individuals with SIBO, the microbial pattern is not random. As bacterial density increases, microbial diversity decreases, and the small intestinal environment becomes increasingly dominated by a narrow group of organisms.

In one analysis, just two dominant strains of Escherichia coli and two species of Klebsiella accounted for more than 40% of the total duodenal microbiota in individuals with SIBO (1).

This is not a random “transfer of flora.” It is selective dominance of specific bacteria.

Both belong to the phylum Proteobacteria — a group that typically represents only a small fraction of the gut microbiota under physiological conditions. Their expansion is associated with reduced diversity, disrupted microbial networks, and intensified fermentative pathways.

In practical terms, this has several consequences:

• increased fermentation of carbohydrate substrates,

• increased hydrogen production,

• increased amino acid metabolism, including histidine — the precursor of histamine.

In such an environment, the potential for increased histamine production rises, which in some individuals may worsen histamine intolerance symptoms. At the same time, dominance of Proteobacteria promotes inflammatory signaling that may secondarily affect small-intestinal barrier integrity and DAO activity.

The result is not only greater histamine production but also altered local neutralization and increased potential translocation into the circulation.

The Endotoxin (LPS) Component

It is also important to recognize that both E. coli and Klebsiella are Gram-negative bacteria whose outer membrane contains lipopolysaccharide (LPS).

An increased proportion of Proteobacteria therefore implies not only altered fermentation but also potentially higher local endotoxin burden.

In the context of impaired small-intestinal barrier integrity, LPS may:

• activate Toll-like receptor 4 (TLR4),

• sustain low-grade inflammation,

• secondarily influence mast cell activity and histamine metabolism.

This means that in SIBO, the issue is not purely fermentative. The entire small-intestinal environment undergoes transformation.

IMO (Excess Methane) — Constipation and Intensified Histamine Symptoms

Methane (CH₄) has long been included in breath testing alongside hydrogen. Over time, it became clear that methane is not merely a fermentation marker but is associated with a distinct clinical profile — primarily constipation.

Methane is produced by methanogens that utilize hydrogen (H₂) to generate CH₄. The best-characterized species is Methanobrevibacter smithii. Its abundance correlates with both breath methane levels and the severity of constipation (2).

Importantly, methanogens are not confined to the colon. They have also been identified in the small intestine, where localized microenvironments with lower oxygen concentrations may allow their colonization.

Methane may:

• slow intestinal transit,

• increase intestinal muscle contractility,

• prolong stool retention time (3).

Slower transit means prolonged contact between microbes and substrates, increasing the potential accumulation of biogenic amines, including histamine. During such periods, histamine-related symptoms may intensify.

The standard recommendation to increase fiber intake for constipation often fails in patients with IMO. In some cases, it may even worsen bloating, fullness, and transit delay. For this reason, in my clinical practice I typically recommend only moderate fiber intake from sources low in FODMAPs (fermentable oligo-, di-, monosaccharides and polyols) for individuals with methane overproduction.

ISO (Excess Hydrogen Sulfide) — Inflammation and Barrier Integrity

There is growing discussion of intestinal sulfide overproduction (ISO), meaning excess hydrogen sulfide (H₂S) production in the small intestine and/or colon.

Elevated H₂S levels in breath testing, in the context of the small intestine, correlate among other factors with the presence of Proteus mirabilis. This bacterium has also been identified in research on histamine intolerance as a potential histamine producer, and in one study its relative abundance decreased during a low-histamine diet (4).

In the colon, major hydrogen sulfide producers include bacteria from the genera Desulfovibrio and Fusobacterium (3).

Clinically, higher H₂S levels correlate primarily with diarrhea and abdominal pain (2).

However, the significance of hydrogen sulfide extends beyond fermentation. H₂S has biphasic effects: in low concentrations it may exert protective functions; in higher concentrations it can promote oxidative stress and cellular injury. Its impact depends on local concentration, duration of exposure, and the surrounding microbial and inflammatory context (5).

