The AMA is not, and never will be, a replacement for a consultation. I cannot and will not answer personal or individualized health questions. Where a question is specific to one person, I’ll answer the general version of it instead.

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Question 4: How long can dandelion root and yellow dock root be used regularly, particularly for chronic constipation?

Okay! I’ve been sitting on this question for a bit because I really wanted to dig into the research before answering it.

The original question was about the regular use of dandelion root (Taraxacum officinale) and yellow dock root (Rumex crispus) for chronic constipation, with the reader mentioning that she had heard dandelion wasn’t a “forever herb.”

Which immediately made me wonder...what exactly is a forever herb?

Because really, how long can we take an herb? We talk about some plants as being better suited for short-term use and others as being appropriate for longer periods, but I wanted to know what we actually have to support those recommendations for these two plants.

Okay, Let’s Start With Dandelion

Dandelion (Taraxacum officinale) has a pretty long history of use for digestive complaints, including constipation, dyspepsia, flatulence, and loss of appetite (Martinez et al., 2015). So, its appearance here isn’t strange at all. People have absolutely been using this plant for digestive purposes for a very long time.

When I started looking specifically for evidence supporting its use for constipation, though, things got thin pretty quickly.

A 2015 review of Taraxacum found plenty of traditional use, but the authors couldn’t find clinical studies establishing efficacy or dose-response relationships. They also noted that information on dosage, duration of use, and use in specific populations was unavailable (Martinez et al., 2015).

There is some newer research! A 2025 study found that T. officinale increased gastrointestinal motility and fecal output in rats, which sounds pretty relevant to our question (Ali et al., 2025).

Except...they weren’t studying dandelion root.

The researchers used the aerial parts of the plant, extracted with 70% methanol, and administered that extract to rats at doses of 10, 100, and 500 mg/kg (Ali et al., 2025). That gives us some interesting evidence that T. officinale can influence gastrointestinal motility, but we can’t take a methanolic extract of the aerial parts given to rats and use it as evidence for what happens when someone regularly drinks a decoction of dandelion root.

Different plant part. Different preparation. Different population.

So, while dandelion has a long history of digestive use, including for constipation, the research doesn’t give us a nice answer to our original question of how long dandelion root can be taken regularly. And that’s kind of the problem!

So, How Long Can We Take It?

The European Medicines Agency (EMA) has a monograph specifically for dandelion root, recognizing its traditional use for mild digestive complaints, temporary loss of appetite, and increasing urine output. Interestingly, constipation isn’t among the listed indications (EMA, 2022).

When it comes to duration, the EMA recommends consulting a doctor or qualified healthcare practitioner if symptoms persist for longer than two weeks while using dandelion root (EMA, 2022). I’ll admit, when I saw “two weeks,” my little research brain perked right up! Maybe this was where the idea that dandelion shouldn’t be used indefinitely came from?

Buuut monograph doesn’t establish two weeks as the maximum duration of use. The recommendation is about how long someone should continue self-treatment when their symptoms are persisting.

Also, the original AMA question involved a five-year-old, so of course I wanted to know what the monograph had to say about children:

The EMA states that dandelion root isn’t recommended for children under 12 because its use in this age group hasn’t been established due to a lack of adequate data (EMA, 2022).

So...where does that leave us?

We have a LONG history of traditional digestive use, some interesting preclinical research suggesting that T. officinale can influence gastrointestinal motility, and an EMA monograph giving us some guidance around duration of self-treatment. What I couldn’t find was good long-term data giving us a defined duration for regular use of dandelion root.

There’s another problem I have with the statement that “dandelion isn’t a forever herb.”

Which part of the dandelion are we talking about?

Because that isn’t specified. And if I had to make an herbalist/medically trained guess about what someone meant by that statement, my first thought would be the leaves and their action as a diuretic.

Dandelion leaf contains a relatively high amount of potassium, which often comes up when discussing its diuretic action. But I have questions!

1. How much potassium are we getting from the amount of dandelion leaf someone would realistically consume?

2. How much makes it into the preparation?

3. Is that amount enough to compensate for what may be lost through increased urination?

So, my best guess is that the “not a forever herb” thing may have originated from concerns about using dandelion leaf as a diuretic over a long period of time, specifically because of the potential for ongoing fluid loss.

That’s my interpretation, though! And this brings us right back to why plant part matters so much! SO MUCH!

I do not have a direct source for this image, but I wish I did! It’s wonderful!

What About Yellow Dock?

Yellow dock (Rumex crispus) has a long history of traditional use as a laxative, among several other uses (Qian et al., 2024). And unlike dandelion, we have something in its phytochemistry that gives us a little more to work with when we’re trying to understand that use: anthraquinones!

Researchers have identified several anthraquinones in yellow dock root, including emodin, chrysophanol, physcion, rhein, and aloe-emodin (Eom et al., 2020). You may recognize that group of compounds from some of our much more familiar stimulant laxative herbs, which makes their presence in a traditionally laxative plant pretty interesting.

There’s a catch, though. (Why is there always a catch?) How much of those anthraquinones researchers found depended quite a bit on the preparation method. Let me walk you through how:

In one study, researchers first extracted dried yellow dock root with ethanol. They then suspended that extract in water and separated it using n-hexane, dichloromethane, ethyl acetate, n-butanol, and finally water (Eom et al., 2020). Those became the different “fractions” they analyzed.

Basically, they were taking one big extract and separating its compounds into smaller groups based on their chemical properties and which solvents they were more likely to dissolve into.

This let the researchers see that the anthraquinones weren’t distributed evenly across all of those fractions.

And they REALLY weren’t, like really were NOT.

The dichloromethane fraction had the highest total anthraquinone content, followed by the n-hexane fraction, the original ethanol extract, ethyl acetate, and n-butanol. None of the five anthraquinones the researchers measured were detected in the aqueous fraction, though (Eom et al., 2020).

And since our original question was specifically about roots being boiled in water...THIS study doesn’t tell us what would end up in that decoction. Their aqueous fraction was the water-soluble portion left after starting with an ethanol extract and separating it with several other solvents.

They didn’t take yellow dock root, boil it in water the way someone would at home, and analyze the resulting tea.

Truthfully, I really couldn’t find a study that did. I’m not sure the research on a traditional yellow dock root decoction for constipation is out there yet. (If I’m wrong, please please please correct me and drop the study in the comments!) Science likes to make things a bit more complicated, unfortunatelyyyy.

Rumex crispus

But How Long Can You Use Yellow Dock?

This is one place where I did find a much more specific recommendation. YAY!

Ethnobotanist James A. Duke, a longtime USDA researcher and author of the Handbook of Medicinal Herbs, recommends using yellow dock for no longer than 8–10 days (Duke, 2002).

(A little honesty: before researching this article, I hadn’t come across Duke’s work before, but I’m glad I did!)

Duke describes the anthraquinones in yellow dock as laxative compounds that can irritate the gastrointestinal tract. He warns that overuse may cause abdominal cramping and diarrhea, while prolonged use may contribute to hypokalemia and electrolyte imbalance (Duke, 2002).

But I couldn’t find clinical research establishing that 8–10 day limit for yellow dock root. A recent review of R. crispus also calls for more research into its acute, subchronic, and chronic toxicity (Qian et al., 2024).

So, I’d treat 8–10 days as a short-term-use recommendation, rather than a safety cutoff that has been established in clinical research.

But What About the Constipation?

After ALL OF THAT, I personally wouldn’t choose either of these herbs as something to take every day indefinitely for chronic constipation.

With dandelion root, I couldn’t find evidence giving us a clear maximum duration of use. With yellow dock, we have an 8–10 day recommendation from Duke, but we’re missing the clinical research that would establish that as a specific safety cutoff.

For me, though, there’s a bigger issue with using either one as a daily strategy: the constipation is still chronic.

If someone needs an herb every day in order to have a bowel movement, I’d want to start paying attention to what might be contributing. I’d gently introduce more fiber, promote daily movement if they’re able, and start monitoring hydration because, plain and simple, half of us probably aren’t drinking enough water.

I’d definitely pay attention to diet, too! If you want to and you’re able, keeping a food journal for a little while can be really helpful. But you absolutely don’t need a spreadsheet documenting every bite of food you’ve ever eaten. If you can notice how you feel after certain foods, what seems to make constipation better or worse, or any patterns that keep popping up, that’s useful information too. I say that because I personally have an aversion to food journals, like, just let me eat?

And then I’d start asking some bigger questions:

1. Could a medication be contributing?

2. Is gut motility impaired?

3. Is there an underlying digestive issue?

4. Is something else going on that needs to be addressed?

I might also bring in a mucilage-containing herb supportively, just to make things a little more slippery in there and help things along while working on the larger picture. I wouldn’t expect that herb to fix the underlying cause either.

So, for chronic constipation, I’d be much more interested in figuring out why it keeps happening and supporting the things that can help bowel function along the way. The herbs can absolutely be part of that conversation, but I’d want to look at the whole picture, too.

And I guess this is also a small invitation into the kind of thinking I hope to encourage with this publication. It’s really easy to learn herbalism as a series of pairings: this symptom = this herb. Constipation? Find the constipation herbs. Trouble sleeping? Find the sleep herbs. Headache? Find the headache herbs.

Sometimes that can be useful! But I think we can dig deeper than that.

What is happening physiologically? What could be contributing to the symptom? What patterns are showing up around it? What can we support with food, movement, hydration, lifestyle, or other changes? And then, with that bigger picture in front of us, where might an herb fit?

That’s the kind of herbalism I want to teach here. I want us to zoom out, ask more questions, and understand what we’re trying to support before reaching for a plant.

Until next time,
— Agy | The Buffalo Herbalist

References:

Ali, H. Z., Ali, N., Nabi, M., Ali, M., & Jahan, S. (2025). Evaluation of the laxative effects of Taraxacum officinale using experimental animal models. Journal of Ethnopharmacology, 353, 120264. https://doi.org/10.1016/j.jep.2025.120264

Duke, J. A. (2002). Handbook of medicinal herbs (2nd ed.). CRC Press.

Eom, T., Kim, E., & Kim, J.-S. (2020). In vitro antioxidant, antiinflammation, and anticancer activities and anthraquinone content from Rumex crispus root extract and fractions. Antioxidants, 9(8), 726. https://doi.org/10.3390/antiox9080726

European Medicines Agency. (2022). European Union herbal monograph on Taraxacum officinale F.H. Wigg., radix (EMA/HMPC/475726/2020).

Martinez, M., Poirrier, P., Chamy, R., Prüfer, D., Schulze-Gronover, C., Jorquera, L., & Ruiz, G. (2015). Taraxacum officinale and related species—An ethnopharmacological review and its potential as a commercial medicinal plant. Journal of Ethnopharmacology, 169, 244–262. https://doi.org/10.1016/j.jep.2015.03.067

Qian, H., Jia, Y., Zheng, K., Li, C., Shao, J., Wang, J., Xu, H., & Zhou, X. (2024). Rumex crispus L.: A comprehensive review on botany, traditional uses, phytochemistry, pharmacology, and safety. International Immunopharmacology, 143, 113569. https://doi.org/10.1016/j.intimp.2024.113569

And don’t worry! We’re doing this in easy mode!

Alright, in this issue:

• What a virus actually is

• How a virus gets inside your cells

• Viral replication, easy mode

• Where we can interrupt that process

• Why calling an herb “antiviral” doesn’t actually tell us very much

• The Antiviral Herb Guide :)

  

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Okay, So What Is a Virus?

Viruses are strange little things. They aren’t cells, which means they’re built very differently from bacteria, fungi, or the cells that make up our own bodies. At their simplest, viruses carry genetic material, either DNA or RNA, tucked inside a protein shell called a capsid. Some have one more layer on the outside: the viral envelope (Kausar et al., 2021).

This is our cute little piece of stationery; except it’s actually a lipid membrane surrounding certain viruses!

Much of that membrane originally belonged to us. (which is crazy to think about!) Enveloped viruses pick it up from the host cell as newly formed viral particles leave, taking a portion of the cell membrane with them on the way out. Viral proteins embedded within that membrane can then help the virus recognize or interact with the next cells it encounters (Kausar et al., 2021).

Underneath all of that packaging is a pretty major limitation: a virus doesn’t really have everything it needs to reproduce independently. It needs a living host cell to copy its genetic material, make viral proteins, then assemble new viral particles. That dependence on a host is one of the defining features of viruses (Adeosun & Loots, 2024).

So, for something capable of causing this much trouble, a virus is surprisingly dependent on us, right?! Without a host cell to hijack, it can’t make more of itself.

Getting Into the Cell

Before a virus can use a cell to make more of itself, it has to get inside. That starts with attachment, when proteins on the surface of the virus bind to specific receptors on a host cell. Those receptors matter because viruses can’t necessarily infect every cell they encounter. The virus has to be able to recognize and bind to something on that particular cell first (Kausar et al., 2021).

Which, already, is a lot of work for something that can’t reproduce on its own.

Attachment gets the virus to the cell, but now it has to actually cross the membrane. Exactly how it manages that varies between viruses. Some enveloped viruses can fuse their own envelope with the host cell membrane, allowing their contents to enter the cell. Others use endocytosis, a completely normal cellular process where the membrane folds inward and brings material from outside the cell with it (Kausar et al., 2021). In that case, the virus is essentially taking advantage of something the cell already does.

Once inside, there’s still one more layer to deal with. The viral genetic material is tucked away inside its capsid, so that DNA or RNA needs to be released before it can actually be used. This is called uncoating. The capsid is broken apart or removed, leaving the viral genome accessible inside the host cell (Kausar et al., 2021).

So, our virus has now found a cell it can infect, attached itself, made it across the membrane, ditched its packaging, and deposited its genetic material inside.

All of that just to get through the front door. Jeez Louise.

SARS-CoV-2 virus entry into the cell

Viral Replication, Easy Mode

Okay, our virus is inside the cell, its genetic material is unpacked, so now we get to the whole reason it went through the trouble of getting in there in the first place. It needs to make more viruses!!

This can get complicated FAST because viruses don’t all replicate the same way. Some carry DNA, others carry RNA, plus there are different enzymes and strategies involved depending on the virus we’re talking about. We absolutely do not need all of that today, thankfully.

For easy mode, what matters is that the virus now has access to a living cell, along with all the cellular resources it was missing on its own.

The viral genome needs to be copied so every new virus gets its own set of genetic instructions. Viral proteins have to be produced too, since those will eventually become the structural pieces of new viral particles or carry out jobs the virus needs during replication. Viruses rely heavily on the host cell to make this happen, while some also bring or produce specialized enzymes of their own to complete particular steps (Kausar et al., 2021). Your cell, which was minding its own business moments ago, has essentially been recruited into manufacturing viruses, involuntarily. Rude.

