Best Tools for Gut Health & Weight Loss | Dr. Chris Thompson | Andrew Huberman Transcript

Andrew Huberman interviews gastroenterologist Dr Chris Thompson on gut health, metabolism, and weight loss

Andrew Huberman speaks with Dr Chris Thompson, professor of medicine at Harvard Medical School and chief of interventional gastroenterology at Mass General Brigham in Boston.

Summary

Dr. Chris Thompson, a gastroenterologist and interventional endoscopist who has pioneered new endoscopic procedures for treating obesity and metabolic disease, joins Andrew Huberman for a deep dive into gut physiology and metabolic health. He provides a comprehensive walkthrough of the gastrointestinal tract — from the esophagus to the colon — explaining how each segment contributes to digestion, satiety signaling, and metabolic regulation. He argues that the gut is far more than a digestive tube: it is an endocrine organ producing hormones such as ghrelin, GLP-1, GIP, CCK, and peptide YY that govern hunger, fullness, and insulin sensitivity. A central theme of the conversation is that metabolic dysfunction follows a predictable sequence — from glucose excess to high fasting insulin, ectopic fat deposition, insulin resistance, and finally metabolic inflexibility — and that this sequence can be detected and interrupted far earlier than conventional medicine typically does. He also traces the historical development of the incretin concept from 1930s London through the discovery of exendin-4 in Gila monster venom, describes his development of the endoscopic sleeve gastroplasty (ESG) procedure and magnetic small-bowel anastomosis techniques that replicate gastric bypass effects, and discusses early-stage gene therapy aimed at producing GLP-1 in a nutrient-responsive way as a potential one-time treatment for obesity and diabetes.

Key Takeaways

FULL TRANSCRIPT

Overview of the Gastrointestinal Tract

Andrew Huberman: A lot of us hear these days about the gut microbiome, the gut-brain axis. We hear about GLP drugs that help people lose immense amounts of weight and stop feeling this food noise thing and on and on. But could we start by just having a conversation about this tube that is the digestive tract and get real basic — just educate people a bit on what happens that stimulates them to want to eat, why perhaps for certain periods of day or night they don't want to eat, and then what the passage of food through us looks like as a series of steps.

Dr Chris Thompson: This is such a critical part of our biology and our lives. It's becoming more and more complex all the time. The gut does a lot of things. It's obviously involved in digestion, but it's also an endocrine organ. You can hear it called the second brain. There are a lot of different ways we think about the gut, and it is compartmentalized — each area has a different job.

First, you have the esophagus, and its job is to just move the food into the stomach safely. It's thick, it has a different lining so it can handle things that might be a little rougher, and it pushes sequentially down into the stomach. It's taking that food bolus and driving it into the stomach. You can have all sorts of problems in your esophagus. Each one of these organs has things it's supposed to do and then things that it doesn't do well. Sometimes people don't swallow well. It gets too tight at the bottom. There's a condition called achalasia where the bottom of the esophagus doesn't relax. We have procedures we can do in my line of work where you can tunnel down in between the layers of that esophagus — it's very thin, a few millimeters — and cut that muscle to relieve the obstruction.

Andrew Huberman: What are the symptoms of that?

Dr Chris Thompson: Inability to swallow. They'll swallow food, it'll get down and stop, and then they'll feel pressure. They'll feel really uncomfortable. If they drank some fluid with it, it might start coming back up. It'll just stay there. And then sometimes they'll have to induce vomiting to remove it. It's very uncomfortable for them. It's not a terribly common condition, but it's becoming more and more frequent. I see it every week.

That inability to swallow can also occur for other reasons that are far more common. Chronic heartburn — if someone has reflux, that burning sensation can damage the lining of the esophagus and lead to a precancerous condition called Barrett's esophagus, which needs to be treated, looked at, and followed. With time, it can actually cause scarring, so you get a stricture — very fibrotic tissue. That's another reason why people might have difficulty swallowing.

Then you have the stomach. First, what the stomach does is stretch to accommodate and accept a meal. Normally it's like a tube in your abdomen, but when you start to smell food, it starts stretching and becoming more like a bag.

Andrew Huberman: Really — just the odor of food?

