I’m going to talk to you about something today that totally changed my career. When I finished my gastroenterology fellowship and started seeing patients on my own, I noticed something I could not stop thinking about.

A number of my patients with Parkinson’s disease shared an interesting common thread. Long before the tremors, long before changes in movement posture or the shuffling gait that most people picture when they hear the word “Parkinson’s,” they had come to doctors like me with a gut that was not working right. Usually it was constipation — sometimes it was nausea. And it started years, maybe decades, before their Parkinson’s diagnosis.

At first I told myself it was a coincidence. Constipation is common, and Parkinson’s mostly arrives later in life, when a lot of things about the body have already started to slow down. But the pattern kept repeating in my exam room, and as I dug more into the literature, it turned out I was not imagining it. As many as 8 in 10 people with Parkinson’s develop gastrointestinal problems, and for those with severe disease, the burden of those symptoms can weigh on quality of life even more heavily than the tremors themselves.¹ Somewhere in there, a question took hold of me that I have now spent years of my career trying to answer: what if, for some people, Parkinson’s does not begin in the brain at all? What if it begins in the gut?

What the gut-first hypothesis actually says

Parkinson’s has long been understood as a disease of the brain, and in the most literal sense it is. Its motor symptoms come from the loss of dopamine-producing neurons deep in a region called the substantia nigra. By the time a neurologist can make the diagnosis, a great many of those neurons are already gone.

But in the early 2000s, the neuroanatomist Heiko Braak proposed something that reordered the story.² He and his colleagues observed that the misfolded protein that defines Parkinson’s, called alpha-synuclein, did not appear in the brain first in a predictable way. In a subset of people, it seemed to show up earlier, and lower, in the nerves that line the gut. From there, the theory goes, the misfolding spreads the way a rumor spreads: one badly folded protein induces its neighbor to misfold, and the corruption travels upward along the vagus nerve, the great information highway that connects the gut to the brainstem. Only after this slow migration, which may take years or even decades, does the pathology reach the substantia nigra and begin to kill the neurons that produce the visible disease.

If that is true, then the gut is not a bystander. It may be the origin.

The evidence is genuinely striking. Gastrointestinal symptoms are among the earliest features of Parkinson’s, appearing as much as 20 years before any movement problem. Working with my colleagues, I helped identify four gut symptoms that tend to cluster in this long prodromal window: dry mouth, heartburn, difficulty swallowing, and constipation.³ These findings have also been shown in other studies across the world. Constipation in particular has become such a reliable early flag that it’s been formally added to the research criteria for prodromal Parkinson’s.⁴ One large study found that people with severe constipation went on to develop Parkinson’s at strikingly higher rates than those without it.⁵ And in perhaps the most tantalizing clue of all, people who underwent a surgery decades ago that severed the vagus nerve — a procedure once used to treat severe acid reflux — turned out to be almost half as likely to develop Parkinson’s later in life.⁶ If you cut the highway, the theory suggests, the pathology cannot make the trip to the brain.

I want to say something here that I say to my patients, because I know how a paragraph like the one above can land: most people who get constipated will never develop Parkinson’s. We all get constipated. These are population-level patterns and risk signals, not personal prophecies. Please do not read this and diagnose yourself tonight. But if you’re someone who has new constipation and many other “prodromal” signs of Parkinson’s disease, such as loss of smell or acting out your dreams and trouble sleeping, it’s worth talking to your physician about.

How I ended up studying a “brain” disease

People are often surprised to learn that a gastroenterologist has spent years studying Parkinson’s. I was surprised too, honestly, when I realized where my own curiosity was taking me.

What began as a pattern I kept noticing in clinic became a review of the literature, which became a set of questions I could not shake, which eventually became my research program, supported by a career development award from the National Institutes of Health, called a K23. The purpose of that award is to protect the time of early-career physician-scientists so we can build a body of work around a single hard problem. Mine is this one: understanding how, and why, Parkinson’s may begin in the gut, and whether we might intervene before it ever reaches the brain. I’m also trying to better understand the complexities of dopamine signaling in the gut — as it turns out, the brain in your gut, also known as the enteric nervous system, is also producing hormones and neurotransmitters like dopamine, and these play a big role in many diseases, as I recently wrote in a Nature review.⁷

There is a practical reason this work matters beyond the elegance of the hypothesis. Despite how common gut symptoms are in Parkinson’s, only a small fraction of patients — in one analysis from our own center, roughly 1 in 8 — are ever referred to a gastroenterologist.⁸ These are treatable symptoms in a population that suffers with them quietly. Even if we set the origin question aside entirely, there is real relief we are failing to deliver.