Once enough copies of the genome and viral proteins have been made, those pieces can start coming together into new virus particles. Those newly assembled viruses eventually leave the cell, giving them the opportunity to find more susceptible cells and run the whole process again (Kausar et al., 2021).

So, viral replication on very easy mode:

Get inside → unpack → copy the genome → make viral proteins → assemble new viruses → get out.

There’s a tremendous amount of molecular biology stuffed into those six little steps, but that’s enough for what we need today :)

Steps in the viral replication cycle.

So, What Are We Trying to Stop?

Now that we have a virus successfully making copies of itself, we can look back at that whole process and see something useful: there are quite a few places where it could potentially be interrupted.

Depending on the virus, an antiviral might interfere with:

• Attachment and entry: The virus has to bind to a susceptible host cell before it can get inside. Interfering with that interaction can stop the infection process before the viral genome ever enters the cell.

• Uncoating: Once inside, the virus still has to release its genetic material from its protective capsid. Prevent that from happening and the genome stays packaged away instead of becoming available for replication.

• Genome replication: The viral DNA or RNA has to be copied to make new viruses. Some antivirals interfere with this process or with the viral enzymes required to carry it out (Kausar et al., 2021).

• Viral protein production and processing: A copied genome isn’t enough. The virus also needs proteins to build new viral particles or perform specific jobs during replication, which gives us another part of the process to interfere with (Kausar et al., 2021).

• Assembly and release: All of those newly made pieces still have to be assembled into complete virus particles, then successfully leave the cell. Interrupt either step or you can interfere with the virus spreading to more cells.

• The virus itself: Some substances demonstrate direct virucidal activity, meaning they act directly on virus particles. This is different from interfering with something the virus does once it has already entered a host cell (Adeosun & Loots, 2024).

• The host response: Not every antiviral effect has to involve attacking the virus directly. Some compounds influence cellular signaling or parts of the immune response involved in antiviral defense (Adeosun & Loots, 2024).

So, when we say something is “antiviral,” I don’t want you to automatically picture “supporting the immune system” or “stimulating immune function.” Those can absolutely be part of the picture, but now we know there are a whole lot of other places where a plant or one of its constituents might interfere with the process.

We can get way more specific than that!

When you’re choosing herbs or explaining their actions to someone else, you can talk about an extract interfering with viral attachment to a host cell. You can point to a constituent that inhibits an enzyme required for viral replication, or explain that an antiviral effect happens directly against the viral particle before it ever enters the cell.

Instead of stopping at, “this herb has antiviral activity,” you can actually say, “This plant has been studied for its ability to interfere with viral replication by inhibiting an enzyme the virus needs for that process.” 😎

Look at you talking mechanisms!

Now We Can Talk About the Plants

Okay! Finally, the herbs!

Plant extracts and their constituents have been studied at several points in the viral life cycle, including attachment and entry, replication, viral protein activity, cellular signaling, plus direct activity against the virus itself (Adeosun & Loots, 2024).

The research gets messy pretty quickly, though, because “plant” can mean a lot of different things in a paper. Sometimes researchers are testing a whole extract, while other studies pull out one constituent and test that on its own. There are cell studies, animal studies, computational models, plus some human research scattered throughout the literature. cue Agy’s head spinning. All of those can tell us something useful, but they aren’t giving us the same kind of evidence.

And when we’re looking at an isolated constituent, we have to be careful about how far we carry that finding. If a compound from a plant inhibits a viral enzyme in a cell study, we can’t automatically give that activity to every preparation of the whole herb. The concentration used in the study matters, the extraction matters, absorption matters, plus we have to account for what happens to that compound after we actually swallow it.

I know, I know. I sound like a broken record about this. Phytochemistry matters!

So I put everything into a guide for you:)

The Antiviral Herb Guide takes the mechanisms we just went through and organizes the plants around them, with the virus studied, what preparation or constituent was actually tested, plus the level of evidence behind it. I wanted something you could pull up when you see “antiviral” attached to an herb and actually figure out what that means.

So again: we’re getting REALLY specific here. This isn’t an exhaustive or complete guide by any means! It was created to give you a head start in understanding what to look for when you’re researching on your own.

Download it here:

If you enjoyed this free Field Notes and have been thinking about upgrading, this is a lovely time to join us. Your subscription gives you access to this guide, the rest of The Library, plus the paid deep dives!

And, of course, it helps fund my ongoing habit of opening a research paper because I had one small question and resurfacing several hours later with an entire PDF and/or article :) Whoops.

Until next time,
— Agy | The Buffalo Herbalist

PS: I’m going to be taking the time to update and revamp The Library this week and next as it’s very clearly been collecting a few cobwebs.

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References:

Adeosun, W. B., & Loots, D. T. (2024). Medicinal plants against viral infections: A review of metabolomics evidence for the antiviral properties and potentials in plant sources. Viruses, 16(2), 218. https://doi.org/10.3390/v16020218

Akbari, A., Bigham, A., Rahimkhoei, V., Sharifi, S., & Jabbari, E. (2022). Antiviral polymers: A review. Polymers, 14(9), 1634. https://doi.org/10.3390/polym14091634

Kausar, S., Khan, F. S., Rehman, M. I. M. U., Akram, M., Riaz, M., Rasool, G., Khan, A. H., Saleem, I., Shamim, S., & Malik, A. (2021). A review: Mechanism of action of antiviral drugs. International Journal of Immunopathology and Pharmacology, 35, 20587384211002621. https://doi.org/10.1177/20587384211002621

Melkikh, A. V. (2022). Viruses, immunity and evolution. Biosystems, 220, 104761. https://doi.org/10.1016/j.biosystems.2022.104761

Perera, W. P. R. T., Liyanage, J. A., Dissanayake, K. G. C., Gunathilaka, H., Weerakoon, W. M. T. D. N., Wanigasekara, D. N., Fernando, W. S. K., Rajapaksha, R. M. H., Liyanage, R. P., & Perera, B. T. (2021). Antiviral potential of selected medicinal herbs and their isolated natural products. BioMed Research International, 2021, 7872406. https://doi.org/10.1155/2021/7872406

Okay, first, let's get you familiar with the virus itself, and then we'll get into the fun stuff :) Well, its honestly all fun stuff in my opinion!

This was incredibly enlightening for me to research. All the dots seem to be there just STARING AT US, blinking in anticipation, but we’re just patiently waiting for science to find the lines to connect them all.

ALSO don’t forget to grab your notebooks and be prepared to come back to this a few times. It’s a bit dense, but I didn’t want to leave anything out. :)

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What Is EBV?

If you’re an adult reading this, there’s a very good chance EBV is already living in your body right now (kind of a wild thing to sit with, honestly). It infects somewhere around 90 to 95% of adults worldwide (Shabnam and Khan, 2026), making it one of the most common viruses on the planet!

EBV is a member of the herpesvirus family, technically classified as a B-lymphotropic gammaherpesvirus, or human herpesvirus 4 (HHV-4) if you want the formal, fancy name (Shabnam and Khan, 2026). Most of us pick it up in early childhood, and childhood infection is usually so mild it comes and goes without anyone noticing. No fever, no drama, nothing. In adolescence, though, first exposure carries much higher odds of actually making you sick. Around 30 to 70% of teens and young adults infected for the first time develop infectious mononucleosis (Draborg et al., 2013), the “kissing disease” most of us have at least heard of by name (Shabnam and Khan, 2026).

How It Gets In

EBV’s main route in is saliva, which is why infectious mononucleosis earned the “kissing disease” nickname. The virus enters through the oropharynx, the back of your throat, and works its way into the surrounding tissue before finding its real target: B cells, the immune system’s antibody factories (Draborg et al., 2013). Saliva isn’t the only way in, though. Sexual contact, organ transplantation, and blood transfusion can all transmit EBV as well (Shabnam and Khan, 2026), so this isn’t purely a childhood-cooties situation.

But once it reaches a B cell, EBV stops behaving like the virus you’d probably picture in your head.

dramatic pause for effect

Model illustrating the infection of EBV in human.

How It Hides

Once inside of us, EBV has two very different ways it can behave. It can enter an active, or lytic, cycle, where it uses the infected cell to produce new copies of the virus that can go on to infect other cells. But EBV can also do something that explains how an infection you picked up as a kid can still be hanging around decades later: it can go latent.

During latency, the viral genome literally curls itself into a loop, forming a circular piece of DNA called an episome that sits inside the nucleus of the B cell, separate from your own chromosomes. Then EBV starts shutting things down. Depending on the stage of latency, most of its genes get switched off, and in resting memory B cells, viral protein production can become extremely limited or even undetectable (Draborg et al., 2013). SO! Now you’ve got a B cell carrying the entire EBV genome around inside of it while giving the immune system very little indication that anything unusual is happening. Sneaky.

But just hiding inside the cell isn’t enough. EBV also has to keep that cell alive.

B cells carry a protein called Bim, whose job is to trigger apoptosis, essentially cellular self-destruction, when something inside the cell has gone wrong. Very useful when the cell in question is carrying around an entire viral genome! EBV, naturally, would prefer that not happen. Through epigenetic changes, it can suppress the gene responsible for making Bim, turning down this self-destruct signal without actually changing the underlying DNA sequence (Paschos et al., 2009). Less Bim means less pressure for that infected B cell to undergo apoptosis, giving the cell, and the EBV genome sitting inside of it, a better chance of sticking around.

And it can stick around for a VERY long time. EBV establishes this reservoir inside the memory B-cell population, which is how a virus you may have picked up before you could even spell Epstein-Barr can still be sitting there decades later.

Latency in EBV

How Your Immune System Keeps EBV Contained

Of course, EBV isn’t getting away with all of this completely unopposed. A huge part of keeping the virus under control comes down to T cells, particularly CD8+ cytotoxic T cells, which can recognize and destroy infected cells (Draborg et al., 2013).

For those T cells to know what’s happening inside a cell, they need a way to actually see in there. That’s where MHC I comes in. Almost every nucleated cell in your body displays MHC I molecules on its surface, and those molecules hold up tiny pieces of proteins from inside the cell for CD8+ T cells to inspect (Wieczorek et al., 2017). If those pieces look normal, carry on. If one of them is viral? Now the immune system knows something is in there that absolutely shouldn’t be.

EBV, naturally, has found ways to interfere with this too. During active infection, it can disrupt the MHC I antigen-presentation pathway, reducing how effectively viral proteins get displayed to CD8+ T cells (Draborg et al., 2013). And during latency, EBV creates a different problem altogether by keeping its viral protein production extremely limited. Fewer viral proteins being made means fewer obvious signs of infection for the immune system to catch.

So, there’s this constant push and pull happening in the background. Your T cells are keeping watch over EBV-infected cells, while EBV is doing everything it can to give them as little to work with as possible. For most people, the immune system maintains that balance remarkably well, which is how you can carry EBV for the rest of your life without ever knowing it’s there.

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What Molecular Mimicry Is, and EBNA1’s Role in It

One of EBV’s more interesting tricks involves molecular mimicry, where something made by the virus resembles something made by us. EBV takes advantage of that resemblance in a couple of different ways.

One is functional mimicry, where EBV makes its own version of a human protein that can do a very similar job. EBV actually carries the instructions for making a viral version of IL-10, one of our own anti-inflammatory cytokines (I know, what the heck). This viral IL-10 can suppress interferon-gamma production and dampen CD8+ cytotoxic T cell responses, the very cells we just talked about that help keep EBV-infected B cells under control (Draborg et al., 2013). IMPOSTER!

But there’s another kind of mimicry that becomes especially interesting when we start talking about autoimmune disease. Here, a viral protein resembles one of our own proteins closely enough that an immune response meant for the virus can cross-react with our own tissue. Your body builds an immune response against an EBV protein, completely correctly, but if part of that viral protein looks enough like something your own cells make, some of those antibodies or T cells may recognize both (Shabnam and Khan, 2026).

Your immune system is working off of bad information. :(

Side-by-side 3D models comparing how viral gp350 (green, left) and endogenous C3d (pink, right) map onto the B-cell receptor CR2 (gray).

And keep the concept of molecular mimicry in your back pocket during your immunology studies, because this is NOT just an EBV thing! Other pathogens are capable of doing this too.

Alright, now remember from earlier that when EBV goes dormant, it shuts down most of its genes and keeps only a small amount of viral activity going? One of the proteins that can stick around during latency is called EBNA1, or Epstein-Barr nuclear antigen 1. This one is especially interesting when we start looking at autoimmune disease (Shabnam and Khan, 2026).

In lupus, for example, parts of EBNA1 resemble Ro (SSA), one of the autoantigens targeted by the immune system in SLE. Antibodies produced against EBNA1 can cross-react with Ro, meaning the same antibody can recognize both the viral protein it was originally made to target and one of your own proteins (Draborg et al., 2013). From there, something called epitope spreading can happen, where an immune response that started against one small target gradually expands to recognize additional parts of the same protein, and eventually other proteins too (Fahlquist-Hagert et al., 2023). What started as a response against EBV has now widened into an autoimmune response against multiple targets.

EBNA1 doesn’t seem to have just one human look-alike. In MS, researchers have found cross-reactivity between EBNA1 and anoctamin-2, or ANO2, a protein expressed in the central nervous system. Antibodies against ANO2 are found more often in people with MS than in controls, and experiments have shown that antibodies recognizing ANO2 can also recognize a specific region of EBNA1 (Shabnam and Khan, 2026). Same viral protein, completely different human target.

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When EBV Wakes Back Up

So, what happens when EBV stops hiding?

Remember that latency isn’t permanent in the sense that EBV gets locked away inside a B cell and can never become active again. The virus can switch back into its lytic cycle, start producing new viral particles, and begin infecting other cells again. This is EBV reactivation!

Researchers still don’t have a complete picture of what makes that switch happen every time, but part of it comes down to the normal life cycle of the B cell itself. When a latently infected B cell differentiates into a plasma cell, the cellular changes involved in that process can activate EBV’s lytic program and push the virus back into active replication (Draborg et al., 2013). Reactivation can also happen spontaneously, during periods of acute or chronic stress, or alongside infection with another pathogen (Tarasco et al., 2025).

A lot of this comes back to the balance we talked about earlier between EBV and the immune system. If that balance gets disrupted, the conditions that were keeping a latent infection under control can change. Both immune suppression and an excessively inflammatory immune response have been associated with reactivation, which sounds a little backwards at first because those are opposite ends of the immune spectrum (Tarasco et al., 2025). But either one can interfere with the coordinated immune response that normally keeps EBV contained.