Sulfur metabolism in the gut is complex and influenced by both bacterial factors and host regulatory mechanisms. Although experimental models suggest that certain sulfur metabolites may affect immune cells, including mast cells, the precise relevance of these interactions in histamine intolerance remains unclear (6).

From this perspective, ISO may not be a direct source of histamine but rather a component of a microbial environment that modifies inflammatory signaling and barrier integrity.

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Fungal Overgrowth and Small Intestinal Fungal Overgrowth (SIFO) in Histamine Intolerance

So far, I have focused primarily on bacterial and methanogen-driven mechanisms influencing the intestinal environment. However, it is important to broaden the perspective to another component of the micro-ecosystem — fungi. Their overgrowth may further modulate histamine metabolism and intensify environmental imbalance.

Bacteria–Fungi Interactions in a Pro-Inflammatory Environment

Studies examining so-called histamine-producing flora have shown that excess histamine-producing bacteria often coexist with overgrowth of opportunistic fungi such as:

• Candida albicans,

• other Candida species,

• Geotrichum spp.,

• selected molds.

This indicates that increased histamine production is rarely an isolated phenomenon. More commonly, it is part of a broader dysbiotic pattern involving:

• expansion of amine-producing bacteria, including histamine producers,

• reduction of acid-producing bacteria such as Lactobacillus and Bifidobacterium,

• alkalinization of intestinal contents,

• concurrent overgrowth of opportunistic fungi.

Changes in acid–base balance play a significant role. Reduced production of organic acids (lactic, acetic, propionic) favors expansion of proteolytic bacteria and amine-producing microorganisms. Fungal overgrowth may further amplify this shift through production of alkalinizing metabolites and competition with protective bacteria (7).

Candida and Mast Cell Activation

Candida is not merely a passive participant in environmental shifts. It has been shown to produce alcohol and glycoproteins capable of stimulating mast cells to release inflammatory mediators, including histamine and prostaglandins.

In addition, Candida produces proteases that degrade secretory IgA — an antibody crucial for mucosal protection. Disruption of this immune barrier may promote chronic inflammation, increased permeability, and secondary mast cell activation (8).

In this setting, excess histamine does not have to result solely from bacterial production. It may also arise from intensified mast cell-mediated histamine release in response to fungal factors.

SIFO — The Small Intestinal Context

In recent years, small intestinal fungal overgrowth (SIFO) has been increasingly described. In two studies involving participants with unexplained gastrointestinal symptoms, SIFO was identified in approximately 25% of cases.

The most common symptoms included:

• bloating,

• belching,

• indigestion,

• nausea,

• diarrhea,

• excessive gas production.

Predisposing mechanisms are not fully clarified but may involve:

• impaired small-intestinal motility,

• use of proton pump inhibitors,

• prior antibiotic exposure (9).

This suggests that the small intestine may serve not only as a site of bacterial but also fungal modulation of the histamine environment. In this context, fungal overgrowth is not a separate entity but part of a broader dysbiotic network in which bacteria and fungi jointly shape conditions favoring histamine production and release.

Broader Clinical Context

Histaminogenic dysbiosis — involving excess histamine-producing bacteria together with Candida albicans overgrowth — has been described, among others, in women with irritable bowel syndrome (IBS) and recurrent lower urinary tract infections. This pattern also included reduced levels of Lactobacillus and Bifidobacterium (7). It is worth noting that this study did not directly measure histamine or DAO levels and relied on culture-based microbiota assessment, which captures only the cultivable fraction of the microbial community.

This picture suggests that excess histamine may represent one element of a complex disruption of the gut ecosystem, involving:

• proteolytic bacteria,

• opportunistic fungi,

• disturbed acid–base balance,

• weakened mucosal barrier function.

Fungal overgrowth fits within this same disrupted network of microbial interdependencies.

Histamine Intolerance as an Environmental Gut Disorder

Small intestinal bacterial overgrowth, methane-associated fermentation shifts, hydrogen sulfide excess, and concurrent fungal dysbiosis do not operate in isolation. They create an environment in which histamine production, release, and degradation follow different rules than under physiological conditions.

Microbial composition changes. Transit dynamics change. Local immune signaling and barrier integrity change.