The question that keeps me up at night: what is the trigger?

If Parkinson’s can start in the gut, the natural next question is: what starts it in the gut? What is the first insult, the inciting event that convinces alpha-synuclein to begin misfolding in the first place?

This is where my lab has tried to add a piece to the puzzle. We reasoned that if something injures the gut lining to set this process in motion, then a visible, documentable injury to that lining ought to leave a fingerprint in people’s later risk. So we looked at the upper gut, and specifically at mucosal damage: the ulcers, erosions, and inflammation that we can actually see and biopsy during an endoscopy.

In a study published in JAMA Network Open, my colleagues and I followed more than 9,000 patients who had undergone an upper endoscopy with biopsy between 2000 and 2005, tracking them for roughly 15 years to see who went on to develop Parkinson’s.⁹ The people who had shown mucosal damage on that early endoscopy were about 76 percent more likely to be diagnosed with Parkinson’s down the line, even after we accounted for age, sex, and other risk factors. On average, the damage preceded the diagnosis by more than 14 years — squarely inside that long prodromal window the theory predicts.

I want to be careful about what this does and does not prove. An association is not a mechanism. There are at least two honest ways to read our findings. The first is the one that excites me: that injury to the gut lining may be one of the triggers that precipitates alpha-synuclein misfolding, an early domino in the chain. The second is more sobering and equally possible: that dopamine helps protect the stomach lining, so a person whose dopamine signaling has already begun to falter — silently, years before any tremor — might simply be more prone to mucosal damage in the first place. In that version, the damage is not the cause but an early symptom. We do not yet know which is true, and untangling that is exactly the kind of work these years are for.

Where this is going and how to lower your risk

Here is why I find all of this worth a career. Parkinson’s affects millions of people worldwide, and we still do not have a single therapy that changes its course. Everything we offer treats the symptoms while the underlying disease marches on.

But a disease that begins in the gut, years before it reaches the brain, is a disease with a long open window — a window in which we might learn to detect it early, and eventually to intervene before the neurons that matter most are lost. The NIH has recognized the gut-brain axis as a genuine frontier in neurodegenerative disease and convened researchers specifically around this question.¹⁰ That is not a guarantee of success. We are, to be honest, still several years and many experiments away from anything I could hand a patient. But it is the first time in a long time that the shape of a real solution feels visible.

For now, what I can offer is this: the gut is not the humble downstream organ we once took it to be. It talks to the brain constantly, and sometimes, it seems, it speaks first. Learning to listen to what it is saying — early, and carefully — may turn out to be one of the most important things we can do.

In the meantime, there is one intervention with real evidence behind it, and it costs nothing: moderate to vigorous aerobic exercise. I’m not talking about a leisurely walk with the dog (which is great for many other health reasons) — but here I want you to do something that gets your heart rate up, like tennis, swimming, biking, or a real jog. Large studies have found that as little as one to three hours a week of this kind of exercise in your 30s is associated with a meaningfully lower risk of developing Parkinson’s later in life, and the benefit keeps climbing the more you do.¹¹ It also appears to help people who already have the disease — slowing its progression, and in at least one small study, showing signs of protecting the dopamine neurons themselves on brain scans.¹² Very few interventions, drug or otherwise, can claim both of those things at once.

And if you’re the kind of reader who’s been following the gut angle closely: protecting your gut lining is worth doing regardless — going easy on NSAIDs, moderating alcohol, cutting back on ultra-processed foods — even though we’re not yet able to say definitively that this lowers Parkinson’s risk specifically. Consider it a plausible bonus on top of everything else your gut is asking for.

Digestifs

Last month, I had the honor of joining Norah O’Donnell on Healthful, her new women’s health podcast with CBS News, for an episode called “The Gut-Brain Secret: What Your Body Knows Before You Do.” To me, Norah is the queen of news — every interview she does is truly a master class — so being invited as the second guest on a show she is just beginning felt like a genuine privilege. The podcast is a fantastic mix of journalistic rigor and health evidence that is hard to find in our murky online world, and I urge you to check it out.

We spent much of the conversation on the very ideas in this post: the gut-brain connection, the vagus nerve, and the gut-first story of Parkinson’s. Norah pictured the vagus, rather perfectly, as a long octopus reaching its tentacles into every organ in the body, which is one of the better descriptions of that nerve I have heard. And when I mentioned that people who once had their vagus nerve cut to treat ulcers went on to develop Parkinson’s at nearly half the usual rate, she stopped and marveled at it. I never tire of that fact, and it was a joy to watch it land with someone who asks questions for a living.