Dr Chris Thompson: Yes, it can stretch and relax to accept that meal. And if it doesn't do that properly, it causes symptoms like nausea. Then it accepts the meal and has to do its job, which is to break it down and pass it on. The stomach isn't just transporting — it's breaking it down. It does that mechanically. The fundus, the top of the stomach, is holding that meal. The body of the stomach, the next segment, is breaking it down, grinding the food into smaller bits. Acid is part of this as well. And then the bottom of the stomach, called the antrum, will push the food out slowly into the duodenum — that's the first part of the small bowel.

Satiety and satiation all become part of this because the stomach is what secretes ghrelin. The stomach secretes ghrelin, and this is part of your satiety signaling. All sorts of problems with the stomach, too — food might not leave as it should. That can happen due to ulceration, scarring, or something called gastroparesis, where for a variety of reasons — postviral, due to diabetes, neural or hormonal origins — the stomach just doesn't empty as it should. People have nausea and vomiting with that.

Then you get into the small bowel. The small bowel's job is primarily to absorb calories. You do a little digestion early on because you have pancreatic and biliary secretions going in there, but its main job is absorbing calories and moving things down. It's very thin — one cell thick — and has about the surface area of a pickleball court.

Andrew Huberman: One cell thick?

Dr Chris Thompson: Yes, one cell thick. The lining is one cell thick.

Andrew Huberman: That's where the cell type — enterocytes?

Dr Chris Thompson: Columnar epithelium. Yes. They're pretty sturdy. They rely on more than just the cell itself to maintain that barrier. There are certain cells called goblet cells that produce mucin, and that creates a nice thick layer there as another part of the barrier. They have something called tight junctions between the cells, which are complex little structures that are part of that barrier as well. And there are immune cells in there. It is one cell layer thick, which is why the esophagus and stomach do a good job of processing that food so that it's safe to go down through the small bowel and be absorbed.

All sorts of issues with the small bowel — celiac disease, Crohn's disease, different inflammatory conditions. And what we're learning now, and hopefully will get into, is that it plays a central role in metabolic disease. That's very exciting — its role in obesity, diabetes, and other similar conditions.

Then eventually you have the colon, and that's where your microbiome is the star. The colon's job is usually just to absorb water. Most of the nutrients are gone by then. But it does play an important role working hand-in-hand with your microbiome. The microbiome is producing short-chain fatty acids, and one of the most important is butyrate, which has a lot to say about your metabolism. It's involved in satiety signaling. You also have a lot of GLP-1 produced in the colon. So you're getting these endocrine functions of your colon that are very involved.

And again, diseases in the colon — colon cancer is a big one. Colon cancer screening is important. They've moved the age back to 45 now. Everyone should start getting screened. You can do it different ways. There are genetic tests like Cologuard, and if you do that you have to do it every few years. You can do screening colonoscopy every 10 years if it's normal. CT colonography is less common. Those are the two most common approaches. It's important to do that.

Andrew Huberman: How common is colon cancer?

Dr Chris Thompson: In our line of work, it's the most frequent cause of cancer, unfortunately.

Andrew Huberman: Are more people being diagnosed because of more diagnostic procedures, and are more people surviving colon cancer?

Dr Chris Thompson: The survival rates are definitely improving due to screening programs. So it is definitely important to get screened. Starting at 45 is better than many people who started at 50 and wouldn't get screened until 55 or 60. But also, if you have a family member who has had cancer, you want to start at 40, or if they were younger, you want to start 10 years younger than when they were diagnosed.

Things like Cologuard and other genetic tests are going to keep getting better and help, because you don't have to have that uncomfortable screening procedure. Colonoscopy is not a great way to do screening — you shouldn't have to have a relatively invasive procedure to be screened for something. It should be something you just do with a blood test or a stool study. I think we're getting there with technology, and that will definitely show dividends. You can have the colonoscopy to remove the lesion, which is something we can do now. It's a newer technique where we can actually go in and remove these very early cancers endoscopically — we call it organ-sparing surgery. You don't have to actually remove a piece of the colon anymore. You just take the lining where that precancer is residing. It's a complicated procedure, but it's easy for the patient. They keep their colon, they go home the same day.

So that's pretty much the quick overview of the gut. One thing we haven't touched on too much yet is its role in satiety and how it's involved in processing food in detail, and the endocrine system that's involved.