Not every individual presents with all of these elements simultaneously. In some, fermentative processes dominate; in others, motility disturbances; in others still, chronic immune activation or fungal overgrowth. However, when several of these layers overlap, the clinical picture becomes more complex and less predictable.

In this context, a low-histamine diet and DAO support may reduce histamine intolerance symptoms, but for most individuals they do not provide a lasting solution. The key lies in identifying which regulatory levels are disrupted and in what direction the intestinal environment has shifted.

In the next part, I will move from mechanisms to practice. I will outline specific strategies aimed at reducing histamine production in both the small intestine and colon, improving barrier function, and modulating the microbial environment. I will also explain why certain popular interventions — despite short-term improvement — may not support long-term stabilization of the intestinal ecosystem.

Histamine Intolerance Series:

Part 1 — When Histamine Is Produced Inside the Gut
Part 2 — SIBO, Methane and Fungal Overgrowth
Part 3 — Rebalancing the Gut Environment
Part 4 — Stabilizing the Histamine Regulatory System

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Histamine Intolerance: Is It Only About Diet and DAO?

Histamine intolerance is most often described in relatively simple terms: either dietary intake exceeds individual tolerance, or the body’s capacity to degrade histamine — particularly via diamine oxidase (DAO) — is insufficient.

In my clinical practice, this framework is frequently helpful. Reducing foods especially rich in histamine often leads to meaningful symptom relief. In some patients, DAO supplementation provides additional support and further improves tolerance.

At the same time, the response is not always uniform. I occasionally work with individuals who require a very restrictive low-histamine diet to achieve stability, and even then certain symptoms may persist in a milder form. In other cases, DAO supplementation brings clear improvement, while in some patients its effects are less noticeable.

These patterns suggest that dietary intake and enzymatic degradation are important components of the picture — but they may not fully account for total histamine burden.

Histamine is not only ingested. It is also produced locally within the gut by host cells and by specific members of the microbiota. Its metabolism depends not only on DAO activity in isolation, but on the broader intestinal environment, including barrier integrity, inflammatory tone, and microbial composition.

When these regulatory layers shift, overall histamine load may reflect the combined effect of dietary input and endogenous production.

In this article, I explore how histamine generated within the gut may contribute to symptom patterns and how this internal source interacts with dietary exposure.

Histamine Intolerance Symptoms Across Multiple Systems

Histamine intolerance rarely presents as a single isolated complaint.

Symptoms often span multiple systems, including:

• bloating and abdominal pain,

• postprandial fullness,

• diarrhea or constipation,

• nasal congestion or rhinorrhea,

• itchy, watery eyes,

• flushing, itching, or skin redness.

Additional symptoms may include:

• painful menstruation,

• palpitations,

• dizziness,

• headaches, particularly migraines (1).

A characteristic feature is the coexistence of multiple symptoms — often fluctuating in intensity and not always predictably tied to a specific food. This variability is one of the reasons why histamine intolerance symptoms are often interpreted in isolation rather than as part of a broader regulatory pattern.

DAO (Diamine Oxidase) and Histamine: Part of a Regulatory Environment

DAO is often viewed as a fixed, genetically determined enzyme. In practice, its activity is strongly influenced by the condition of the intestinal mucosa.

When the gut barrier is compromised, mucosal inflammation persists, or microbial composition becomes altered, DAO activity may decline secondarily.

One study suggested that lower abundance of Prevotellaceae may be associated with reduced mucin synthesis, increased intestinal permeability, and sustained inflammatory activation. In such an environment, DAO efficiency may be limited (2).

Some data suggest that certain bacterial strains can also influence DAO secretion. For example, in an in vitro model of the intestinal barrier, Lactiplantibacillus plantarum LP115 increased DAO secretion by epithelial cells (3). These findings require further clinical validation, but they suggest that DAO functions within a broader regulatory system.

From this perspective, DAO supplementation may reduce symptom burden in selected individuals. However, it does not necessarily explain why histamine load exceeds degradative capacity in the first place.