Near the end, Norah asked what I would want people to remember if they remembered nothing else. I told her the truth: stop thinking about your gut as plumbing, and start thinking about it as a brain. But the words that have stayed with me since are the ones she chose for the title — what your body knows before you do. That gap, between what the gut has quietly begun to say and the moment we finally learn to listen, is very nearly the whole of my work, and the whole of this post. So if there is one thing I hope you carry away from today, it is a little more faith in that first brain of yours. It has been paying attention all along. The least we can do is start paying attention back.

— Dr. Trisha

References

1. Pasricha TS, Guerrero-Lopez IL, Kuo B. Management of gastrointestinal symptoms in Parkinson’s disease: a comprehensive review of clinical presentation, workup, and treatment. J Clin Gastroenterol. 2024;58(3):211–220.

2. Braak H, de Vos RAI, Bohl J, et al. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett. 2006;396:67–72.

3. Gadi SRV, Chang J, Videnovic A, et al. Upper and lower gastrointestinal symptom association and duration preceding Parkinson’s disease. Gastro Hep Adv. 2023;2:343–345.

4. Heinzel S, Berg D, Gasser T, et al. Update of the MDS research criteria for prodromal Parkinson’s disease. Mov Disord. 2019;34:1464–1470.

5. Lin CH, Lin JW, Liu YC, et al. Risk of Parkinson’s disease following severe constipation: a nationwide population-based cohort study. Parkinsonism Relat Disord. 2014;20:1371–1375.

6. Liu B, Fang F, Pedersen NL, et al. Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology. 2017;88:1996–2002.

7. Pasricha TS, Kulkarni S. Dopaminergic signalling in gastrointestinal health and disease. Nat Rev Gastroenterol Hepatol. 2025;22:696–707. doi:10.1038/s41575-025-01112-5

8. Chang JJ, Gadi SRV, Videnovic A, et al. Impact of outpatient gastroenterology consult on pharmacotherapy and management of gastrointestinal symptoms in Parkinson’s disease. Clin Park Relat Disord. 2023;9:100215.

9. Chang JJ, Kulkarni S, Pasricha TS. Upper gastrointestinal mucosal damage and subsequent risk of Parkinson disease. JAMA Netw Open. 2024;7(9):e2431949.

10. Mawe GM, Browning KN, Manfredsson FP, et al. 2021 workshop: neurodegenerative diseases in the gut-brain axis—Parkinson’s disease. Gastroenterology. 2022;162:1574–1582.

11. Xu Q, Park Y, Huang X, Hollenbeck A, Blair A, Schatzkin A, Chen H. Physical activities and future risk of Parkinson disease. Neurology. 2010;75(4):341–348. doi:10.1212/WNL.0b013e3181ea1597

12. de Laat B, Hoye J, Stanley G, et al. Intense exercise increases dopamine transporter and neuromelanin concentrations in the substantia nigra in Parkinson’s disease. npj Parkinsons Dis. 2024;10:34. doi:10.1038/s41531-024-00641-1

And the second question, almost always, is: But aren’t they terrible for your gut?

I understand the concern. If you have been anywhere near the internet in the last two years, you have heard about Ozempic burps, gastroparesis, and endless anecdotes about nausea. The gastrointestinal side effects are real, and I am not going to pretend otherwise. In the original clinical trials, GI symptoms were the most common adverse events, and they are the number one reason people stop taking these medications.

But here is what I wish more people knew: as a gastroenterologist and a scientist who runs a lab studying GLP-1 and the gut, my honest answer to most patients who ask is usually pretty enthusiastic. The benefits — including some real, measurable benefits to the gastrointestinal tract itself — are stunning.

Let me walk you through what the newest science actually shows.

They calm inflammation everywhere, including your gut

GLP-1 medications do not just make you less hungry. They act on receptors found throughout the body — including on immune cells like macrophages and lymphocytes — and one of their most important effects is dialing down chronic, low-grade inflammation.¹ They quiet pro-inflammatory signals like TNF-α, IL-6, and IL-1β, block activation of NF-κB (a master switch of inflammation), and boost anti-inflammatory signals like IL-10.¹

Why does that matter? Because chronic inflammation is the quiet engine behind a lot of the diseases I see every day in clinic: fatty liver, peptic ulcers, and certain cancers. When you turn systemic inflammation down, good things start to happen in places you were not necessarily targeting.