Bowel Movements as Health Indicators

Andrew Huberman: There's a weird thing about the GI tract and bowel movements in particular. With babies, with puppies, and to some extent with ourselves — but especially with babies and puppies — we have a couple of key readouts that we intuitively understand reflect their health. One is the color of their skin, the eyes — if eyes are looking glassy or tired. And then the quality or lack thereof of their bowel movements: quality, frequency, etc. But then something happens where speech comes online and we get toilet trained, and then everyone's responsible for understanding their own bowel movements. And we're never really told what healthy bowel movements look like. I'd be lying if I didn't say these are important metrics of health.

Dr Chris Thompson: There's so much you can tell from bowel movements. The rule of thumb is you don't want to have more than three a day, and you don't want to go longer than three days without having a bowel movement. You want one formed bowel movement, or a couple. You don't want little tiny pebbles — that's called scybala stool, and that's a sign something's going on.

There's a lot you can tell about how much fiber someone is taking in. The World Health Organization published something in The Lancet years ago on fiber synthesis, and they found that the vast majority of the population — especially in western countries — just are not getting enough fiber, which is obviously concerning because that causes a lot of issues long term. If you're having scybala stools, if you are constipated — meaning you're having a bowel movement less than once every three days and they're hard stools — that's a sign you're not getting enough fiber. That's one thing you really have to think about.

Additionally, if a bowel movement is very dark, tarry, and shiny, that's a sign you have blood in your GI tract. There are different things you can tell from the stool that are important to keep an eye on. Having more than three a day is probably leaning towards being too loose, and if you're not having one every three days, you're probably bound up and you really have to think about fiber.

Andrew Huberman: As I recall, the recommendations were 35 grams of fiber per day for adult men and 25 for women. Does that sound about right?

Dr Chris Thompson: Yeah, that's about right. And it kind of depends on the quality too. There are a couple of other really interesting studies that came out recently looking at the importance of fiber related to certain conditions. One was fatty liver. It was an interesting study — they were using resistant starch, level two, basically raw powdered potatoes, something like that. They were supplementing at 40 grams and found a significant improvement in fatty liver, which is phenomenal, and it was relatively weight-stable. So it has important treatment effects.

Another group studied insulin sensitivity. They did clamp studies where they could really detect insulin resistance and look at glucose utilization and clearance. They found that with this RS2 type resistant starch, they were able to improve insulin resistance and insulin sensitivity as well. So fiber is very important. It's not just about the bowel movements — it's also about really just having health.

The Microbiome, Fiber, and Fermented Foods

Dr Chris Thompson: It probably helps the microbiome. There's all sorts of evidence that if you don't have a lot of fiber, your microbiome is not healthy. You get less diversity in your microbiome. It is important to have that fiber, and constipation is an early window into it — an early sign that maybe you're not getting enough fiber.

Andrew Huberman: I make it a point to eat fruits and vegetables because I like them. But recently I started supplementing with a powdered psyllium husk, and some of them actually taste pretty good. My expectation was that I was going to feel really bloated. It was quite the opposite. It normalized things — actually, post-meal, subjectively the sensation was just like feel good, feel great. I didn't expect that. I thought, okay, more fiber — I think a perception people have is like more fiber, more regularity, and more bloat.

Dr Chris Thompson: That might be true for some people, but it certainly wasn't your experience. I think the messaging on fiber to the general public is pretty lousy — people are told to take it, that's great, but I think people think, "Oh, if I have a lot of fiber, I'm going to be really gassy, I'm going to be really bloated." But as you point out, it's not just about regularity and speed of digestion. It's about creating a healthy milieu for the gut. I think if more people knew that, they'd probably make a move to consume more fiber.

It's like feed your microbes, or they're going to eat you. They need to be fed. And what they eat is fiber. That's what you want them eating. And if you're not feeding them fiber, they'll eat your mucous layer. We already talked about how thin that barrier is, and all of a sudden they start eating your mucous layer. They're not producing the butyrate you need. And the butyrate is needed to maintain the tight junctions. So there are layers to this. It's like a snowball effect — if you're not feeding the microbiome and keeping it healthy, you're going to run into all sorts of trouble.