Dietary Histamine and Other Biogenic Amines

The classical approach focuses on limiting dietary histamine.

High levels are found in:

• aged meats,

• aged cheeses,

• fermented soy products,

• sauerkraut,

• wine,

• certain fresh and processed fish.

However, some foods trigger symptoms despite containing relatively low histamine levels. Other biogenic amines — such as putrescine, cadaverine, or tyramine — may compete for degradation pathways or indirectly potentiate histamine’s effects (4).

Following a low-histamine diet often improves symptoms. In some individuals, however, the response is partial or requires considerable dietary restriction to maintain stability.

This observation suggests that dietary exposure is important but may not be the sole determinant of total histamine burden.

Importantly, this does not diminish the value of dietary intervention. When endogenous production is elevated, reducing concentrated dietary sources can lower overall load and improve tolerance, particularly while underlying contributors are being addressed.

Histamine Produced by Gut Bacteria

Increasing evidence indicates that histamine can be produced directly by gut bacteria.

Studies comparing individuals with histamine intolerance to controls have identified recurring microbial patterns. Patients tend to show:

• reduced abundance of bacteria associated with gut health (Prevotellaceae, Ruminococcus, Faecalibacterium, Faecalibacterium prausnitzii),

• increased abundance of histamine-producing bacteria (e.g., Staphylococcus, Proteus, Clostridium perfringens, Enterococcus faecalis) (2).

This pattern reflects both weakened protective functions and increased local histamine-producing potential.

In another study, a nine-month dietary intervention in women with histamine intolerance was associated with measurable shifts in gut microbiota composition. A reduction in the relative abundance of several histamine-producing bacteria — including members of the Pseudomonadaceae family, Proteus species (including Proteus mirabilis), and Raoultella — was observed during dietary treatment.

At the same time, the abundance of Roseburia spp. increased — a genus commonly associated with short-chain fatty acid production and improved mucosal environment.

These findings suggest that dietary management may influence not only exogenous histamine exposure but also the microbial environment that shapes endogenous histamine production (5).

Taken together, these findings support the view that histamine intolerance may reflect a dynamic interaction between dietary exposure, microbial composition, and mucosal function rather than a single isolated defect.

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Histamine Production in the Colon and Its Potential Effects

The colon is a major site of microbial metabolism and therefore an important location for the production of biogenic amines, including histamine.

Under physiological conditions, saccharolytic fermentation predominates in the colon. Carbohydrates are metabolized into short-chain fatty acids (SCFAs), such as butyrate, which help maintain an acidic luminal environment, support epithelial integrity, and modulate local immune tone.

When SCFA production declines — due to dysbiosis, dietary patterns, or chronic inflammation — the metabolic profile of the colon may shift toward increased protein fermentation.

This shift may involve:

• greater availability of free amino acids, including histidine,

• increased bacterial conversion of amino acids into biogenic amines,

• increased local production of biogenic amines, including histamine.

Such metabolic patterns have been described in inflammatory bowel disease, but similar mechanisms may also occur in other states characterized by barrier dysfunction or altered microbial ecology (6).

Histamine produced in the colon may exert primarily local effects, contributing to diarrhea, urgency, abdominal discomfort, or mucus production. When barrier integrity is compromised or inflammatory activity is increased, a portion of locally generated histamine may also enter the circulation and contribute to extraintestinal symptoms.

From a clinical perspective, the colon represents an important intestinal site where histamine production, barrier function, and degradation capacity interact to shape overall histamine burden.

Histamine Intolerance and Irritable Bowel Syndrome (IBS)

Histamine appears to play a role in at least a subset of patients with irritable bowel syndrome.

It influences key processes involved in IBS symptoms, including:

• gut motility,

• visceral sensitivity,

• local immune signaling.

In some patients, elevated histamine levels have been detected in intestinal tissue, often alongside increased mast cell activity near enteric nerves. This may contribute to abdominal pain and heightened sensitivity.

Many individuals with IBS also report symptom worsening after consuming histamine-rich or histamine-releasing foods. In addition, alterations in gut bacteria that can produce histamine have been described in these patients (7, 8)

Not every case of IBS is histamine-related. However, in certain individuals, histamine may amplify an already sensitive intestinal environment.