Here are three of the most striking examples.

1. They may protect against cirrhosis — but only if you start early

Metabolic dysfunction-associated steatotic liver disease (MASLD), what we used to call NAFLD, is now the fastest-growing cause of cirrhosis in the United States. Until recently, we had almost nothing to offer people beyond eating better and hoping for the best.

In 2024, a landmark study of more than 16,000 patients with MASLD and diabetes changed that picture.² Compared with patients on a similar diabetes medication (a DPP-4 inhibitor), those started on a GLP-1 had a 14% lower risk of progressing to cirrhosis, a 22% lower risk of developing serious cirrhosis complications, and an 11% lower risk of dying from any cause during follow-up.²

The most important finding, though, was this: the protection was only seen in patients who started a GLP-1 before they had developed cirrhosis. Patients who started after cirrhosis was already established did not see the same benefit.² That is a clarifying message for anyone weighing the decision because the window matters.

2. They are linked to fewer stomach ulcers

This is the research I am most excited about because it came out of my own lab. In a nationwide cohort study of more than 66,000 adults with type 2 diabetes, we found that GLP-1 use was associated with 44% lower odds of being diagnosed with a peptic ulcer.³

We also looked at a stricter comparison — people starting a GLP-1 versus insulin as their second-line diabetes medication — and the signal held: a 56% lower hazard of developing an ulcer.³ Those results held up even after we adjusted for the usual culprits behind ulcers, like NSAIDs, steroids, and blood thinners, all of which were themselves associated with higher risk in our data.³

That is a big deal for a condition that affects roughly one in ten people at some point in their lives and can lead to hospitalizations, bleeding, and even death. The likely mechanisms? Reduced inflammation, better blood flow to the stomach lining, and a sturdier protective mucus layer.

3. They are associated with a lower risk of colorectal cancer

This one still surprises me every time I say it out loud. In a study of more than 1.2 million treatment-naïve patients with type 2 diabetes, GLP-1s were associated with a 44% lower risk of developing colorectal cancer compared with insulin, and a 25% lower risk compared with metformin, over 15 years of follow-up.⁴ The effect was even more pronounced in overweight patients or patients with obesity.⁴

This is an observational study, not a randomized trial, and the authors are careful to say so. But it is biologically plausible: obesity is a major driver of colorectal cancer, and GLP-1s help with both weight loss and inflammation — two of the pathways that fuel this disease.

What to do about the side effects

None of the above changes the fact that nausea, constipation, and the occasional Ozempic burp are annoying. In my practice, I do not ask patients to white-knuckle their way through it. There is a lot we can do.

A few things I tell almost everyone starting a GLP-1:

• Start low and go slow. Most side effects peak in the first few days to weeks of a new dose and then fade. If they do not, we pause before escalating.⁵

• Change how you eat, not just what. Smaller portions, a slower pace, eating only when you are actually hungry, and stopping when you are satisfied make a real difference. Skip the very fatty and very spicy meals early on.⁵

• Get ahead of constipation. A daily fiber supplement like psyllium husk, plenty of water, and, if needed, an over-the-counter osmotic laxative are your friends.

• Have a nausea plan. Ginger, small frequent meals, and short-term over-the-counter antiemetics work for most people. If they do not, we have prescription options.

• Talk to your doctor before quitting. Fewer than 5% of patients in the major trials stopped GLP-1s because of GI symptoms.⁵ Most side effects are manageable, and the potential benefits are too significant to walk away from without a real conversation.

The bottom line

Obesity is a chronic disease rooted in large part in inflammation. When we are talking about a drug class that may lower the risk of cirrhosis, ulcers, and colorectal cancer — on top of everything else it does — we are talking about far more than weight loss. We are talking about public health.

Are GLP-1s right for everyone? No. There are real contraindications, real side effects, and real conversations to have with your own doctor about your own history. But if you have been avoiding them purely out of fear of what they might do to your stomach, I hope this gives you a little more to work with.

Digestifs

Two little bits of joy to share.

The first: This past Wednesday July 8, NPR’s Science Friday released the episode I taped with Dr. Emeran Mayer called “How does the gut-brain connection work.” Emeran and I sat down with host Flora Lichtman for a live recording at the Aspen Ideas: Health conference back in June, and I could not have asked for better company. Emeran has shaped so much of how we understand the conversation between the gut and the brain, and Flora is one of the smartest, most generous interviewers in science journalism today. If you have ever wondered why a gut feeling actually feels like something, give it a listen. The episode is available wherever you get your podcasts. It is also airing on all NPR stations across the country today.