And we actually have a very big, very recent example of what that can look like: COVID-19.

Factors associated with EBV reactivation.

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• Where the alarm system sits and what sets it off

• Why tissue swells, and what leaves the vessel first

• The loop that keeps inflammation escalating

• How your body shuts the whole thing down on purpose

• What chronic inflammation looks like at the tissue level

I had to memorize this piece by piece, cell by cell, for a course conference (more like an oral exam) for my immunology course this semester. It was interesting that I was studying this the same week I got stung by a bee on my finger (DIABOLICAL). It was fun to actually kind of SEE it happening in realtime, even though I know all of us have experienced a cut, a bug bite, a scratch, etc.

We all know what it looks like, but ever wonder what’s happening inside that cut? What our immune cells are doing? How they’re acting? What causes all the swelling and itchiness?

Wonder no more, my friends, let me explain it all to you!

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Phase One: Initiation

Okay, so let’s say you slice your finger open on the lid of a can. THE WORST.

Two things come in on that lid. Bacteria ride through the break in your skin. Right alongside them, a bunch of your own cells get crushed in the process, spilling their insides out into the surrounding tissue. Your body picks up on both of these using two separate sensing systems, each one watching for a different kind of trouble.

The cells doing the watching were already there before you even opened the can. Macrophages, dendritic cells, and mast cells (often termed “resident cells”) sit parked in your tissues on guard.

What does this mean? Well, they’re kind of decked out in receptors called PRRs, or pattern recognition receptors, and these are what pick up on trouble and sound the alarm to get the inflammatory response started (Roh & Sohn, 2018).

So, what counts as trouble? The bacteria riding in on that can lid are covered in PAMPs, or pathogen-associated molecular patterns, and they’re pretty self-explanatory, right? The PRRs recognize molecular patterns that come from pathogens, which could be LPS (lipopolysaccharide) from gram-negative bacteria, or even the little tail some bacteria use to swim around (flagellin). These are things our human cells just don’t make!

Then we’ve got DAMPs (also self-explanatory), damage-associated molecular patterns, coming from all those cells that were just sliced open by the sharp lid. Here the PRRs recognize things like ATP or mitochondrial DNA :( , the normal stuff that’s supposed to stay INSIDE the cell but sets off the alarm the moment it turns up OUTSIDE (Roh & Sohn, 2018).

This is why you’ll see swelling when you sprain your ankle, for example. No visible damage, no way for any outside bacteria to GET IN, but you still end up with some inflammation.

In the scenario we’re working with, though, you get both....sorry :(

PAMPs and DAMPs

The Mast Cell Opens

Remember those resident cells? Yeah? Okay, let’s focus on mast cells. And I know, you’ve probably heard all about them with the MCAS discourse online, but here, they’re not really our enemy. I’ll explain!!

So, the second the mast cell “senses” trouble, it degranulates, which is really just the fancy way of saying it dumps out everything inside of it: histamine, serotonin, leukotrienes, proteases, and cytokines like TNF-α and IL-1 (Granger & Senchenkova, 2010). And I literally mean the “second,” because this whole thing happens in seconds. Histamine is the one I want to zero in on here, because it reaches the endothelial cells lining your blood vessels and tells them to contract (Granger & Senchenkova, 2010).

Those cells are normally standing shoulder to shoulder, holding hands, sealing the vessel wall TIGHT. Now they’re scrunching up, letting go of each other, letting little gaps open up all along the blood vessel wall.

This leads to what’s called “increased vascular permeability,” meaning more things are able to get in and out of the blood vessel. And we want this to happen! (More on that coming up.) Histamine working on our vessels is actually what’s behind the swelling. Plasma proteins are the first thing to squeeze through those gaps into your tissue, and water follows right behind them (Granger & Senchenkova, 2010).

Meanwhile, In the Nucleus

While the mast cell was doing its thing in a matter of seconds, those resident cells that first caught the PAMPs and DAMPs have been working on something a whole lot slower behind the scenes.

Their PRRs switched on a protein called NF-κB, which heads straight into the nucleus and starts flipping genes on (Liu et al., 2017). Those genes code for the next big wave of the response: pro-inflammatory cytokines and chemokines like IL-1, IL-6, IL-12, and TNF-α (Liu et al., 2017). None of this stuff was sitting pre-packed and ready like the mast cell’s stash. The cell has to build every single one of these from scratch, which is exactly why this part takes hours instead of seconds. The chemokines are basically a flare going up into the sky, and the neutrophils are the ones who come running.

NF-κB target genes involved in inflammation development and progression.

Phase Two: Amplification

Alright, so initiation got the ball rolling. Now amplification is what turns a small, contained response into something big enough to actually deal with the threat.

Those neutrophils we called in don’t just show up, do their job, and file out. As they arrive and get to work, they release their own batch of signaling molecules, the same kind of cytokines and chemokines that called them in the first place. So the first responders are basically radioing for backup, and that backup shows up and radios for even more. One cell calls in ten, those ten call in a hundred, and the whole thing snowballs. Yikes.

A feedback loop like this, a response that feeds itself and keeps building instead of staying flat, is what makes amplification its own phase. And it’s exactly what you want when there’s a real threat, because a handful of cells was never going to be enough to clear a wound full of bacteria. You need the crowd.

The neutrophils are the muscle. They swarm the site, gobble up bacteria, and dump out enzymes and reactive molecules that kill off invaders (Filippi, 2019). It’s messy, effective work, and it’s a big part of why an inflamed area gets hot, swollen, and tender. You’re feeling the crowd doing its job.

But a response that only knew how to grow would be a disaster, right? Something has to eventually tell everyone to stand down. Aaand that’s exactly where we’re headed next.

Amplification Loop

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Phase Three: Resolution

Okay so the threat is handled! The bacteria are cleared, the wound is under control, and now your body has the opposite problem on its hands: a site absolutely packed with neutrophils that showed up ready to fight, with nothing left to fight. You can’t just leave that crowd standing around, because all those enzymes and reactive molecules they’ve been flinging will start chewing through your own tissue if nobody calls them off. So resolution is where the body winds everything down and clears out the mess.

Resolution is an active program, something the body switches on deliberately, with its own dedicated set of signals (Sugimoto et al., 2016). It runs a full shutdown sequence here, every bit as coordinated as the ramp-up was. A fresh crew of molecules called pro-resolving mediators clock in, and their job is to call off the recruitment, so that “send backup” signal from phase two finally goes quiet and no new neutrophils get waved in.

The neutrophils already on-site are pretty short-lived to begin with, so once the reinforcements stop arriving, the crowd starts thinning out on its own. Then the cleanup crew rolls in. Macrophages move through the area and clear away all the spent, dying neutrophils, tidying up the site (Ge et al., 2022). Clearing those dead cells does something extra, too, because eating them flips a switch inside the macrophage. It shifts from its aggressive, inflammatory M1 setting into a much calmer M2 setting, where it stops pumping out attack signals and starts releasing soothing, anti-inflammatory ones like IL-10 instead (Ge et al., 2022). The same cell that was running the war is now running the cleanup, calling for peace instead.

Once the mess is cleared and those calming signals are flowing, your tissue can finally start to rebuild, and everything settles back to baseline. That is a healthy inflammatory response from start to finish: it fires up right when you need it, does the messy work, and shuts itself off once the job is done.

Resolution Phase

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When Inflammation Won’t Shut Off

Everything so far describes inflammation working the way it’s supposed to. It fires, it does its job, it shuts down. Sometimes, though, that last step doesn’t happen, and the response that was meant to be temporary just keeps running. This is chronic inflammation, and it sits behind a huge number of long-term diseases.

Think back to that cleanup crew for a second, because a lot of chronic inflammation traces to the cleanup going wrong. When the macrophages can’t clear the dead cells fast enough, or the clearing process breaks down, those dead neutrophils pile up and rupture instead of getting cleared away (Ge et al., 2022). All the toxic contents they were holding spill straight into the tissue. To your body, that spill reads as fresh damage: new DAMPs, new alarm signals, another round of recruitment. The very thing that was supposed to end the response ends up feeding it.

Without that cleanup, the macrophages never get the message to change. That soothing M2 program, the one that produces IL-10 and starts calming everything down, only comes online when the macrophage receives the right signal, and eating those dead cells is the signal. No cleanup, no signal, so the M2 genes never get transcribed. The macrophages stay in their aggressive, inflammatory M1 mode, and the site stays hot (Ge et al., 2022). Now damage and repair are both running at once, indefinitely, with neither one ever finishing.

When tissue is caught in that loop of constant injury and constant attempted repair, the repair signals keep telling your fibroblasts to lay down collagen into a site that never heals. Fibroblasts are the connective-tissue cells that produce collagen and the other structural proteins making up the extracellular matrix, the scaffolding your tissues are built on. Here they just keep building, with no signal telling them to stop. Over time all that excess collagen accumulates as scar tissue, a process called fibrosis, and it slowly stiffens and reshapes the tissue until the organ can no longer work the way it used to (Chimenti et al., 2022).

So the story of inflammation comes down to balance. You want a response strong enough to protect you but smart enough to know when to quit, firing hard when a threat appears and then standing down once the work is done. Your body is good at the firing part. Staying well depends just as much on the shutting down, on that whole resolution program running the way it should and pulling the response to a close.

Pathogenesis of fibrosis.

We started with a single cut on a can lid, and from there your body ran an entire operation: resident cells spotting the intruders, mast cells throwing open the vessel walls, a crew of neutrophils swarming in to fight, then a careful, deliberate shutdown that cleared the mess and handed the site over for repair.

That’s initiation, amplification, and resolution, each phase flowing into the next.

So much of whether this protects you or harms you comes down to the ending. All that firepower stays safe only because the body has an equally strong system for standing down, so when that standing-down fails, the same response that defended you begins wearing at your own tissue, which is why the stopping carries just as much of the work as the starting ever did.

If this piece helped inflammation click for you, the biggest way to support the work is to consider a paid subscription.

I’m keeping it free because this foundation should be available to anyone, and paid members are what make that possible, so I can keep publishing work like this without putting the important pieces behind a paywall.

Every subscription helps keep this accessible for everyone.

If you found this useful or helpful, please like, comment, restack, or share it with someone who’d enjoy it! It really means a lot.

Until next time,

— Agy | The Buffalo Herbalist

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References:

Chimenti, I., Sattler, S., Del Monte-Nieto, G., & Forte, E. (2022). Editorial: Fibrosis and inflammation in tissue pathophysiology. Frontiers in Physiology, 12, 830683. https://doi.org/10.3389/fphys.2021.830683

Ge, Y., Huang, M., & Yao, Y.-m. (2022). Efferocytosis and its role in inflammatory disorders. Frontiers in Cell and Developmental Biology, 10, 839248. https://doi.org/10.3389/fcell.2022.839248

Granger, D. N., & Senchenkova, E. (2010). Inflammation and the microcirculation. Morgan & Claypool Life Sciences. https://www.ncbi.nlm.nih.gov/books/NBK53374/

Liu, T., Zhang, L., Joo, D., & Sun, S. (2017). NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy, 2(1), 17023. https://doi.org/10.1038/sigtrans.2017.23

Roh, J. S., & Sohn, D. H. (2018). Damage-associated molecular patterns in inflammatory diseases. Immune Network, 18(4), e27. https://doi.org/10.4110/in.2018.18.e27

Sugimoto, M. A., Sousa, L. P., Pinho, V., Perretti, M., & Teixeira, M. M. (2016). Resolution of inflammation: What controls its onset? Frontiers in Immunology, 7, 160. https://doi.org/10.3389/fimmu.2016.00160

I wrote this paper for my doctoral program. It’s about Sjögren’s syndrome and mucosal dysbiosis, specifically how the disease affects the microbiome (are we surprised?) across the different organ systems it touches.

This post will not contain an edited version in my Substack educator voice. It’ll stay as is, exactly as I submitted it, and I won’t be adding the usual graphics I use for visualization. Fair warning: this is going to read VERY dry. Academia calls for rigor that gets straight to the point, and you’ll see that here. I love writing these kinds of paper AND for Substack, as it allows me to dip my toes into both voices, it’s fun for me!

I feel like I'm showing you guys the other side of me and it’s a little vulnerable!

What I found while writing this was actually super interesting, though. Sjögren’s affects multiple organ systems, and it was fascinating to see how the microbiome in each of those areas gets disrupted differently. Even in the EYEBALLS. Integrative therapies are included too.

Let me know what you think! And if this sounds interesting to you and you’d like a more digestible version, just say the word :) your wish is my command!

I really feel like I missed my calling as a microbiologist or something. The CHOKEHOLD our microbiome has one me is CRAZY.

ALSO: I've disabled the AI detection scan on this post. Dense academic writing tends to trip those tools up and get flagged as 'AI-generated' even when it's not, and I'd rather not have a flawed detector attached to something I worked hard on and submitted for my doctorate, nor do I really want this work uploaded to the program itself, to be completely honest. I hope you understand.

Quick side note: I just wanted to remind everyone about the Skool community I’ve been (very, very) slowly growing!

Substack is always going to be my spot for long-form deep dives, but over on Skool, we get to mix things up a bit. Think more video presentations, narrated slide decks, mini-breakdowns, more community vibes :)

The content topics are pretty much the same, but the formats are way more versatile and interactive. I’d love for you to join us over there too!

Come hang out with us here:

Skool Community!

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• What oral tolerance is and why your gut cannot function without it

• How your body sorts a harmless antigen from a dangerous one

• The cells that carry that decision out and make it stick

• Why tolerance travels through the whole body while inflammation stays put in the gut

• How a few common plants support the gut barrier, and how licorice constituents drove its effect on regulatory T cells

Okay so, I decided on this topic while studying for my immunology course conference, where I had to learn the ins and outs of it (like I had to memorize the whole thing).

Learning how the body tells friend from foe, particularly in the gastrointestinal tract, was fun because it let me connect a few dots between this topic and past research I’ve done, specifically on autoimmunity and Treg cells. I wanted to share this topic and explain it because I know a lot of us deal with food sensitivities and allergies, and since the food quality in the US isn’t really the best, it helps to understand why our bodies react the way they do to an organic piece of bread compared to something store bought and highly processed. I know you know what I mean.

I’m going to walk you through what happens cellularly, AND a few herbs to help the process along. :)

Okay, So How Much Is Your Gut Handling?

Let’s start here, with the numbers, because they’re a little unhinged…

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The AMA is not, and never will be, a replacement for a consultation. I cannot and will not answer personal or individualized health questions. Where a question is specific to one person, I’ll answer the general version of it instead.