DAO in the Context of IBS

Given the evidence that histamine may contribute to symptom generation in IBS, reduced degradation capacity has been proposed as one possible factor.

DAO is one of the main enzymes responsible for breaking down luminal histamine in the gut. Reduced DAO activity may allow histamine to accumulate locally, potentially intensifying symptoms such as abdominal pain, bloating, or diarrhea in susceptible individuals.

Several studies have reported associations between higher histamine levels, lower DAO activity, and greater symptom severity in IBS. For this reason, DAO supplementation has been explored as a supportive strategy in selected patients (8).

At the same time, an important question remains:

In IBS, does reduced DAO represent a primary abnormality — or a relative limitation in the face of increased histamine production?

If histamine generation is amplified — whether through mast cell activation or microbial metabolism — even physiologically normal DAO activity may become insufficient. In such cases, symptoms may reflect an imbalance between production and degradation rather than a single enzymatic defect.

SIBO and Histamine: An Additional Site of Production

The colon is not the only intestinal segment where microbial histamine production may become clinically relevant.

Under physiological conditions, the small intestine contains relatively low bacterial density. When small intestinal bacterial overgrowth (SIBO) develops, bacterial metabolism expands into a region optimized for digestion and absorption.

In this setting, the small intestine becomes an additional site of histamine production.

In many cases of SIBO, the local environment of the small intestine is altered. Increased bacterial density may coexist with low-grade inflammation, impaired barrier integrity, reduced DAO activity, and altered motility. Together, these factors may influence both histamine generation and its local handling.

As with the colon, the clinical relevance of histamine produced in the small intestine depends on context — including the degree of barrier disruption, inflammatory activation, and overall degradative capacity.

Rather than representing a separate mechanism, SIBO can be understood as another component within the broader network regulating histamine burden across different segments of the gut.

Histamine Intolerance Series:

Part 1 — When Histamine Is Produced Inside the Gut
Part 2 — SIBO, Methane and Fungal Overgrowth
Part 3 — Rebalancing the Gut Environment
Part 4 — Stabilizing the Histamine Regulatory System

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Low testosterone is commonly approached as a primary hormonal disorder. In clinical practice, however, it often coexists with broader metabolic and gastrointestinal patterns.

Men presenting with reduced testosterone frequently also report:

• digestive symptoms,

• insulin resistance,

• central adiposity,

• chronic low-grade inflammation.

These constellations do not always fit neatly into a purely endocrine framework. In some cases, the question is not only how to correct testosterone levels, but whether low testosterone may reflect upstream dysregulation involving metabolic and immune signaling.

One framework that attempts to answer this is the GELDING hypothesis (Gut Endotoxin Leading to a Decline in Gonadal Function) (1). It proposes that chronic exposure to gut-derived endotoxins may gradually suppress gonadal function through disrupted metabolic signaling and sustained immune activation — without requiring primary damage to the testes or pituitary gland.

The GELDING hypothesis does not replace classical endocrinology, nor does it claim to explain every case of androgen deficiency.

Instead, it shifts attention upstream:

• gut function,

• liver metabolism,

• immune signaling,

• and the regulatory networks shaping hormonal output.

In the sections that follow, I outline:

• what metabolic endotoxemia is,

• how it may influence the hypothalamic–pituitary–gonadal (HPG) axis,

• and which strategies may help reduce its impact in selected patients.

What Is Metabolic Endotoxemia?

Endotoxemia refers to the presence of lipopolysaccharides (LPS) — components of the outer membrane of Gram-negative bacteria — in the systemic circulation.

In contrast to the acute endotoxemia observed in sepsis, metabolic and hormonal disorders are typically associated with chronic, low-grade endotoxemia. This state is characterized by modest but persistent elevations of circulating LPS that do not trigger an overt inflammatory crisis, yet sustain activation of pro-inflammatory signaling pathways, particularly via Toll-like receptor 4 (TLR4).