Andrew Huberman: That raises some interesting questions about intermittent fasting. I think very few people are doing long-term fasts of more than a day or so. Most people do time-restricted feeding or skip breakfast. I had a colleague at Yale who studied the microbiome and I said, "Does fasting improve the gut microbiome?" And he said, "No, actually during the fasting period, your microbiome starts eating up your digestive tract." But then he said the rebound often puts you at a slightly better place afterward. Should people avoid intermittent fasting if they're having gut issues?

Dr Chris Thompson: I don't see it as being a major issue. I think the benefits of intermittent or time-restricted eating probably outweigh that risk. You need to give your pancreas time to relax. If you're eating frequently, your insulin levels are always up, and that causes problems. I do think the benefit of time-restricted eating definitely outweighs that potential risk.

Andrew Huberman: Great to hear, especially as somebody who just by default doesn't eat breakfast and doesn't get hungry until 11.

Dr Chris Thompson: I skip breakfast as well. But there are studies — initially they used to say, well, you have a cortisol spike in the morning and you're more likely to store the food you take in if you eat in the morning. Turns out maybe that's not so true. It might be better to eat earlier and then have your fasting window start in the afternoon. I think doing it is better than not doing it. I still skip breakfast.

Andrew Huberman: The topic of fermented foods — low-sugar fermented foods — as a possible benefit for gut health has come up since Justin Sonnenberg and colleagues published that study. It was a small number of people admittedly, but taking in some low-sugar fermented foods really helped lower inflammation. What are your thoughts on low-sugar fermented foods? We're not talking beer — we're talking kimchi, sauerkraut brine.

Dr Chris Thompson: I think they're important. And they're missing in the western diet, which is an issue. The study you referred to — I think they compared it to fiber, right? With the fermented foods, you had reclaimed some diversity in the microbiome, which was great, as well as reduced inflammatory markers, where the fiber didn't seem to do that. And you saw all these benefits in the fiber trials we're talking about with the resistant starches. So it stands to reason that we'd probably see that as well as we do more research into fermented foods.

They're beneficial for a variety of reasons. One, they're prebiotic — you're feeding your microbiome things they want. And it's already kind of started — it's a little partially digested, which is really helpful. They're also a little bit of a probiotic as well, because you do have some live cultures in there. They usually have bifidobacteria, lactobacillus, or something like that, and a variety of other things. So it gets the ball rolling. It's sort of like when you're trying to grow something, you want to plant the seeds but also have the fertilizer. This is what fermented foods do for you.

It's all about maintaining this healthy microbiome that can produce things like butyrate, which has a lot of benefits. You can't just take butyrate and have it make it to the colon — it needs to be in the colon to have its effect. What these bacteria do is they cross-feed in a sense. You have that first layer of bacteria that will take the fiber and break it down, creating acetate and lactate and whatnot. That can then be used by other bacteria, which turn it into butyrate. The butyrate is magical. It feeds your colon cells. Your colon cells live on it. Butyrate is needed for those tight junctions. It does all sorts of things via GLP-1 pathways and satiety pathways. Additionally, it keeps your bowel acidic, which is great to make sure you're protected from certain pathologic organisms that might want to take root. Aerobic organisms and other organisms you don't want don't survive as well in an acidic environment.

Andrew Huberman: Do you make it a point to consume fermented foods?

Dr Chris Thompson: I do. I like kefir — I think it's phenomenal. Kimchi is good, sauerkraut. There are all different types. Yogurt, kombucha. There are different types I think everyone should be able to find. And it's certainly missing in our diets. So I think it's important to recommend that folks do consume them.

Ulcers: Bacteria, Acid, and Stress

Andrew Huberman: Canker sores and ulcers — my understanding for a long time was they were caused by stress or wounds to the mouth. Then a couple of folks won a Nobel Prize for identifying a soil-based bacterium that causes ulcers. That was a very surprising set of findings. But at the same time, I think many millions of people across history would say stress gives people ulcers. So there's something going on there that's more than a soil-based bacterium, right?

Dr Chris Thompson: Definitely. That's the problem with the way the media covers these findings. Stress can play a role. Barry Marshall was phenomenal in Australia — he found H. pylori could cause gastric ulcers. No one believed him, so he had to consume it himself and then he had gastric ulcers.