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Question 3: Could there be a relationship between a newly added S. boulardii CNCM I-745 supplement and a recent rosacea flare?

I love this question because it’s exactly the kind of dot-connecting I’m hoping to teach through my writing here, so I’m really glad it was asked! When something new goes into the body (herb, supplement, etc) and something new shows up on your skin (or any new symptoms really), I want your mind to reach for a possible connection between the two. That instinct is the whole foundation of thinking physiologically about your own health, and it’s the instinct I’d rather see too often than not enough.

So, let's follow the thread and see where it leads. My answer is that I don't suspect this particular organism, though the conclusion itself is the least interesting part of this. What I'd rather hand you is the reasoning, because that's the thing you get to carry into the next question you have about your own body. Let me show you how I got here!

A Quick Look at the Gut-Skin Axis

The gut-skin axis is a bidirectional relationship between the gut and the skin that runs along immune, neuroendocrine, and metabolic pathways. And if you’re reading this thinking, “Agy, I thought the gut had an axis to the brain and the liver? There’s more?” Yup! The gut has an axis with just about everything at this point, the brain, the liver, the lungs, and to be honest I’m here for all of it, because the gut microbiome really does have its hands in every body system.

The gut and the skin actually have more in common than you might expect, because they’re both essentially doing the same job! They’re barriers, right?

So, your skin has three layers, the hypodermis sitting deepest, then the dermis, then the epidermis on top. That outer epidermis is the one meeting the world first, along with its hair follicles and its sebaceous and sweat glands, and it lives under constant stimulation from all the bacteria, fungi, viruses, and parasites making a home on its surface (Jimenez-Sanchez et al., 2025). Your gut’s got the same thing going on, just tucked way further inside you. An epithelial barrier stands guard there, keeping pathogenic bacteria, viruses, and food antigens confined to the lumen rather than letting them cross into the tissue and the bloodstream beyond it (Jimenez-Sanchez et al., 2025).

Both of these surfaces are standing between you and a world full of things that would love to get in, both of them are covered in their own microbial communities, and both of them lean on those communities to stay intact.

Now, that intestinal barrier is held together by tight junction proteins sealing the space between neighboring cells, and when those proteins come apart, permeability goes up, which leads us to the well known “leaky gut” (Jimenez-Sanchez et al., 2025). Bacterial components and dietary particles that belonged in the lumen cross into the gut mucosa and travel out into circulation, where the immune system meets them and responds (Jimenez-Sanchez et al., 2025). That response travels wherever the blood goes, which includes your skin.

Links between GI disorders and cutaneous diseases.

A Quick Look at What’s Happening in Rosacea Skin

BUT, before we can talk about whether a probiotic could have caused a flare, we need to know what a flare even is at the level of the tissue. So let me walk you through it, because rosacea turns out to be a fascinating condition mechanistically, and knowing this will make the rest of my answer make a lot more sense!

Okay so, two things are going on in rosacea skin at once, and the first one you already know by feel.

Think about what sets off a flush: heat, a stressful moment, something spicy.

Those all land on the same family of receptors, called transient receptor potential channels, or TRPs, which sit in sensory neurons, mast cells, and keratinocytes throughout your skin (Geng et al., 2024). TRPV1 is important here because it responds to heat, emotional stress, and capsaicin, and when it fires you get that burning sensation along with the vasodilation behind the flushing and the redness (Geng et al., 2024). So the common triggers in rosacea, heat and capsaicin and alcohol among them, are understood to work by activating these receptors and driving the inflammation that follows (Geng et al., 2024).

Rosacea skin also has an overactive innate immune response running in it, and this is where the inflammation itself comes from. A receptor called toll-like receptor 2 comes back elevated in rosacea skin, and when it fires, it drives up production of an antimicrobial peptide called cathelicidin, which gets chopped into an active fragment called LL-37 (Geng et al., 2024). It sounds like a lot, I know but bare with me.

That LL-37 is what sets the rest of it off, pushing neutrophils to produce reactive oxygen species, driving the release of inflammatory cytokines, and signaling for the growth of new blood vessels, which is a big part of why rosacea skin ends up so vascular over time (Geng et al., 2024). The cytokines that come out of all this are IL-1β, IL-8, and TNF-α, and just keep these in the back of your head, because I’ll be coming back to them later (Geng et al., 2024).

Summary representation of the main aspects involved in the development and manifestation of signals of rosacea (produced with Biorender).

Rosacea and the Gut Microbiome

The concept of connecting rosacea and our gut microbiome isn’t anything new as researchers have been looking into it for years. Here are just two instances that I found interesting:

Helicobacter pylori, the bacteria known for causing gastric ulcers, has certain strains that produce continuous gastric inflammation that activates mast cells, increases substances like histamine, prostaglandins, AND pro-inflammatory cytokines including IL-8 (Geng et al., 2024).

One study compared rosacea patients with controls of the same age and sex and found H. pylori in 88% of the rosacea group versus 65% of controls, and clearing the infection resolved rosacea symptoms and brought IL-8 and TNF-α levels back to normal (Geng et al., 2024). A second study using a different eradication regimen found significant improvement as well, while two other independent studies cleared the bacterium and saw no improvement at all (Geng et al., 2024). Complicating it further, the drugs used in the studies that worked, metronidazole among them, are anti-inflammatory in their own right and are used to treat rosacea directly, so we can’t tell whether the improvement came from clearing the bacterium or from the medication itself (Geng et al., 2024).

The second one is small intestinal bacterial overgrowth. Rifaximin is a broad-spectrum antibiotic that’s poorly absorbed when taken orally, which means it acts locally in the gut rather than traveling through the rest of the body (Geng et al., 2024). It went into a phase II trial for rosacea specifically because of the association between rosacea and SIBO, and in a separate trial, 46% of rosacea patients with SIBO who were treated with rifaximin reported cleared or markedly improved rosacea (Geng et al., 2024).

The skin–gut–brain axis in rosacea

So Where Does S. boulardii Land in All This?

Now we can answer the question properly. (Finally, sorry hehe)

Manfredini et al. (2025) reviewed the evidence on probiotics in rosacea, and the findings they describe run, interestingly, in the opposite direction from a flare. Probiotics seem to modulate immune response, reduce neurogenic inflammation, improve skin barrier function, help barrier restoration after damage, and reduce vasodilation, edema, mast cell degranulation, and TNF-α release. That’s A LOT, but read that list against with what we covered in the rosacea section and you’ll see the overlap!

S. boulardii shows up specifically, alongside Bifidobacterium strains, as an organism that helps inflammatory factor release by increasing IL-10 (anti-inflammatory) while suppressing NF-κB , inducible nitric oxide synthase, and IL-17A (all 3 are pro-inflammatory) (Manfredini et al., 2025).

Again, IL-10 is an anti-inflammatory cytokine, so raising it acts as a brake on immune activation. NF-κB is a transcription factor, meaning it switches on whole programs of inflammatory genes, and it sits upstream of the cytokines we talked about earlier, so turning this off is really really helpful!

Manfredini et al. (2025) also note that both live and heat-killed S. boulardii can restore the composition, structure, and function of the intestinal microbiota toward normal in experimental models of inflammatory gut conditions. So, the type of supplement you buy has some wiggle room.

So, the organism the question asks about raises the cytokine that calms inflammation and suppresses the switch that turns it on. :) It seems very peaceful!

But of course, I want to be careful here, though, because the evidence base is young. The research itself sits largely in experimental models rather than in people with rosacea, and I’m not aware of a trial testing S. boulardii in rosacea specifically. I may have just not come across it while I was looking.

What I can tell you is that nothing in the current literature gives me a plausible route by which this organism would drive a flare, and quite a lot pointing the other way.

Which is a good thing!

What Could Cause A New Flare?

Since we know what sets off the inflammation now, we can easily go looking in the right places.

The TRPV1 triggers are the place to start because they act fastest, and that means heat in all its forms, so hot showers, hot drinks, hot weather, just HOT. Capsaicin lands here too, so anything spicy! Also alcohol and emotional stress, which fires the same receptor that physical heat does (Geng et al., 2024).

We can’t forget about sun exposure, especially now in the summertime! UV radiation damages the small blood vessels near the surface of your skin along with the collagen and elastin underneath, and it Cretes reactive oxygen species that feed straight back into the LL-37 production we talked about earlier (Geng et al., 2024). This is why sun protection sits so high on every rosacea list you'll ever read!!

Then there’s everything else that changed alongside the supplement, whether that’s new topicals, new foods, a new laundry detergent, a stressful month, or a course of medication. So it definitely helps to think back and see what else could be the culprit!

With S. boulardii, the mechanism runs toward calming inflammation rather than provoking it, and the gut organisms with real evidence behind them in rosacea, H. pylori and the bacteria behind SIBO, are the ones causing gut inflammation rather than resolving it.

If you want to test it properly, the approach is the boring one that works: change one thing at a time, give it a few weeks, and write down what you did and what your skin did. That record will teach you more about your own triggers than any mechanism I can hand you from the outside.

Alright friends, that’s Question 3! Two more left for June! Question 4 will be out next week, and this weekend I’m publishing a Field Notes covering the phases of inflammation, which pairs nicely with everything we just walked through.

And a friendly reminder before I go: this kind of work, the reading, the sourcing, the physiology-first writing, takes real time to do properly. If these pieces have been useful to you and you’re able to, consider upgrading your subscription. It’s what keeps this whole thing going, and it means more to me than I can easily say. You also get the opportunity to ask questions in the AMA threads and have access to the Body System Index & Materia Medica Index (PDFs! Downloadables! Fun!)

I’ll see you there. :)

— Agy | The Buffalo Herbalist

References

Geng, R. S. Q., Bourkas, A. N., Mufti, A., & Sibbald, R. G. (2024). Rosacea: Pathogenesis and therapeutic correlates. Journal of Cutaneous Medicine and Surgery, 28(2), 178–189. https://doi.org/10.1177/12034754241229365

Jimenez-Sanchez, M., Celiberto, L. S., Yang, H., Sham, H. P., & Vallance, B. A. (2025). The gut-skin axis: A bi-directional, microbiota-driven relationship with therapeutic potential. Gut Microbes, 17(1), 2473524. https://doi.org/10.1080/19490976.2025.2473524

Manfredini, M., Barbieri, M., Milandri, M., & Longo, C. (2025). Probiotics and diet in rosacea: Current evidence and future perspectives. Biomolecules, 15(3), 411. https://doi.org/10.3390/biom15030411

We all see what’s happening right now, whether it’s through our TV screens or through the actual first-hand experience of stepping outside and breathing it in. The sky takes on that flat, weird hazy color, the sun turns a strange apocalyptic shade of orange, and within an hour your eyes are stinging, your nose won’t settle, and there’s a scratch at the back of your throat, but you know you aren’t sick

The air quality apps light up with numbers most of us never paid attention to before (or knew existed?!), and suddenly we’re all checking them the way we check the weather.

So today I want to slow down and work through what this is. We’re going to cover:

• What particulate matter is and where it comes from

• Why its size is the whole story when it comes to the danger it poses

• What it does to your airways and your body once you breathe it in

• How to think about herbal support and prevention in a way that maps onto that physiology

My goal is that you leave this piece understanding the why and the what of wildfire smoke, so that when you reach for a supportive herb or set up an air purifier in your bedroom, you’re doing it from a place of understanding rather than guessing.

Before we get into any of that though, it helps to have a reference point for the numbers we’re all watching, because the Air Quality Index is the tool telling us how concerned to be on any given day. (I know you’ve seen this plastered on the news and weather apps) The EPA calculates it for five major pollutants regulated under the Clean Air Act, and particulate matter is one of them (Friis, 2018). The scale runs from 0 to 500, where higher numbers mean more pollution and more risk, and the guide below breaks down who needs to be careful and what to do as the number climbs.

Air Quality Index guide for particulate matter. Source: U.S. Environmental Protection Agency (2014).

During a wildfire smoke event, the number climbing through those upper bands is largely being driven by the fine particulate matter we’re about to get into, so the AQI is really giving us a live readout of how much of that particulate is in the air around us.

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Breaking Down the Smoke

Particulate matter is the term for the mix of tiny solid particles and liquid droplets suspended in the air we breathe, and during a wildfire event that mix is made of soot, smoke, dust, and finely divided material carried along in the air (Friis, 2018). Those particles are rarely just inert specks, because they carry polycyclic aromatic hydrocarbons and volatile organic compounds along with them, and it’s largely those chemical passengers that drive the toxic effects we’re concerned about (Crinnion & Pizzorno, 2018).

Wildfire smoke is a particularly messy version of this, combining particulate matter with a whole range of trace gases (Rizzo & Rizzo, 2024). And it reaches far more of us than you might expect, because recent estimates attribute 25% of the fine particulate matter in the air across the United States to wildfires, with 95% of the population breathing wildfire smoke for at least one day a year (Rizzo & Rizzo, 2024).

When it comes to how particulate matter behaves once it’s in the body, size drives almost everything, so it helps to picture the scale we’re working with. A single human hair runs somewhere around 50 to 70 microns across, and the particles we classify as air pollution are only a fraction of that width (Friis, 2018). PM10 covers the coarser particles, the ones larger than 2.5 microns and ranging up to 10, while PM2.5 covers the fine particles from 0.1 to 2.5 microns, and finer still are the ultrafine particles at 0.01 to 0.1 microns (Friis, 2018). The smaller a particle gets, the easier it slips past the body’s normal defenses to settle deep in the lungs, and once it’s down there, if it doesn’t dissolve, our clearance mechanisms struggle to move it back out (Friis, 2018). That is where the real trouble starts, and where we’re headed next.

Size comparison of PM2.5 and PM10 particles against a human hair and fine beach sand. Source: U.S. Environmental Protection Agency.

Why Size Is the Whole Danger

Particulate matter smaller than 10 microns is readily absorbed in the lungs and then distributed throughout the body (Crinnion & Pizzorno, 2018). The smallest of these particles don’t stay where they land, and the distances they travel are hard to overstate.

When researchers measured ultrafine particulate in the livers of rats 18 to 24 hours after exposure, the levels in the liver were five times higher than in the lungs the particles had entered through (Crinnion & Pizzorno, 2018). Sit with that for a second, please. Five times higher, in the liver, in about a day. When we think about breathing in smoke, our minds go straight to the lungs, and that makes complete sense, because the lungs are the door it comes in through. What that liver finding tells us is that the door is not the destination, and the organ taking the biggest hit may be one we weren’t thinking about at all. Keep the liver in the back of your mind, because it’s going to come back around when we talk about support.