Distinguishing acute infection from chronic low-grade endotoxemia is essential, as their physiological and hormonal consequences differ substantially.

Where Does Gut-Derived LPS Come From?

LPS are integral components of the outer membrane of Gram-negative bacteria that physiologically reside within the intestinal lumen.

Under normal conditions:

• the gut barrier limits their translocation into circulation,

• small amounts that cross are largely neutralized by the liver.

Problems arise when:

• luminal LPS quantities increase,

• gut barrier integrity is compromised,

• hepatic detoxification mechanisms are impaired.

When endotoxin exposure exceeds the body’s compensatory capacity, persistent circulation of LPS may occur.

When Does Gut-Derived LPS Enter the Circulation?

Overweight and Obesity

In individuals with overweight or obesity, elevated plasma LPS levels have been repeatedly observed and are often accompanied by alterations in gut microbiota composition. Chronic low-grade inflammation within adipose tissue and insulin resistance may further impair gut barrier function, amplifying endotoxin translocation.

Increased Intestinal Permeability

Gut barrier integrity depends on:

• proper tight junction function,

• continuous epithelial renewal,

• balanced local immune regulation.

Factors such as:

• chronic inflammation,

• metabolic stress,

• short-chain fatty acid deficiency,

• exposure to certain medications

can disrupt this system. When this occurs, LPS more readily enter the portal circulation, increasing hepatic burden and reinforcing systemic inflammatory activation.

Dysbiosis With Gram-Negative Predominance

The composition of the gut microbiota strongly influences the amount of LPS present in the intestinal lumen.

Dysbiosis characterized by relative expansion of Gram-negative bacteria:

• increases luminal LPS load,

• reduces butyrate-producing bacteria,

• weakens barrier integrity.

From this perspective, endotoxemia reflects not only barrier dysfunction but also shifts in microbial ecology.

SIBO

Small intestinal bacterial overgrowth (SIBO) represents a distinct clinical scenario in which bacteria — often Gram-negative — colonize segments of the gastrointestinal tract normally dedicated to digestion and absorption.

The presence of LPS in close proximity to the small intestinal epithelium, combined with impaired motility, may substantially increase the risk of endotoxin entry into the circulation.

Across these conditions, the common denominator is not bacterial presence per se, but an altered relationship between:

• the microbiota,

• the gut barrier,

• and host regulatory mechanisms.

The Liver as a Metabolic Bottleneck in the GELDING Hypothesis

Venous blood draining from the intestines enters the portal circulation and passes first through the liver, where potentially harmful molecules — including bacterial endotoxins — are neutralized.

Under physiological conditions, even small amounts of LPS crossing the gut barrier are efficiently captured and detoxified by Kupffer cells and hepatocytes, preventing systemic dissemination.

How Chronic Endotoxemia Disrupts Hepatic Function

Problems arise when the quantity of LPS reaching the liver exceeds its detoxification capacity.

This may result from:

• increased gut translocation,

• impaired liver function,

• or both.

Chronic LPS exposure activates Kupffer cells via TLR4, triggering NF-κB–dependent signaling and the production of pro-inflammatory cytokines such as:

• TNF-α,

• IL-1β,

• IL-6.

While protective in the short term, persistent activation promotes chronic inflammation and disrupts hepatic metabolism.

What Happens When the Liver Stays Inflamed?

Sustained inflammatory activation within the liver leads to:

• hepatic insulin resistance with impaired glycemic control,

• disturbances in lipid metabolism promoting steatosis,

• reduced capacity to neutralize subsequent endotoxin exposure,

• altered synthesis of liver-derived proteins, including sex hormone-binding globulin (SHBG).

In the GELDING model, the liver is not a passive conduit. Declining liver function amplifies endotoxemia. Rising endotoxemia further impairs liver function. This feedback loop may explain why purely hormonal correction sometimes fails to deliver lasting results when metabolic and inflammatory context is not addressed.

Implications for the Hypothalamic–Pituitary–Gonadal (HPG) Axis

Although the GELDING hypothesis centers on gonadal function, the liver plays a critical intermediary role.