Andrew Huberman: I love it when scientists do self-experimentation.

Dr Chris Thompson: That's crazy, right? But that was phenomenal. He proved H. pylori, and we need to treat that. H. pylori was actually found even in Ötzi the Iceman — this 5,000-year-old Homo sapiens found frozen in the Italian Alps. You could actually get into his stomach and see what's in there. He had H. pylori in his stomach. That thing's been around a long time.

There are other lessons there, like a loss of diversity of the microbiome with industrialization — we have far fewer species and less genetic diversity in our microbiome. But regarding ulcers, I actually did study this in gastric bypass patients. Sometimes it was a relative ischemia. Type two diabetes causes microvascular ischemia. Smoking can cause microvascular ischemia. In gastric bypass patients, the distal part of the small bowel that's connected to the stomach doesn't have bicarbonate being secreted from the pancreas in the area. So there's no way of neutralizing acid. If the pouch of the gastric bypass is too large and makes acid, the jejunum has no natural defense against that. So acid clearly plays a role, and if you're stressed it can produce more acid. Generally there's probably multiple hits. We don't fully understand things, but clearly it's not just an infectious organism — it depends on individual circumstances and susceptibilities.

Andrew Huberman: So important for people to hear that. Just because one thing can cause something doesn't mean it's always the case.

GLP-1 Drugs: Benefits, Limitations, and Micro-Dosing

Andrew Huberman: So let's talk about metabolic health, hunger, obesity, weight loss. These are areas squarely in my wheelhouse. Can't have this conversation without talking about the GLPs. Most everyone has heard of these things nowadays. Millions and millions of people — I've heard as many as 20% of people 18 and older have taken or are currently taking a GLP, either semaglutide, tirzepatide, or soon retatrutide will be out to market. What's your thought on these compounds? Are they the perfect solution to weight loss?

Dr Chris Thompson: Well, I'm grateful we have them. Obesity is a serious problem, and all the metabolic issues that come with obesity need to be addressed, and we weren't doing much with it unfortunately until the GLP-1s came around. So GLP-1s are fantastic from that standpoint. They're not perfect — there are limitations — but it's much better to have them than not.

Dr Chris Thompson: There are issues with adherence, unfortunately. Over a million people a month are coming off GLP-1s. About 30% come off in the first month, and 50% or so by the end of the year. And it's not specific to GLP-1s — you see that with any medicine, with blood pressure medicines, with cholesterol medicine.

Andrew Huberman: What's the primary driving force in the case of GLP-1? Is it the side effects? Is it they don't like having to inject themselves?

Dr Chris Thompson: Because the numbers are so curiously similar to all the other medicines, maybe there's some underlying thing where people just don't like taking medicines frequently. Sticking yourself is probably for some people something they don't want to do once a week — needle fatigue. When you take a medicine orally every day, it gets hard to remember to take it. And then I think there are issues with how you ramp them up to the effective dose and side effects. Nausea is an issue with some of these. Muscle loss is an issue. And then additionally, long-term, you're taking a super-physiologic dose of something and we don't know what the long-term ramifications could be. So even though I believe the benefits outweigh the costs — you're treating obesity, we know obesity is a problem, we don't know GLP-1 to be a problem long term — that does weigh heavy on some people's minds and that might be why they stop as well.

In my practice where we do endoscopic therapies, over 85% of people have already been on a GLP-1 and either they're struggling on it or they've come off.

Andrew Huberman: There are a number of people now who are micro-dosing the GLPs and finding that they're getting some benefits without taking the prescribed amount. I'm not recommending people do that. But I know people are doing that — initially because of cost and pen sharing, but also people feeling like they get the same effect. Do you have any knowledge of whether lower dosing takes people away from side effects?

Dr Chris Thompson: I think it's actually very useful. The approved dosages are kind of just an effect of our regulatory system, as you've alluded to. It's too expensive to do different doses. Plus it takes away personalization. We're all trying to get to precision medicine and personalized medicine, and that's what micro-dosing allows you to do.

The first time I heard about micro-dosing was from one of my patients who was a physician. He said it was too expensive, he didn't feel great on it, and he was doing this thing where he takes the pen and injects it into a sterile vial, uses an insulin syringe, takes a small amount out, and gives it to himself. He said he was doing great — not feeling nauseous, his weight was staying off. He was a physician so he was familiar with the equipment. That was the first time I came across it. I thought, wow, that's actually a great idea.