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In this issue:

• How the immune system fights a virus: why the misery of being sick is the response working correctly

• The off switch: the built-in brake that shuts inflammation down once the threat is cleared, and the protein that runs both the accelerator and the brake

• What drives the damage: how cleanly you shut the response down, not only how much virus you had

• What persists in Long COVID: the altered T-cell populations and immune mediators still circulating long after the virus is gone

• Brain fog: the inflammasome, cytokine, and blood-brain barrier story underneath it

• Post-exertional malaise: what’s happening in the muscle tissue itself, and why being out of shape doesn’t explain it

Next issue: the plants! I’m testing out splitting this into parts, because from the feedback I’ve been getting, smaller and more digestible posts land better, and honestly, I agree. I wish Substack had a cleaner way to organize a series, but I’ll figure something out. Next issue will get into which plants have research behind them for Long COVID, where that research is strong, and where it runs out, and I may even go a little crazy and put together some PDFs for you. It’s been a while :) I’m pretending I don’t have a lot on my plate, so please don’t told me to it lol!

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* Read in a dramatic, deep, narrator-style voice *
The following is based on a true story lol

I got COVID in the summer of 2020, back when the strain going around was still fully capable of humbling a person, and it knocked me out for three horrific, agonizing weeks.

I should mention that I rarely get sick, and I mean rarely. I don’t think I’ve ever actually had the flu, I don’t get colds, and while some of this is probably immunological good fortune, a lot of it is that I am an introvert who does not particularly want to leave the house, which turns out to be a wildly underrated infection control strategy. So, three weeks of my lungs hurting, my eyeballs actively attempting to vacate their sockets, insomnia stacked on top of an exhaustion I did not know was available to me, and all of it completely alone because it was 2020 and nobody was coming inside anybody’s house, was deeply destabilizing.

My dad would drive an hour after work to leave groceries at my door, and I would stand behind the glass and wave at him like a sad Victorian orphan. My stepdad once actually came inside to bring me groceries and I cried, openly, with real tears, because a fellow human being was standing in my kitchen. That entire period was trash, and I would like to formally request that we never do it again.

Anyway.

After those three weeks I was in the clear, thankful it was behind me, hopeful that my body had learned something useful from the whole ordeal and stockpiled whatever immune cells it might need next time, and I took an enormous deep breath through my finally unobstructed nostrils and went on with my life.

For a lot of people, that is not where the story ends.

They test negative and go back to work, and then months later they are standing in their own kitchen holding a coffee mug with absolutely no memory of what they walked in there to do, or they take the dog around the block and spend the next two days horizontal, or they find themselves reaching for words that used to be automatic and coming up with nothing. Their heart races when they stand up too fast. They are tired in a way that sleep does not touch, and every lab their doctor runs comes back looking perfectly, infuriatingly normal.

The virus left, but it seems like something else stayed.

What Your Immune System Is Doing When You Feel Like Garbage

Let’s go back to the couch, back to that bus-hit feeling, and follow what’s happening inside you while you’re lying there.

Somewhere in your body a cell has just been infected, and I want you to picture how that goes down, because the virus is not kicking in the door like the Kool-Aid man. The virus is an assassin. It’s covert, it’s silent, it slips inside without your cell registering a thing, and once it’s in there it starts using your cell’s own equipment to build copies of itself. Hacker of the year. Your cell is sitting there doing its job, running its ordinary operations, with absolutely no idea that it’s equipment has been turned against it and is now churning out virus on someone else’s orders.

So, what are we supposed to do with that? How does the body track down an intruder it cannot see?

Thankfully we do have something in the arsenal, and they’re called pattern recognition receptors (Chakravarty et al., 2023). They sit inside the cell and scan for molecular patterns that have no business being there, like a blip showing up on the radar in a stretch of space that’s supposed to be empty.

What they’re looking for, essentially, is a shape. Viral genetic material carries structural features that your own genetic material doesn’t, and these receptors have evolved to recognize those features and nothing else. Your cell can’t identify the virus by name, it has no idea what it’s up against, and it technically doesn’t need to. It just needs to notice that there’s nucleic acid in here wearing the wrong outfit.

And when they do notice, they set off a signaling cascade that activates two transcription factors working together, IRF3 and NF-κB (Chakravarty et al., 2023). These two divide the labor between them, and they’re doing very different jobs, which is where things start getting good.

Viral replication cycle.

IRF3 is the one that goes directly after the virus, driving the production of interferons and the interferon-stimulated genes, which inhibit a huge range of viruses by making it physically harder for them to copy themselves (Chakravarty et al., 2023). NF-κB, meanwhile, is the one bringing the inflammation, switching on the genes that summon immune cells to the scene, open up the blood vessels, and turn the local tissue into somewhere no pathogen wants to be (Chakravarty et al., 2023).

And NF-κB, my friends, is the one you feel. The aching, the fever, the swelling, that specific sensation of your body having been repossessed overnight and handed over to someone with much worse taste than you. All of that misery is inflammation doing precisely what it evolved to do, and as much as it ruins your week, it’s a large part of why you eventually get better.

In COVID specifically, the acute response mobilizes substantial quantities of pro-inflammatory cytokines along with inflammatory cells like neutrophils and macrophages, and it generates virus-specific CD4+ T cells, CD8+ T cells, and B cells, all of them working to clear the pathogen and limit its replication (Bohmwald et al., 2024). So, while you’re lying there feeling like you’ve been personally cursed, nothing is broken. Your body is pouring an enormous amount of energy into a defense operation, and the misery is the price of running that operation at full throttle. (Would it kill it to be a little more discreet about the whole thing? Apparently yes.)

Inflammation feeling terrible is not the problem, then. It feels terrible on purpose, and it's supposed to. The part I want to dig into is what happens after, when the virus has been cleared and the whole thing is supposed to wind down and go home.

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The Off Switch

Inflammation cannot run forever, and your body knows it.

It earns its keep in the early days of an infection, when the threat is live and the tissue needs defending, and then those same inflammatory genes turn on you in the later stage, driving cytokine storm and cell death (Chakravarty et al., 2023). What protected you on day two starts costing you on day twelve. The body has to have some way of calling the whole thing off before it gets there, and it does, and the mechanism is a little bit delightful.

Remember IRF3? The one we just met, out there driving the antiviral response and calling in the interferons? Turns out it’s been moonlighting. It has a second job, one that Chakravarty et al. (2023) call RIKA, and the job is to grab NF-κB and refuse to let go. How romantic.

Let’s slow down for this one though: NF-κB is a transcription factor, which means it can only do anything at all if it can physically get into the nucleus, since the nucleus is where the genes live and switching genes on is the entire point of its existence. What IRF3 does is intercept it out in the cytosol, which is the fluid filling the inside of the cell, everything sloshing around outside the nucleus, and pin it there. NF-κB never makes it to the door. The inflammatory genes it was on its way to switch on stay switched off, and the cytokines it would have summoned, IL-1β and TNF-α among them, never show up in the numbers they otherwise would have (Chakravarty et al., 2023).

So, IRF3 is out here running the antiviral response with one hand and holding inflammation back with the other. The accelerator and the brake, same protein, same cell, same infection. (Multitasking icon, frankly.)

Chakravarty et al. (2023) also make a point about what drives the damage. Virus-induced inflammation causes disease on its own, separately from viral load. How sick you get, and how much damage you walk away carrying, tracks with how cleanly you shut the response down, not only with how much virus you had in you.

Two people can clear the same infection and come out of it with very different bodies, and a lot of that difference lives in the ending.

RIKA, a new anti-inflammatory function of IRF3. IRF3 is widely known for its transcriptional function involving the production of IFNβ and ISGs which antagonize various stages of viral replication

What Stays Behind

For most people, the ending goes fine. The virus gets cleared, the brake comes on, inflammation packs up its things and goes home, and you get your body back. Yay!

But for others, the response never fully stands down. :(

The rest of this one is for paid subscribers.

Below the line, we get into what that failed shutdown does once it settles into tissue: how inflammation crosses a barrier your brain spent your whole life protecting, what your microglia start doing when nobody tells them to stop, and why the muscle of someone with Long COVID looks different from the muscle of someone who simply stopped moving.

Paid subscribers keep this work possible, and it unlocks the full archive, the Body System Index, and the Materia Medica Index while you’re at it.

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The AMA is not, and never will be, a replacement for a consultation. I cannot and will not answer personal or individualized health questions. Where a question is specific to one person, I’ll answer the general version of it instead.

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Question 2: What’s helpful for supporting and soothing the joints and the muscles around them, especially after the extremes between a fixed seated position and intense or prolonged movement?

Two very different things are happening in this question, and they call for two different answers. Long stretches of sitting fixed in place do one kind of damage; intense or prolonged movement does another, and they land on the same joints and muscles from opposite directions. Let me take each one in turn!

A Quick Look at the Joint

BUT! Before we get into what goes wrong, it helps to picture what a joint actually is, so you really can get a feel of what’s going on. Most of the joints we’re talking about here, knees, hips, shoulders, elbows, are synovial joints, the freely moving kind. Two bones meet inside a capsule, and the ends of those bones are capped with articular cartilage, a smooth, slick surface that lets them glide against each other without grinding. That cartilage has no blood supply of its own, so it depends entirely on the synovial fluid inside the joint for its nutrition and lubrication. Around all of it sit the muscles, and they do quite a bit more than just move the joint. The muscles and tendons crossing a joint act like a set of dynamic ligaments, actively bracing and stabilizing it, which is why muscle strength and joint health are so tightly linked (Juneja et al., 2026).

Source Unknown

The Two Extremes

The two ends of this question ask for almost opposite things, so let's look at what each one does to the body before reaching for any herbs. Prolonged stillness and hard movement wear on the same joints and muscles, just from opposite directions.

Okay so, let me start with the prolonged position/sitting. When you hold one position for a long stretch, circulation to the area drops and the surrounding muscles settle into a low, sustained tension. The joints feel it too, because the cartilage inside a joint has no blood supply of its own and relies on motion to circulate synovial fluid, the slippery stuff that lubricates the joint and moves nutrients into the cartilage. Without that movement, the fluid can go stagnant, its nutrients depleted and acidic waste building up, so the cartilage ends up underfed and the joint stiffens while the muscles around it go tight (O’Hara et al., 1990).

On the other side, intense or prolonged movement loads those same tissues hard, especially through the eccentric, lengthening-under-tension contractions that create the microscopic muscle damage behind that next-day soreness, along with the inflammatory cleanup response that follows it (Proske & Morgan, 2001). So, the tissue is moving between stagnation and overload, and a good herbal approach respects both ends of it.

Warming the Stagnation

For the stagnation end, I'm generally thinking about circulation. Sluggish, pooled blood is a big part of what we're fixing, and this is where the warming circulatory stimulants shine, the herbs whose whole purpose is to push fresh blood back into a stalled-out area and wake it up! Ginger is what I'd reach for here, though cayenne is the one that really gets things moving, especially rubbed on topically, where capsaicin, the compound behind that familiar heat, has a long history with achy joints and stiff muscles. The logic is thankfully pretty direct: sitting starved the tissue of good circulation, so we bring in the herbs that answer that directly.

Calming the Overload

For the overload end, I want to calm the post-exertion inflammation and ease the soreness, which is where the anti-inflammatory herbs come in. Turmeric and ginger lead here, with ginger getting to pull double duty across both ends, part of why I love it for a pattern like this. A systematic review and meta-analysis by Doma et al. (2022) pooled studies of root plants, ginger and turmeric among them, against exercise-induced muscle damage, and found that supplementation lowered the markers of muscle damage and eased soreness across the 24 to 48 hours after a hard effort, right in the window where that sit-then-move pattern leaves you aching. The inflammation itself came down at the 24-hour mark rather than holding all the way to 48, so the clearest, steadiest wins were in the muscle damage and the soreness. When the researchers compared the plants, ginger reduced muscle damage and inflammation at least as much as turmeric, part of why I turn to it so readily.

One honest note on what the research didn’t show, though: the supplements eased the damage and the soreness, but they didn’t measurably speed up the recovery of muscle strength. Just so you have the whole picture.

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The Muscular Tightness

Muscular tightness is where I’m going to perhaps surprise you all and nooot recommend an herb. I know, I know. But hear me out: tense, cramping muscle around a joint responds so beautifully to hands-on work that it’s the first place my mind goes. Massage especially, where pressing and working into the tissue drives circulation straight to the spot that’s stuck, coaxes the muscle out of its little guarding pattern, and does it faster than waiting around for something to absorb and kick in. Acupuncture fits here too (my new fav), another way of getting into the tissue and prompting it to release. The plants still come along for the ride, because a warming liniment or an infused oil makes that bodywork even better, so they’re working alongside the hands rather than off to the side. My acupuncturist put a lovely CBD balm on my neck yesterday after the actual acupuncture session…perfection.

Nourishing the Foundation

For the long game, meaning the supportive side rather than the soothing one, I typically turn my attention to the connective tissue itself. This is where I bring in the herbs traditionally used to nourish the structures that hold a joint together, and horsetail (rich in silica) and gotu kola both carry a long reputation for exactly that kind of support.

One small note on horsetail: it's best used in measured courses rather than taken heavily day in and day out, and it's worth sourcing from a supplier you trust, so you know you're getting the right species, properly prepared. Prolonged use can interfere with Vitamin B1, and we don’t need more things going on.

Again: these aren't your quick-relief herbs. They're the slow, patient, building kind, the ones you bring in when you want to shore up the tissue over time rather than calm a single flare. :)

Bringing It Home

When you step back, the whole picture settles into something pretty intuitive. You warm and move the circulation where sitting let it stall, you calm the inflammation where movement asked too much, you ease the muscle that’s gripping around the joint, and you nourish the connective tissue holding it all together. Each herb is answering a specific part of the story rather than treating “sore joints” as one vague thing.

And one last honest note from me, because I’d be doing you a disservice otherwise. Herbs are only ever one piece of this puzzle. A recurring pattern like this one is also asking, gently, for movement breaks, for water, for a real warm-up before you push into anything intense. So let the plants walk alongside the work rather than stand in for it! That’s why we love an integrative approach!

Alright friends, that’s it for Question 2! Later this week, we’re shifting gears into something a bit heavier: a full deep-dive on saponins, one of my favorite corners of plant chemistry to get lost in. If you’ve ever come across a root that foams like soap when you wash it or wondered why saponin-rich plants turn up again and again in traditional medicine, you’ll love this one!

And a friendly reminder before I go: this kind of work, the reading, the sourcing, the physiology-first writing, is a labor of love, and it takes time to do properly. If you’ve been getting something out of these pieces and you’re able to, consider upgrading your subscription. It’s what keeps this whole thing going, and it means more to me than I can easily say.