Chronic hepatic inflammation and insulin resistance can modulate hormonal signaling at multiple levels:

• hormone bioavailability,

• HPG axis regulation,

• target tissue responsiveness.

Reduced testosterone may therefore represent one manifestation of broader systemic dysregulation, with the liver acting as a bottleneck.

Clinical and Experimental Evidence Linking Endotoxemia and Testosterone

In an observational study of 75 men aged 18–50 years — most overweight or obese — researchers examined relationships between anthropometric measures, endotoxin exposure, and sex hormone levels.

Positive correlations were observed between:

• BMI,

• body fat percentage,

• waist circumference,

• endotoxin exposure,

• inflammatory markers.

Endotoxin exposure was inversely correlated with total testosterone levels and positively correlated with inflammatory markers. No significant association was found between endotoxin exposure and calculated free testosterone.

An experimental study in 33 healthy, lean men evaluated acute endotoxin exposure through intravenous administration of Escherichia coli endotoxin. This resulted in:

• rapid elevations in IL-6 and TNF-α,

• approximately 30% reduction in total testosterone at six hours,

• no significant changes in LH or FSH.

Testosterone levels returned to baseline within 24 hours.

Together, these findings suggest that both chronic low-grade and acute endotoxin exposure may be associated with transient or sustained reductions in total testosterone.

How Endotoxins May Suppress Testosterone Production and Fertility

Leydig cells are essential for testosterone synthesis and regulation of spermatogenesis.

Animal studies indicate that endotoxin exposure:

• induces local inflammatory responses within the testes,

• disrupts steroidogenesis,

• impairs spermatogenesis.

Direct and Indirect Inhibition

Indirect mechanisms involve inflammatory cytokines inhibiting steroidogenic enzymes in Leydig cells.

Direct mechanisms include impairment of steroidogenic acute regulatory protein (StAR), which is essential for cholesterol transport into mitochondria — the rate-limiting step of steroidogenesis.

Effects on Spermatogenesis

Reduced intratesticular testosterone and sustained inflammation may impair Sertoli cell function, compromising sperm maturation and quality.

In this framework, endotoxemia influences fertility through multi-level modulation of hormonal, inflammatory, and metabolic environments.

Evolutionary Perspective: Adaptive Testosterone Suppression?

Some researchers propose that testosterone suppression during endotoxin exposure may represent an adaptive response during infection.

Testosterone has immunomodulatory properties. Temporary suppression during acute infection may enhance inflammatory defense.

In modern contexts of chronic low-grade endotoxemia, however, this once-adaptive mechanism may remain persistently engaged.

Clinical Implications for Low Testosterone and Metabolic Health

From this viewpoint, declining testosterone may represent an adaptive signal in a body under sustained metabolic and inflammatory stress.

As long as that background remains unchanged, attempts to forcibly elevate testosterone may conflict with prevailing regulatory logic.

If endotoxemia is upstream in this cascade, it becomes reasonable to ask which interventions effectively target this earlier layer.

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Strategies to Reduce Metabolic Endotoxemia

In clinical practice, numerous dietary and supplemental strategies are described as “endotoxemia-lowering.” Not all, however, offer comparable safety, tolerability, or predictability.

The approaches discussed below were selected because they combine biologically plausible mechanisms with a relatively low risk of adverse consequences.

Importantly, these interventions do not directly manipulate the hormonal axis.
They act upstream — on gut barrier integrity, microbiota composition, and immune signaling — making them a reasonable starting point when endotoxemia is suspected to contribute to the clinical picture.

Low-FODMAP Diet

A low-FODMAP diet — characterized by reduced intake of fermentable oligo-, di- and monosaccharides and polyols — may help reduce endotoxemia through several mechanisms:

• lowering fermentative burden and bacterial overgrowth in the gut,

• improving gut barrier integrity, particularly in patients with irritable bowel syndrome (IBS) and SIBO,

• reducing luminal Gram-negative bacterial load,

• decreasing mast cell activation and secondary release of inflammatory mediators, including histamine (2).