The second: You’ve Been Pooping All Wrong made NPR’s roundup of nonfiction books their staffers have loved so far this year. Short Wave’s Regina G. Barber wrote that the book was “funny, extremely scientific,” that she “learned so much,” and — my favorite part — that she “was smiling the whole way through.” That last line is the highest compliment I could ask for. When I sat down to write this book, I wanted every reader to come away with better information and a genuine grin. If you are one of the many of you who has already picked it up, thank you — truly.

Until next time — take care of your gut. It is taking care of you.

— Dr. Trisha Pasricha

References

1. Alharbi SH. Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications. Ther Adv Endocrinol Metab. 2024;15:1-18. doi:10.1177/20420188231222367

2. Kanwal F, Kramer JR, Li L, et al. GLP-1 receptor agonists and risk for cirrhosis and related complications in patients with metabolic dysfunction-associated steatotic liver disease. JAMA Intern Med. 2024;184(11):1314-1323. doi:10.1001/jamainternmed.2024.4661

3. Seika P, Chang J, Hong SM, et al. Glucagon-like peptide-1 receptor agonists are associated with a lower risk of peptic ulcer disease: a nationwide cohort study. Clin Gastroenterol Hepatol. 2026;24(4):974-985. doi:10.1016/j.cgh.2025.08.015

4. Wang L, Wang W, Kaelber DC, Xu R, Berger NA. GLP-1 receptor agonists and colorectal cancer risk in drug-naive patients with type 2 diabetes, with and without overweight/obesity. JAMA Oncol. 2024;10(2):256-258. doi:10.1001/jamaoncol.2023.5573

5. Gorgojo-Martínez JJ, Mezquita-Raya P, Carretero-Gómez J, et al. Clinical recommendations to manage gastrointestinal adverse events in patients treated with GLP-1 receptor agonists: a multidisciplinary expert consensus. J Clin Med. 2023;12(1):145. doi:10.3390/jcm12010145

Thank you for being among the first to subscribe to Gut Checker. I want to start with a real note about where I have been the last month, because it has taught me something about why this Substack needs to exist.

On June 4, I went on the TODAY Show to talk about my book You’ve Been Pooping All Wrong and gut health in general. (Here is the segment – and yes, that is Colin Jost opening for us!) The anchor peg was a statistic I keep returning to: 40% of Americans say their daily lives are affected by their bowel habits. Forty percent. That is an enormous number of people who are quietly rearranging their days around a body part that almost none of us were ever taught how to talk about.

Three weeks later, I flew to Colorado for Aspen Ideas: Health. I gave a talk called “How’s Your Poop?” with NBC’s Dr. John Torres, and then sat down with Flora Lichtman to record a live episode of NPR’s Science Friday about the conversation between the gut and the brain. It will air on Science Friday’s feed soon, but in the meantime, you can watch both talks here: https://www.aspenideas.org/speakers/trisha-pasricha

Afterwards, so many people came up to me saying how their jaws fell to the floor during my talks when they learned something about their bodies and their health they had never known before.

I am telling you all of this not to recap my calendar, but because it has made something very clear: there is a huge, hungry, national conversation about gut health happening right now, and most of it is being shaped by people who are not gastroenterologists or the scientists out there trying, one experiment at a time, to better understand how we work. That is the gap Gut Checker is meant to fill.

Here is what I am planning for this Substack.

I’ll be posting articles regularly that you cannot get anywhere else. Sometimes it will be in response to a question or comment that I got on my Instagram. Sometimes it will be a new study I want to walk you through properly, without the “scientists say” headline treatment. Sometimes it will be something happening in my own lab at Beth Israel Deaconess Medical Center and Harvard Medical School. And sometimes (hopefully often) it will be an answer to a question one of you sent me.

My favorite kind of writing has always started with a real person asking a real question. So if there is something you have been wondering about your gut and have been too embarrassed, too busy, or too unsure how to even ask, please share them with me by commenting on my posts. I read everything. I cannot promise a personal reply to your specific situation (I am a doctor, not your doctor, and there are ethical lines I have to hold), but I can promise that the questions you send will shape what I write about.

A quick word on what this Substack is not. It is not a replacement for your own doctor. It is not a place where I will sell you supplements, because I do not sell supplements. It is not a place where I will pretend to have all the answers, because I don’t, and if I did I would be lying. I will tell you when the science is settled, when it is not, and when I am genuinely unsure – because I think you deserve to know the difference.

Thank you for being here.

Warmly,

Trisha