I’ll see you there. :)

— Agy | The Buffalo Herbalist

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References:

Doma, K., Devantier-Thomas, B., Gahreman, D., & Connor, J. (2022). Selected root plant supplementation reduces indices of exercise-induced muscle damage: A systematic review and meta-analysis. International Journal for Vitamin and Nutrition Research, 92(5–6), 448–468. https://doi.org/10.1024/0300-9831/a000689

O’Hara, B. P., Urban, J. P. G., & Maroudas, A. (1990). Influence of cyclic loading on the nutrition of articular cartilage. Annals of the Rheumatic Diseases, 49(7), 536–539. https://doi.org/10.1136/ard.49.7.536

Proske, U., & Morgan, D. L. (2001). Muscle damage from eccentric exercise: Mechanism, mechanical signs, adaptation and clinical applications. The Journal of Physiology, 537(2), 333–345. https://doi.org/10.1111/j.1469-7793.2001.00333.x

The AMA is not, and never will be, a replacement for a consultation. I cannot and will not answer personal or individualized health questions. Where a question is specific to one person, I’ll answer the general version of it instead.

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Question 1: What herbal remedies should I use, and which should I avoid, with an overactive bladder, to soothe and regulate the pressure and urgency?

Before I get into the herbs, it helps to understand what's actually going on with an overactive bladder, because that's what the whole approach is built around. At its simplest, an overactive bladder is a signaling problem, where the bladder tells your brain it's full and urgent long before it actually is. Researchers trace that faulty signal to a few different places (Chen et al., 2024). Sometimes it starts in the urothelium, the lining of the bladder, which is studded with sensors that can become overactive and fire off urgency messages they shouldn't. Sometimes it's the detrusor, the muscular wall of the bladder itself, contracting when it isn't supposed to. And sometimes it comes from higher up, in the nerves and the brain that process those signals and decide how loud the urge feels. Often, it's some combination of all three, layered on top of other contributors like inflammation, hormonal shifts, or anxiety, which is why an overactive bladder rarely traces back to a single cause (Chen et al., 2024).

Pathogenesis of OAB

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This article is a prime example of my researched deep dives. I start by explaining the physiology behind the topic, walk you through the actual research papers (and no, as you’ll see, I don’t cherry-pick studies to strengthen a claim. If I have questions about a paper, I’m going to show you exactly why. This publication isn’t here to sell you on herbs. It’s here to show you what’s out there, no fluff.), and then we look at what an herb is actually doing according to the evidence. These pieces are long, so please feel free to save this and come back to it whenever you’re ready.

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At some point in the last decade, a very specific story about aging started showing up pretty much everywhere.

It usually gets introduced with the exact same analogy: They’re like the plastic caps on the ends of your shoelaces! AND btw the shoelace caps are called AGLETS so this is basically MY topic to write about!

We are told that every time your cells divide, those little caps fray a bit. When they get too short, the cell stops dividing, you age, and everything goes downhill. The marketing pitch that follows is almost entirely predictable: Buy this incredibly expensive extract of Astragalus root, grow your aglets back, and live forever! YAY!

It sounds beautiful, empowering, and incredibly simple. See you in 500 years!

Buuuuut if medical research has a golden rule, it’s that biology is never simple. Those tiny plastic shoelace caps aren’t a design flaw the body forgot to fix. They are actually part of a highly coordinated, brilliant defense system.

Today, we are going to look at the physiology: why your cells shorten their fuses on purpose, how stress gets under your skin to burn through them, and what happens when supplement marketing stretches clinical trials past their breaking point.

The Mitotic Clock: Why Your Cells Have Fuses

So, what are telomeres, actually?

Your DNA is organized into chromosomes, and those chromosomes are linear, meaning they have ends. The problem with having ends is that every time a cell copies its DNA to divide, the enzyme doing the copying can’t quite finish the job. It needs a primer to get started and can only work in one direction, so a small stretch at the very tip of each chromosome gets left behind every single round (Vaziri et al., 1994; López-Otín et al., 2023). This is called the end-replication problem, and your body has been dealing with it since before you were born.

The solution is a buffer zone. Your chromosomes are capped with long repeating stretches of non-coding text, the sequence TTAGGG over and over, thousands of base pairs deep, sitting between your actual genetic code and the edge that keeps getting nibbled (Vaziri et al., 1994). Those buffers are your telomeres. They’re sacrificial by design, because the alternative would be losing functional DNA with every division, and that’s not something you survive for long.

Telomere

Now think about how much cell division your body is actually running. You’re replacing cells constantly, in your skin, your gut lining, your blood, pretty much anywhere tissue needs to be maintained or repaired. Your bone marrow alone keeps a small population of stem cells on permanent duty, and those cells are responsible for generating your entire supply of red blood cells, white blood cells, and platelets, every single day, for your entire life (Vaziri et al., 1994). That’s an almost unreasonable amount of cellular division, and every single round shaves a little more off the telomere.

Back in 1994, Vaziri et al. (1994) tracked telomere length across human life, from fetal tissue to umbilical cord blood to adult bone marrow from donors ranging from 16 to 58 years old. They found that telomeres shortened by roughly 9 base pairs per year of donor age in vivo, and when those same cells were cultured and asked to divide, they lost about 37 base pairs per population doubling. Every cell in your body is carrying a record of how many times it's divided, written into the length of its own telomeres.

When those telomeres shorten far enough, the chromosome ends uncap, genomic stability falls apart, and the cell is forced into one of two exits: apoptosis, which is programmed self-destruction, or senescence, which is permanent cell cycle arrest (López-Otín et al., 2023). The cell either kills itself or locks up forever. And as we're about to get into, both of those outcomes are the point.

Attrition as Defense

Telomeres act as potent tumor suppressors by limiting proliferation (Barnes et al., 2022).

Your cells are constantly bombarded by chemicals, replication errors, and environmental toxins, all of which threaten genome integrity and stability, meaning your DNA’s ability to stay accurate and intact across every round of copying (López-Otín et al., 2023). If a cell picks up mutations that tell it to multiply uncontrollably, its shrinking telomere is the thing that stops it. The fuse burns down, the cell hits a wall, and the runaway replication ends before it can go anywhere.

Now, your body does have a tool that can rebuild telomeres: an enzyme called telomerase. It’s a specialized reverse transcriptase that uses its own RNA template to add telomeric DNA back onto the chromosome ends (Epel et al., 2004; López-Otín et al., 2023). Pretty elegant, right? But most of your somatic cells don’t express it, and that’s on purpose (López-Otín et al., 2023). Your body would rather let those fuses burn down than risk a cell that can copy itself forever. Because when cells do find a way to bypass that arrest signal and flip telomerase back on, that’s typically what you’re looking at in cancer progression (Vaziri et al., 1994). Telomerase reactivation shows up in more than 80 percent of human tumors (Canale & Andreassi, 2025).

So, when a supplement company tells you their pill is a systemic telomerase activator designed to override this safety mechanism in every cell of your body, I want your first reaction to be a healthy dose of caution, not a visualization of your next thousand years on this earth.

Telomere attrition | Source unknown

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How Life Stress Gets Under the Skin

If somatic cells keep telomerase turned off, what causes some people’s fuses to burn down way faster than others? Chronological time is only part of it, because the biological environment matters immensely, and your mind is directly wired to that environment. ,

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Hi! Another bite-sized herbal medicine goodness for you :)

In this issue:

• What secretory IgA does at the mucosal barrier

• Where your body manufactures it

• How fiber, vitamin A, and ginger each turn up production

• The plot twist about which ginger compounds did the work

I picked IgA off a list of antibody isotypes for a discussion post in my doctoral coursework, partly because (as you may have noticed by now) I have a slight obsession with how much our gut influences every other system in the body. As I was annotating the sources, I immediately knew I wanted to share this with you all. If you like this info and want me to over the other immunoglobulins, just let me know!

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Where IgA Comes From

A surprising amount of your IgA is made in Peyer’s patches, which are clusters of lymphoid tissue tucked into the wall of the small intestine.

Min et al. (2023) describe the intestinal mucosa as holding more than 80% of the body’s activated B cells, which makes the gut the single largest antibody-producing structure you have! Inside the Peyer’s patches, dendritic cells release signaling molecules like IL-6 that tell B cells to mature into plasma cells and begin secreting IgA. The entire production line for your mucosal defense sits right there in the gut wall.

Peyer's Patch + Immune System

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There is a specific kind of thrill the first time you build your own herbal formula. You pull down the jars, measure out the herbs you’ve been reading about for weeks, watch the water go gold or green or deep red, and the whole thing feels a little like brewing a potion in the best possible way. You’re taking your health into your own hands, deciding what goes in and why, and it’s SUCH an empowering feeling. It’s also just plain fun.

The dream, the one I think almost every new herbalist secretly carries, is that you could line up every helpful herb you know and collect all of their gifts in a single cup. It's a bit of a fantasy, sure, but you have to admit it would be incredibly convenient.

One tea that calms your nerves and settles your stomach and supports your liver and lifts your mood, every benefit stacked neatly on top of the last. (why did I just list all the attributes of chamomile?! lol okay this piece is done. JUST USE CHAMOMILE)

With exactly the right combination of plants, it's technically possible to pull something like that off. Most of the time, though, it doesn't work out that cleanly, because herbs start behaving differently the moment you put them in the same room together, working on each other in ways that can make the formula stronger, weaker, or occasionally something you never meant to make at all.

This is what's called herb-herb interaction, and it leans on the same biology we already get so careful about when we mix herbs with medications.

So! This piece is about what these interactions actually are, what they look like once they’re sitting in a real cup of tea or extracting together in a tincture, and, most importantly, what to even do about it.

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Borrowing the Language of Pharmacology

Pharmacologists have spent decades building a vocabulary for what happens when two active compounds meet inside the body, and although the whole framework was developed around drugs, it transfers to plants without much trouble, because an enzyme reading a molecule has no way of knowing whether that molecule came from a pharmacy or a garden and simply responds to the chemical structure in front of it (Niu et al., 2019).

A pharmaceutical is usually a single isolated compound doing one or two well-characterized jobs, while an herb is never anything so simple, arriving instead as a mixture of dozens of active compounds that each act on their own targets and their own enzymes (Gamil et al., 2025). That’s what makes herb-herb interactions so much more complicated than they first look.

Zoom all the way in on a single plant and picture every last phytoconstituent it carries, then add in ALL the phytoconstituents of two or three more plants, and it’s like sardines in there. (And yes, I know the nuance here, not every constituent actually makes it into your cup, since what gets extracted depends enormously on your solvent. For picturing what’s going on, though, hold onto the sardines.)

Combining two herbs in a cup isn’t introducing two things to each other so much as introducing two crowds, where any compound in the first can potentially meet any compound in the second, and that crowdedness is exactly why a formula behaves so much less predictably than a clean pairing of two drugs, and part of why this corner of the science stays so thin.

If this whole idea of plants working as complex systems rather than single molecules is calling to you, I went deep on it in an earlier piece, the synergy between a plant's many compounds and why the whole tends to behave differently than its isolated parts. Here's the fuller story:

The technical umbrella for what follows is pharmacodynamic interaction, which sounds heavier than it is and just means that one compound changes what another compound does once they’re both present (Niu et al., 2019).

The Vocab List:

1. Additivity is the straightforward one, where two compounds do the same job and the combined result is their straightforward sum, 1 plus 1 landing at 2, because you brought more of the same kind of action and got more of that action with nothing new emerging that wasn’t already there in each plant alone (Niu et al., 2019).

2. Synergy is the one herbalists tend to love, where the combination delivers more than the parts should add up to and 1 plus 1 lands somewhere closer to 3, the plants amplifying each other to reach an effect neither could have produced alone (Niu et al., 2019). Just keep in the back of your mind that this amplification doesn't only run in the helpful direction, the same teamwork that makes a formula more effective can magnify a side effect or a risk just as easily, something the research calls negative synergy (Yang et al., 2014).

3. Potentiation is the subtler cousin of synergy, where one compound carries the actual effect while a second compound does little or nothing on its own yet makes the first dramatically more powerful, so the math reads less like 1 plus 1 and more like 0 plus 1 landing at 3 (Gamil et al., 2025). It’s worth a closer look, and we’ll cover it more here in a second.

4. Antagonism runs the other direction entirely, one compound dragging down the effect of the other, so the pair accomplishes less than you’d have predicted and 1 plus 1 falls short of 2 (Niu et al., 2019). We’re going to get into this one here as well.

Pharmacodyamics

Take a minute and read through this graphic, as I really think it’s important to understand the different ways herbs (and medications) can interact with each other. This graphic explains the HOW.

Potentiation: The Multiplier

Potentiation deserves its own moment here, because it’s truthfully the easiest of the four to miss in your own formulas, and really only because it isn’t something you can intuitively feel out the way you can with the others. It’s more of a memorization thing, a relationship you have to know is possible before you’ll think to look for it. So, let me give you a couple of examples to make it stick.

Let’s start with berberine, the antimicrobial alkaloid in goldenseal and barberry. Bacteria actually have a defense against berberine (who knew?)! It's essentially a pump that shoves the alkaloid back out of the cell before it can do much harm, so on its own berberine spends a lot of its strength fighting that current.

Certain berberine-producing plants happen to also make a compound called 5'-methoxyhydnocarpin. On its own, this compound does nothing to the bacteria at all. What it does do is jam that berberine-ejecting pump, and with the pump out of commission, the berberine pools inside the bacterial cell and turns dramatically more lethal, in some studies by as much as 100-fold (Yang et al., 2014). The second compound never lands a punch of its own, its entire contribution being to make the berberine's punches connect.

Our next example, and one you’ve probably encountered without knowing its name, is the black pepper that so often turns up in a turmeric blend. The piperine in the pepper slows the breakdown of curcumin so that far more of it survives into your system, which means the same dose of turmeric does considerably more (Gamil et al., 2025). The mechanism is a little different from the berberine story, since pepper is changing how much curcumin gets through rather than disarming a defense, though the shape of the relationship is identical. One ingredient supplies the effect, the other multiplies it.

This is why I want you carrying potentiation around in your head as you build things, because the ingredient responsible for a formula overperforming is so often the one you’d never have suspected, the so-called bystander that turns out to be the entire reason the active herb is pulling its weight. Leave that compound out and the formula underdelivers for reasons that won't be obvious, since the herb you were counting on never reaches its full strength.