In many cases, restricting only those high-FODMAP foods that clearly exacerbate gastrointestinal symptoms is sufficient to modulate the gut environment without implementing a fully restrictive protocol.

In patients with IBS or SIBO, a more structured approach may be warranted for a limited period (typically 4–6 weeks), followed by gradual reintroduction to identify individually tolerated foods.

Clinically, the low-FODMAP diet is often combined — depending on dominant mechanisms — with additional strategies targeting the microbiota, gut barrier, and immune signaling, discussed below.

Probiotics

The effects of probiotics are highly strain-specific and should not be generalized across organisms within the same species.

Saccharomyces boulardii CNCM I-745

S. boulardii CNCM I-745 is a non-pathogenic probiotic yeast. In the context of endotoxemia, its relevant actions include:

• strengthening gut barrier integrity through effects on tight junctions,

• modulating mucosal immune responses,

• limiting adhesion and overgrowth of potentially pathogenic, including Gram-negative, bacteria (3).

This strain is among the most extensively studied probiotics in SIBO. In clinical trials involving patients with SIBO and diarrhea-predominant IBS, supplementation alongside dietary intervention resulted in greater reductions in breath hydrogen levels and more pronounced symptom improvement compared with diet alone (4).

Limosilactobacillus reuteri DSM 17938

L. reuteri DSM 17938 is a well-studied probiotic evaluated across diverse populations. In the context of endotoxemia, its actions include:

• immunomodulation with reductions in pro-inflammatory cytokines (e.g., IL-6, TNF-α),

• support of gut barrier function,

• improvement of microbiota balance,

• production of antimicrobial metabolites such as reuterin,

• enhancement of gastrointestinal motility (5).

Clinical data suggest its usefulness in SIBO, particularly when impaired motility or methane overproduction is present (intestinal methanogen overgrowth) (6). In children receiving proton pump inhibitors, supplementation has also been associated with reduced SIBO incidence (7).

Bifidobacterium longum subsp. longum BB536

This strain has been widely studied and used clinically for gastrointestinal disorders. Its relevant actions include:

• improving bowel regularity and colonic environment, especially in constipation,

• supporting beneficial bifidobacterial populations,

• limiting activity of potentially pathogenic Gram-negative bacteria,

• modulating bile acid metabolism,

• indirectly supporting short-chain fatty acid production through microbial cross-feeding (8).

Clinically, it is particularly useful in patients with constipation, dysbiosis, and gut-environment disturbances that may indirectly promote endotoxemia.

Acacia Fiber

Acacia fiber is a soluble, slowly fermentable fiber metabolized in the colon into short-chain fatty acids, including butyrate. Its potential role in reducing endotoxemia involves:

• supporting SCFA-producing bacteria,

• improving gut barrier function via SCFA signaling,

• modulating local intestinal immune responses,

• accelerating intestinal transit,

• indirectly reducing Gram-negative bacterial burden (9).

Because of its fermentation profile, acacia fiber is generally well tolerated, including by some patients with IBS or SIBO. In these groups, initiating supplementation with very small doses and gradual titration is advisable.

Clinically, acacia fiber may be particularly useful in individuals with overweight, obesity, and constipation, where metabolic endotoxemia is often pronounced.

Lactoferrin

Lactoferrin is an iron-binding protein with antimicrobial, immunomodulatory, and anti-inflammatory properties. In the context of endotoxemia, its actions may include:

• limiting the growth of selected Gram-negative bacteria,

• directly binding LPS and reducing its biological activity,

• modulating immune responses and reducing excessive cytokine production,

• supporting gut barrier integrity,

• attenuating excessive TLR4 activation (10, 11).

Through these mechanisms, lactoferrin may exert both local and systemic effects, particularly in states of heightened metabolic and inflammatory burden.

Conclusion

The GELDING hypothesis remains a working model. Its value lies not in providing universal algorithms, but in organizing relationships between:

• gut function,

• liver metabolism,

• chronic immune activation,

• hormonal regulation.

Low testosterone may not always represent primary endocrine pathology.

Sometimes it is a signal.

A signal that the organism is operating under sustained metabolic and inflammatory load.

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