A lot of my patients actually do micro-dose these things. Generally you get up to the point where you're losing weight, you lose the weight, and then for maintenance rather than just stopping — because if you stop the GLP-1s there are problems, these are kind of lifelong medicines — instead of stopping it, just go to micro-dosing and you'll find a spot where you keep the weight off, you feel good, and you're not taking as much of the medication.

The problem with coming off them is especially with the original drugs like semaglutide — when you lose weight, about a third of the weight you lose would be lean mass, mostly muscle. And the problem is when you cycle on and off: you come off, you put your weight back on, but you're not putting the lean mass back on — you're putting the fat back on. So now you've shifted your body composition to be less favorable than before you ran the GLP-1. Then you go on it again, lose weight, lose a little more muscle. Then you go off and put more fat on, not more muscle. So basically you're taking your body composition and shifting it worse every cycle. There has to be a game plan. If you're coming off the GLP-1, you need either to micro-dose it or have a bridging plan to a procedure or something else that will keep the weight off.

Andrew Huberman: Are there any good studies showing that resistance training can offset the muscle loss from a standard or micro-dose of one of these GLP drugs?

Dr Chris Thompson: Resistance training definitely plays a major role in maintaining muscle, and that's with anything — not just GLP-1 medications, but with the first-generation medications, with any surgical procedure or endoscopic weight loss procedure. If you're doing resistance training, you tend to maintain your muscle because the body realizes, "Hey, I need this muscle. I'm not going to get rid of it as the person's losing weight." When there's a caloric deficit, the body is looking for what it can do to maintain energy levels, and you don't want it chewing up the muscle to do that.

The side effects that I see getting the most coverage are increased feelings of apathy, food noise being down, alcohol appetite being down, appetite for life being down. The other one is that GLP drugs can cause blindness — but that's in a very rare set of individuals who have this ischemic optic nerve head condition. So yes, the GLPs can make certain people blind, but it's a very small number of people. You want to get screened for this structural thing in the eye, but it's not true that GLPs are making people go blind all over the place.

When patients come to me and say they didn't like the GLP or it wasn't working, I think muscle loss honestly is one of the bigger ones. It might just be subtle — "Ozempic face," "Ozempic butt" — you're losing some muscle in places where it's noticeable. Other people actually truly develop sarcopenia, where you have significant loss of muscle. It's rare, but those are people who aren't really exercising a whole lot when they take it and might have had a predisposition to it to begin with.

In people I'm concerned about, it's good to get a DEXA scan beforehand. Make sure you have adequate muscle mass. If you don't, you really have to think twice about whether you want to do the GLP-1 or whether you want another avenue to try to lose the weight — and you definitely have to start hitting the gym. The other common one is nausea. A lot of folks do get nausea on the higher doses, and they will not lose weight on the low dose. If they go on the high dose, they feel nauseous. Some people say it stops working, and that might be because they don't tolerate the higher doses. Those are the primary reasons I hear.

Surgical and Endoscopic Weight Loss Procedures

Andrew Huberman: Maybe we can move a bit towards some of the surgical procedures. When I think of stomach stapling, I think of it purely as a mechanical thing — you're making the stomach smaller, making people feel full earlier in the meal. But of course it stands to reason that you're also removing tissue and changing the chemical milieu of the environment. We had stomach stapling for a long time. Why did we need the GLPs?

Dr Chris Thompson: Surgery really started back in the 1950s. University of Minnesota, I think, was the first place they did it. The first procedures were focusing on malabsorption — the idea was to bypass a portion of the small bowel so that you don't absorb your calories. It was called a jejunoileal bypass. But this procedure was awful. People did lose weight, but the problem was they created a long blind limb — no actual food was going through the limb. You connected the jejunum to the very bottom of the small bowel, and the rest of the small bowel was still in there but no food was going into it. So you had bacterial overgrowth. You had all sorts of problems. The fat that was being malabsorbed was binding calcium, so the oxalate that normally binds calcium got absorbed and then bound calcium in the kidneys. You were having all sorts of renal failure issues. It was a disaster that went on for years because people were desperate, but it was a very bad procedure.