Now, this is what I really need you to sit with, because everything I've described so far makes potentiation sound like a gift. It can just as easily be the thing that hurts someone. The mechanism doesn't care whether the effect it's multiplying is one you wanted, and the same combining that strengthens a formula can just as readily strengthen something harmful (Yang et al., 2014). If a plant potentiates something beneficial, great. If it potentiates something toxic, or a medication the person is already taking, that same multiplying effect is now working against them.

Think back to the berberine pump for a second. Your own body runs similar efflux pumps to clear certain drugs out of your system, and plants are well documented to jam those human pumps and the metabolic enzymes that work alongside them, which lets a pharmaceutical climb to levels the prescriber never intended (Gamil et al., 2025). This is the exact reason potentiation sits at the center of so many herb-drug interaction warnings, and it's why it pays to ask not only what's in the formula, but what else is in the person.

Antagonism: When Plants Work Against Each Other

Antagonism is super important to talk about here, because this action causes the whole formula to fall apart and start working against itself. There are two subcategories I want to touch on: counteraction and incompatibility.

Counteraction is where one plant cancels out the effect of another, deeming the latter essentially useless in the formula. Annoying, I know. Even more annoying is that this can be seen in ginseng (Panax ginseng) and ashwagandha, a pairing I feel the entirety of wellness influencers are pushing right now. Ginseng is a stimulant at its core, revving you up and sharpening your focus, while ashwagandha is doing pretty much the reverse, settling your nervous system and bringing your stress response down (Gamil et al., 2025). So you take them together, and what happens? One foot on the gas, one foot on the brake. You just paid good money for two useful herbs and you’re going to feel the real benefit of, well, neither. (There’s an even weirder one buried in the research, where turnip juice was shown to completely wipe out the genoprotective activity of ginseng. Turnip! Ginseng! Two things you would never in a million years suspect of cancelling each other out (Che et al., 2013).)

Now, counteraction isn’t automatically a bad thing. Sometimes dialing a plant down is exactly what you’re after, like reaching for one herb specifically to take the edge off another that runs too strong or too harsh on its own. The mechanism is identical either way, and it only becomes a problem when the effect getting cancelled was the one you were counting on.

Incompatibility is next, and this is where two plants unintentionally team up to cause a real problem, one that neither would ever have caused alone. This is best explained by an example, and we’re going to call licorice up to the front. Licorice is everywhere and so easy to wave off as harmless. By itself, it nudges your body into holding onto sodium and dumping potassium, and a healthy person on a reasonable dose and timing schedule has no reason to give that a second thought (Yang et al., 2014). The trouble starts when you put it next to another plant doing the same thing. Pair licorice with horsetail, a diuretic that flushes potassium right out of you, and now you’ve got two herbs draining the same mineral at the same time, which can drop potassium low enough to land someone in actual danger, especially anyone with a heart condition or already on blood pressure meds (Gamil et al., 2025). Two perfectly ordinary plants, and put together? A real danger to the wrong person.

The takeaway here is that none of these four interactions is good or bad on its own. Additivity is the predictable baseline, two herbs simply summing their shared effect, no surprises in either direction. Synergy and potentiation can hand you a formula that works better than either herb could alone, or they can amplify something you very much did not want amplified. Counteraction can waste a good herb, or it can soften one that was too strong. And incompatibility is the corner where a careful, good-hearted blend can turn into something that does real harm. What every one of them rewards is the same thing: knowing what’s actually in your cup and what those things do once they’re together.

Before You Build Your Next Formula

The plants in a formula are never just sitting beside one another waiting their turn. They interact the entire time, lifting each other up, cancelling each other out, and every so often combining into something neither one would have managed alone. It all runs on the same biology your body uses to process a pharmaceutical, which is exactly why herb-herb interactions deserve the same caution we already give to herb-drug ones.

So do this for me, pleasepleaseplease. Before you put a formula together, spend a few minutes looking up the herbs you’re combining and check whether any known interactions exist between them. It’s tedious and it won’t always turn something up. Do it anyway. The research here is thin, thinner than most people realize, and a few minutes of checking is what separates a formula you built from one you just hoped about.

I keep thinking that in some mythical pocket of free time (which does not exist for me right now, let’s be honest) I’d love to make a printable for this, something that lays out the interactions you’re most likely to run into, that you could keep near your jars and actually reach for. No promises. But it’s rattling around in my head.

And the big one, the thing I’ll repeat as many times as it takes: natural does not mean safe. It never did. These plants are chemically active and seriously powerful, and that’s the reason they can do so much for us and the reason they have to be handled with care. Taking herb-herb interactions seriously is part of taking the plants themselves seriously.

If you’ve been finding value in this kind of work, consider upgrading to a paid subscription. It’s the most direct way to support these deep dives, and paid subscribers get access to every past and future piece in the archive, the Materia Medica Index, and the Body Systems Index, both of which are growing into a real working reference library you can use alongside your own practice and studies.

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Either way, I’m glad you’re here.

Until next time,
— Agy | The Buffalo Herbalist

References:

Che, C. T., Wang, Z. J., Chow, M. S. S., & Lam, C. W. K. (2013). Herb-herb combination for therapeutic enhancement and advancement: Theory, practice and future perspectives. Molecules, 18(5), 5125–5141. https://doi.org/10.3390/molecules18055125

Gamil, N. M., Elsayed, H. A., Hamed, R. M., Salah, E. T., Ahmed, A. M., Mostafa, H. A., El-Shiekh, R. A., & Abou-Hussein, D. (2025). Insights from herb interactions studies: A foundational report for integrative medicine. Future Journal of Pharmaceutical Sciences, 11, 46. https://doi.org/10.1186/s43094-025-00794-7

Niu, J., Straubinger, R. M., & Mager, D. E. (2019). Pharmacodynamic drug–drug interactions. Clinical Pharmacology & Therapeutics, 105(6), 1395–1406. https://doi.org/10.1002/cpt.1434

Yang, Y., Zhang, Z., Li, S., Ye, X., Li, X., & He, K. (2014). Synergy effects of herb extracts: Pharmacokinetics and pharmacodynamic basis. Fitoterapia, 92, 133–147. https://doi.org/10.1016/j.fitote.2013.10.010

Somewhere early in your herbal education, usually around the time you’re learning about topicals and comfrey, you get handed a huge, glaring red STOP SIGN about ever taking the plant internally, along with some vague hand-waving about pyrrolizidine alkaloids. (How are you even supposed to pronounce that? Don’t ask me.)

We’re told it’s super toxic to the liver, just don’t consume it internally. Okay. Got it. External use only. You learn the same lesson and memorize the same buzzwords for coltsfoot and for borage, not reallllyyyy fully understanding why, but you’re not going to be the one to give someone a toxic spoonful, so you obediently oblige. As you should.

But this piece is for those of you who took the caution to heart and then also asked, bad how? To what? Why only internal ingestion? Those are the questions that separate someone who can repeat a warning from someone who actually understands the plant in front of them, and they happen to have real, knowable answers.

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Why a Plant Would Bother Making a Poison

Start with the plant’s point of view.

Plants are rooted in one spot, they can’t run from anything that wants to eat them, so they fight back with chemistry instead. The compounds these plants make for this kind of job are called secondary metabolites. Where the sugars and proteins keep them alive and growing day to day, these are the extra compounds they invest in for defense, communication, and protection.

You already work with these constantly. The caffeine in coffee, the capsaicin that makes a chili pepper burn, the bitter alkaloids in goldenseal, the aromatic oils in thyme and oregano, all of these are secondary metabolites, and most of them started out as the plant’s way of deterring something that wanted a bite.

Pyrrolizidine alkaloids, PAs from here on, are one of those chemical defenses. The plant makes them to poison the insects and grazing animals that would otherwise treat it like a salad bar (Schramm et al., 2019). They work well enough that they’ve spread across something like 6,000 plant species, roughly 3% of all the flowering plants on earth, and they cluster in families you already know intimately, including the daisy family, the borage family, and the legumes (Schramm et al., 2019). Comfrey, borage, coltsfoot, and the various ragworts are all sitting somewhere on that map.

So the first thing to flip in your head is that PAs aren’t a flaw or a contaminant the plant accidentally picked up. The plant makes them on purpose, and they’re doing exactly the job they evolved to do, which is to make herbivores regret the decision.

Main factors influencing PAs occurrence and contents in plant material (Tábuas et al., 2024).

Not Every PA Is the Dangerous Kind

So are all PAs the same thing? That’s certainly how they get talked about, with one name and one warning and one big red stop sign thrown over the whole sprawling family. The reality is a bit messier, because “pyrrolizidine alkaloid” is a label that covers hundreds of related compounds, and they don’t all behave the same way once they’re inside you, which means some of them are essentially harmless while others are the ones every warning is actually written about.

What decides which camp a given PA falls into is almost absurdly small.

If you looked at the actual chemical structures side by side, they’d all share the same general two-ring shape, and the entire difference between harmless and dangerous comes down to a single bond in one specific spot on that shape. That one bond changes enough that chemists actually file the two versions under different names, but the names are a lot for anyone who isn’t doing this for a living, and you don’t have to file them away or memorize them. I just want you to hold onto the concept as a whole, which is about as simple as it gets: double bond means toxic, no double bond means we’re okay. The molecules that carry a double bond in that spot are the ones the warnings are about, and the molecules where it’s filled in are the ones the body handles without much trouble (Xu et al., 2019). One bond, sitting in one position, is the line between a plant you can work with and a plant that can hurt someone, and it’s the very same bond that lets your liver get involved in the first place.

PA structure depicting double bond

You don’t have to be able to draw any of this! That would be crazy. All I want you to take away is THIS, that the mere presence of that one double bond is what tips a PA from harmless to toxic.

The real questions, when it comes to these compounds, I want you asking instead are: which kind, and how much, since a plant carrying the harmless version isn’t remotely the same proposition as one loaded with the dangerous version, even though both of them would set off the same alarm if the family name is all you knew to look for.

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Body First: What Actually Happens Once You Swallow It

Now to my favorite part, the physiology, where that one little double bond stops being a piece of chemistry trivia and starts explaining everything the warnings were only waving at. Ready?

Let’s follow the PA in, right? You swallow it, down it goes, down the hatch, it crosses out of the gut and into the bloodstream, and like almost everything absorbed from the digestive tract it gets routed straight to the liver before it reaches the rest of you.

At this stage it’s still the potentially harmless version, the intact alkaloid the plant made, drifting along essentially inert, chillin, enjoying the lazy river ride.

The trouble begins when it meets the liver’s enzymes, the cytochrome P450 family, and one of them in particular called CYP3A4 (Xu et al., 2019). These are the same workhorse enzymes your liver leans on to break down all sorts of things, from medications to caffeine, and most of the time that’s exactly what you want them doing.

With one of these molecules, though, the enzyme grabs it right at that double bond (!!!!) and reshapes it into something violently reactive, and that new reactive form is the actual poison, something your own body has just built out of a compound that walked in potentially harmless. (Not super cool of us to do to ourselves if I’m being honest)

Read more about the CYP450 system here:

This is the whole reason the route matters so much, and the buried logic behind that “external use only” rule you memorized years ago. It also unlocks a phrase that may be something you heard while learning about all this, but maybe didn’t really get: bypassing first-pass metabolism.

When you swallow something, it gets absorbed through the gut and sent directly to the liver before it’s allowed out into the rest of your circulation, and that mandatory first lap through the liver is the “first pass.”

For a lot of compounds that first pass just means the liver breaks down a chunk of the dose before it can do anything. For a PA, that first pass is the whole problem, because the liver is exactly where the harmless molecule gets rebuilt into the reactive one. Rubbed into the skin over a bruise, though, these compounds slip into circulation through the tissue directly and skip that mandatory trip through the liver, which is what bypassing first-pass metabolism actually means, and it’s why they never undergo that dangerous conversion in any real amount when they’re used topically. Swallowed, they’re handed straight to the one organ equipped to make them dangerous.

Source Unknown

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That reactive form doesn’t sit around politely once it exists. It’s desperate to bond with something, anything stable it can grab, and the inside of a liver cell offers it no shortage of partners, so it fastens onto proteins and onto DNA and forms what are called adducts, permanent attachments that gum up and corrupt whatever they stick to (Xu et al., 2019).

It even clamps onto a piece of the cell’s energy machinery, jamming up the mitochondria that are meant to keep the cell powered and running. All the while the cell is trying to defend itself, and its main line of defense is a molecule called glutathione, which is easiest to picture as the cell’s built-in fire extinguisher, the thing it grabs to smother reactive threats before they can do their damage. The catch is that a cell only carries so much of it, and the flood of reactive PA burns right through that reserve, so as the glutathione drains away the cell slides into oxidative stress, the state where damaging molecules pile up faster than the cell can clear them (Xu et al., 2019). The injury feeds on itself from there, with the mounting damage to proteins and mitochondria and DNA pushing the cell toward apoptosis, its own built-in self-destruct sequence, until cells begin dying off in earnest (Xu et al., 2019).

The cells that suffer most are the delicate ones lining the liver’s smallest blood vessels, tucked in a specific region of the liver, and they turn out to be especially defenseless as their own glutathione runs dry (Xu et al., 2019). As that lining gets damaged the cells lose their structural footing, pull away from one another, and start sloughing off the vessel walls, and the debris they shed clogs those tiny vessels from the inside. Blood that should be moving through the liver gets choked off, pressure builds up behind the blockage, and with the source still arriving the congestion can climb all the way to scarring, liver failure, and death (Xu et al., 2019).

The injury even has its own name, hepatic sinusoidal obstruction syndrome, and it kills a meaningful share of the people who develop it, and that’s how a molecule that walked in potentially harmless ends up strangling the liver’s smallest vessels from the inside out.

So, when a label flattens all of that down into the single word “hepatotoxic,” this is the physiology hiding underneath it. It’s a specific, traceable chain of events that starts with one double bond and runs straight through the very enzymes you count on to keep you safe. Now you know you the ins and outs of it.

If you have to read this section a few times to let it land, go ahead, there's really no easier way to break it down. Well, let me try anyway:

PA with a double bond → liver converts it into the mean reactive chemical → that chemical floods the cells lining the liver's small blood vessels, binding things it shouldn't and burning through their glutathione defenses → those cells get overwhelmed and start dying off → the dead cells slough away and clog the vessels → blood flow backs up → bad news.

Okay that’s not as bad as I thought!

How Worried Should You Really Be

You can see how the damage actually happens, and the question of risk gets a lot more answerable, because what you actually want to weigh is the realistic exposure, by what route, in what amount, and over how long, and there are a few things that shape the honest answer. (those questions from earlier!)

The first is that the exposure you ought to worry about is usually the one you never see coming, because beyond knowingly brewing a tea from a PA-rich herb, people take these compounds in through ordinary contaminated food like honey, milk, grain, and commercial herbal teas (Schramm et al., 2019; Wei et al., 2021). The way it sneaks in is sneakier than you’d guess, since PA-producing weeds get swept up by accident alongside the crop that was actually meant for harvest (eek!), and their alkaloids simply ride along into the finished product. And it gets stranger than that, because there’s research showing that plants which make no PAs of their own at all, peppermint and chamomile and parsley among them, pulled the alkaloids up out of soil that had PA-containing plant matter decomposing in it, drawing them in through their roots within a matter of days (Schramm et al., 2019). The name on the label, in other words, isn’t always the whole story of what ends up in the cup.

The second is that dose and duration are what truly carry the risk, which is exactly why health authorities frame their guidance as small daily limits rather than banning these plants outright. A single cup of something isn’t going to fell you, you’ll be okay, and that was never really the worry. The danger is the small amount taken steadily over a long stretch, since the damage adds up in the background where you can’t feel it happening, and by the time it announces itself the harm is already done. Comfrey in particular has been the flashpoint here, with the FDA telling supplement makers to pull it from the market all the way back in 2001 (Wei et al., 2021). Acute intake, okay. Chronic exposure? Not so much.

The third loops us right back to where we started, with the two camps, because not every PA plant carries the same weight of risk. The kind of alkaloid and the sheer amount of it swing enormously depending on the species, on which part of the plant you’re using, on how old that plant is, and even on the conditions it grew up in, so the plant making the harmless type is nowhere near the same proposition as the one loaded with the dangerous type, however much they happen to share a family name.

From a Warning to a Working Understanding

None of this is meant to talk you into or out of any particular plant. It’s meant to swap a one-word label for an actual picture of what’s going on. When you can see that only some PAs are the dangerous kind, that the dangerous ones sit potentially harmless until your liver rebuilds them into something that isn’t, that the injury they cause is a specific strangling of the liver’s small vessels, and that the real risk comes down to type, dose, duration, and the contamination you never saw coming, you’re no longer just reciting that comfrey is toxic. You’re reasoning about why, and how much, and by what path.

The warnings obviously exist for a good reason. The chemistry is real and the disease is serious, and I’m not asking anyone to loosen their guard. What I am saying is that understanding the mechanism puts you in a completely different position than just memorizing the verdict did. You can think clearly about exposure, you can read the next contamination headline with the right amount of concern instead of the maximum amount, and you can give the plants in this family the specific, informed respect they’ve actually earned, which is a great deal more than they get from a red stop sign and a word you can barely pronounce.

If you learned something new today, and you’re finding value in this work, please consider upgrading your subscription. Your support is what keeps me able to do this, the long nights with the research, the sourcing, the writing and rewriting until the science actually makes sense.

Upgrading unlocks all of it: the full Body System Index, the Materia Medica Index, and the entire archive of long-form articles sitting and waiting for you to dig in.

Thank you for being here, and for caring enough to really understand the plants you work with. It means the world to me.

— Agy | The Buffalo Herbalist

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References:

Ebmeyer, J., Braeuning, A., Glatt, H., These, A., Hessel-Pras, S., & Lampen, A. (2019). Human CYP3A4-mediated toxification of the pyrrolizidine alkaloid lasiocarpine. Food and Chemical Toxicology, 130, 79–88. https://doi.org/10.1016/j.fct.2019.05.019

Schramm, S., Köhler, N., & Rozhon, W. (2019). Pyrrolizidine alkaloids: Biosynthesis, biological activities and occurrence in crop plants. Molecules, 24(3), 498. https://doi.org/10.3390/molecules24030498

Wei, X., Ruan, W., & Vrieling, K. (2021). Current knowledge and perspectives of pyrrolizidine alkaloids in pharmacological applications: A mini-review. Molecules, 26(7), 1970. https://doi.org/10.3390/molecules26071970

Xu, J., Wang, W., Yang, X., Xiong, A., Yang, L., & Wang, Z. (2019). Pyrrolizidine alkaloids: An update on their metabolism and hepatotoxicity mechanism. Liver Research, 3(4), 176–184. https://doi.org/10.1016/j.livres.2019.11.004

Hi! What I have here for you today is another bite-sized piece of herbal medicine goodness :) ON THE WEEKEND?!

Alright, in this issue:

• What nettle (Urtica dioica) does to a fired-up immune cell

• Why “immunomodulation” is more than an herbalist’s word

• The lectin that blocks viruses at the door

• Science catching up to what tradition already knew :)

Nettle has a reputation as one of the most nutrient-dense plants you can steep in hot water. The leaves carry vitamins A, C, and K, a long roster of minerals including iron, calcium, and magnesium, plus a stack of polyphenols layered on top, all of which Bhusal et al. (2022) document at length. And because my mind has been on the immune system lately, (that sounds like it’s a peaceful little thought but I’m actually drowning in immunology in my DSc coursework, so you’re with coming me) I asked myself the question that kept tugging at me.

What does the literature actually say about nettle and immunity?

I went on a hunt. A quick google, if you will, that turned into something considerably longer.

One thing jumped out before I got anywhere near a mechanism. A surprising amount of the immune research on nettle has been done in animals. Fish, chickens, dairy cows. I have to say, I love that they’re getting their representation. The standout for me was the aquaculture work in Bhusal et al. (2022), where rainbow trout fed a nettle-supplemented diet showed higher lysozyme and complement activity and significantly lower mortality after infection with a common fish pathogen. I hope they’re feeding fish nettle. That would be nice of them, I think.

There’s more out there on poultry and dairy cattle too, and if that’s a rabbit hole you want to go down, say the word and I’ll go digging again. For now, I want to turn to the question I actually came for, which is what nettle does in us (the humans).

One quick thing before we get into it: if you want to get your hands on any of the herbs I talk about here, you can use my Mountain Rose Herbs link to grab them. Full transparency, I do earn a small commission on anything you purchase through it, at no extra cost to you.

Moluntain Rose Herbs

NOTE : This article is for educational purposes only. Nothing here is intended to diagnose, treat, cure, or prevent any disease, and it isn't a substitute for individualized care from a qualified healthcare provider.

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The lymphatic system has a branding problem, in my humble opinion.

Ask most people what it does and you’ll get something vague about drainage, maybe a comment about swollen lymph nodes during a cold, and then a trailing off. Which is fair, because that’s also roughly how it gets taught: fluid transport, waste removal, filters things. All true! But they’re collectively the least interesting things this system can do – hear me out.

If you’ve spent any time studying herbs for the lymphatic system, you’ve probably noticed something a little odd. Cleavers comes up. Calendula comes up. Echinacea too. You go looking for the explanation and what you usually get is some version of “it gets things moving,” which isn’t really an explanation so much as a description with zero context. And if you look even a little closer, those same plants keep showing up in the immune category too.

So, which is it? Are two completely different mechanisms converging in the same plants, or are lymphatic actions and i…

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Last summer I spent an entire day at a horseshow with my shoulders out and didn’t reapply sunscreen once. By the time I got home my skin was screaming, so I did what most people would do and reached for a bottle of aloe vera gel sitting in my bathroom. It worked (thank goodness)! The redness calmed within hours and the skin underneath healed without scarring. I do have freckles though, but that’s fine.

This is the relationship most of us have with aloe vera. It lives in the bathroom, shows up after a burn, and the bottle says something reassuring like pure aloe on the front. The plant has thousands of years of medicinal use behind it and a long-earned reputation as one of the gentler healers in the materia medica.

What I want to bring to your attention today is that the word aloe on a label can point to several different preparations with profoundly different safety profiles, and the labeling system in the United States gives consumers almost no way to tell which one they’re actually b…

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Back in the fibermaxxing series we spent a lot of time on what happens once soluble fiber finally makes its way down to the colon, where the bacteria living there ferment it and produce a small family of short-chain fatty acids as a result, mostly acetate, propionate, and butyrate. That part of the story has been having a moment lately, and honestly, it deserves the airtime.

But here’s the thing nobody talks about at the dinner party: we spend all this time obsessing over fiber and butyrate as if the molecule itself is the prize, when really, butyrate is just the beginning. The bacteria make it, sure, but then what? Where does it go? What does it actually do once it leaves the bacterial cell that produced it? That’s the part of the story I want to spend some time with today, because once you understand it, the whole picture of why fiber matters for everything from autoimmunity to mood to brain fog starts to click into place.

But also - if anyone is having a dinner party where these topics are being discussed, please invite me. I don’t like olives or capers but otherwise I’m a great guest lolol.

Here’s where we’re headed:

• How butyrate works as a signaling molecule, not just a fuel source

• Why butyrate-producing bacteria keep showing up as the missing piece in conditions that look nothing alike

• How a molecule made in your colon ends up influencing immune cells in your brain

• What all of this means when you’re sitting across from a client wondering where to start

Buckle up buttercup!

This piece is also serving a little amuse-bouche to the larger gut-immune deep dive I’m working on. I want to give you some of the fundamentals, so when that piece rolls around it actually lands. Why do I keep using food analogies? I must be hungry.

PS. Don’t forget about The Body System Index! All physiology-first articles organized for you by body system :) I’ll be spending the weekend updating it!

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Hey friends!

I promised you wild lettuce this week, and wild lettuce is not what’s landing in your inbox. The species sprawls in ways that deserve more attention than I could give it, the human studies on Lactuca virosa are thin in the places I most wanted them thick, and after a week that asked a lot of me for reasons I’m going to keep off the page, the idea of producing that monograph on the deadline I’d set for myself stopped being realistic. I didn’t want to leave you with silence, and I’m already so late with this post, so I’m reaching into the coursework folder and pulling out an assignment I actually liked.

I’ve cleaned it up, added a closer on the most-researched immune herb in the Western materia medica, and put the whole thing here for you.

I’m not sure if the wild lettuce piece will come. I’m hitting a lot of resistance with it and maybe that means it’s just not for me to write. So, why fight it and write a piece I’m not fully present in. You know? I hope that’s okay. I’m really sorry.

Anyways, here’s what we’re covering today:

• How the body’s three layers of defense are actually structured (the barriers, the innate response, and the adaptive response)

• What macrophages and the rest of the innate cells are doing in those first minutes after an invader gets past the barriers

• How the adaptive immune system gets called in when the innate response isn’t enough, and how it builds the memory that protects you for years afterward

• Where the two arms differ in speed, specificity, and memory, and why that distinction shapes how everything else works

• The bridge between innate and adaptive immunity, where dendritic cells essentially teach the adaptive system what kind of response to mount (this is the most beautiful piece of the architecture, in my opinion)

• What happens when the system fails, through immunodeficiency, hypersensitivity, and autoimmunity

• A closing look at echinacea, the most-researched immune herb in the Western materia medica, and where its mechanism actually fits in the framework we just built

At the end of this, I want you to be able to look down at a splinter poking out of your skin, or take internal stock of exactly what's happening during a pesky cold, and actually narrate it to yourself. "My B cells are working hard replicating these antibodies right now." "My macrophages are eating some delicious gunk right now." :) That kind of thing.

Alright. The immune system, on a cellular level. Let’s get into it.

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The Body’s Layered Defense

Most of what gets sold to you as immune support assumes the immune system is a single thing, one knob you can turn up or down, one circuit you can stimulate. The actual architecture is layered, redundant, and gorgeous in a way that I think gets lost in the supplement-aisle version of the story. It’s an intricate dance.

Your body keeps invaders out through three coordinated tiers, each with its own primary role in the larger response (Sompayrac, 2022):

• The physical barriers, which keep most invaders out entirely before any cellular response ever has to happen

• The innate immune system, which mounts a fast, broad response when those barriers are breached

• The adaptive immune system, which builds a slower, more precise response tailored to the specific invader and remembers it afterward

• The handoff between these layers is where most of the real intelligence in this system lives, and that handoff is the part of the story I want to spend the most time on today.

Here's what I want you to sit with for a second, because the layering itself is the point. Every tier of this system is doing intentional work, with each layer covering what the others can't quite reach and the gaps in one filled by the strengths of another. Even the old textbook line that the innate arm has no memory has started to soften in the last decade or so, as researchers have found that some innate cells can in fact be primed for stronger responses on subsequent exposures (more on that in a minute). The shape of the whole thing is intentional, and the more closely you look at it, the more obvious that becomes.

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The First Lines: The Innate Immune System

Once something has gotten past your barriers and is loose in the tissue, the first cells likely to encounter it are macrophages. They sit in tissues throughout your body, ready to recognize what doesn’t belong, and they do this using surface receptors tuned to pick up specific fats and carbohydrates that pathogens carry on their surfaces, the so-called “danger molecules” (Sompayrac, 2022). When a macrophage recognizes one of these patterns, it engulfs the pathogen into a phagosome, which then fuses with a lysosome packed with enzymes and reactive chemicals that destroy the invader from the inside. This whole process is called phagocytosis, and it’s happening in your body constantly, mostly without your awareness (Sompayrac, 2022).

While the macrophage is doing the eating, it’s also doing the talking. As it engulfs the pathogen, it secretes cytokines, which are hormone-like messengers that coordinate communication between immune cells and signal for the inflammatory response to begin (Sompayrac, 2022).

Inflammation has been miscast as a villain in a lot of the wellness conversation, when in practice it’s the recruitment mechanism the body uses to pull additional players to the site of trouble. The redness, the heat, the swelling, all of it is the body actively mobilizing, calling in neutrophils, which are the most abundant phagocytes in circulation, and natural killer cells, which target host cells that have already been compromised by viruses or other stressors. In parallel, the complement system activates, a cascade of plasma proteins that marks pathogens for destruction and amplifies the recruitment of immune cells to the site (Wang et al., 2024).

This entire response can mount within minutes to hours, and for most everyday encounters with pathogens, it’s enough. The infection is contained at the site, the affected tissue heals, and you never have any sense that anything happened.

The rest of this piece is for paid subscribers. Below the paywall, I cover how the adaptive immune system gets called in when the innate response isn’t enough, the bridge between the two arms where dendritic cells essentially teach the adaptive system what kind of response to mount (this is the most beautiful piece of the architecture, in my opinion), what happens when the system fails through immunodeficiency, hypersensitivity, and autoimmunity, and the full closing section on echinacea, including the caveat about who I’d hesitate to give it to, the mechanism mapped onto the innate response, and traditional preparation notes.

If you’ve been finding value in this work, please consider upgrading to support it. Paid subscribers also get access to the Materia Medica index and the Body Systems index, both of which are building out into a real working library you can use alongside your own practice.

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