It was replaced by something called gastric bypass, which I think came about in the mid to late 1960s. Mason, I think, was the surgeon who came up with this. His goal was to avoid the problems with the jejunoileal bypass and still get a treatment effect. He thought of this as restriction — the stomach is smaller so you'd have some element of restriction, and then also an element of bypass where you're not absorbing all your calories. Turns out that's not really how this thing works, but that's what he thought was going on.

From there you keep moving forward — you have lap bands, adjustable gastric bands that were purely restrictive. True stomach stapling, which was the VBG, and now the sleeve gastrectomy. These are the real surgeries, and they were created conceptually thinking about either restriction or malabsorption, but they work entirely differently than what they thought.

Andrew Huberman: I have a question about your profession generally. I'm guessing there are not large-scale clinical trials of each of these surgeries. How much license do surgeons have to try something new?

Dr Chris Thompson: I don't think the proper channels are unworkable. I do think that there are compassionate use cases where you need to make exceptions, and they have expedited protocols for that. I remember one time I had a person who was bleeding chronically and it couldn't be stopped, and we needed something that was not yet approved in the United States but was approved in Canada. The person had no other option, and we were actually able to get approval within 12 hours to use it as compassionate use, and it worked for the patient. So there are even pathways for that.

There are also examples where you have a device that's approved for one thing and the company doesn't want to get it approved for everything — no money to do that — so you use it off-label. That happens every day in every hospital.

Andrew Huberman: Just like drugs are used off-label.

Dr Chris Thompson: Same thing. Like we use wires when we're accessing a bile duct to remove a stone — that wire has not been approved for that. It was approved for some vascular indication, and we've been using it that way forever because no company ever went through and did it. So the whole field is based on this. But if you're developing something truly new, generally the proper channels are very workable. And actually a lot of times they give you even better ideas — like, "Oh, why don't you think about checking these studies? If you're doing this, check this gut hormone." They give good feedback that helps improve the study.

Gut Hormones: Ghrelin, GLP-1, GIP, and the Incretin Story

Andrew Huberman: When it comes to the chemicals associated with hunger and satiety, what are some of the big players?

Dr Chris Thompson: Ghrelin is a big one. That's the hunger hormone. It's produced in the fundus of your stomach — the very top of the stomach, where the esophagus comes in. A lot of the ghrelin is produced there. When that goes up, that's how you feel hungry.

Andrew Huberman: So it leaves the gut and travels to the brain?

Dr Chris Thompson: Yes, and stimulates hunger. And I have to say I'm still processing in the background about this thing where the gut expands in anticipation of food and that it's odor-based. Does that mean the olfactory neurons are communicating with the gut directly?

Insulin actually does go up too. Before you eat, you'll have a little spike in insulin. I don't know if they ever figured out exactly the mechanism by which smell, tasting food early on, or even seeing food triggers this whole process to start. But before you swallow any food, you already have insulin coming up a little and your stomach's already starting to stretch to accommodate the meal. Maybe some of it's learned as well. But it's very interesting — it certainly plays a critical role.

After ghrelin — that's your hunger hormone — when you eat, it drops, and then it comes back again sometime after the meal. Ghrelin is one to watch because we actually use ghrelin. It's one of the mechanisms we use to get our treatment effects with endoscopic procedures and with surgical procedures too.

Then after the food leaves the stomach, you have CCK, which goes up. CCK will cause the gallbladder to dump bile, but it also acts as a satiety signal. It's secreted from the first part of the duodenum. You also have peptide YY and GLP-1. Before you get there, there's GIP from the K cells proximally too. GIP is like GLP-1 — it's kind of similar, not quite as potent. People think of it as Batman and Robin with GLP-1 and GIP.

Andrew Huberman: People might be curious to know that retatrutide — the more cavalier peptide-curious folks are already getting off compounding and gray market — as I understand it, promotes GLP-1, GIP, and glucagon. The clinical trial Lilly ran showed a 30% reduction in body weight, which is really striking. It's curious that GIP never really took off as a druggable thing, but now by combining with other things, maybe you actually get some synergistic effects.

Dr Chris Thompson: It does help. I think it helps with nausea, so it allows you to have higher doses potentially of GLP-1 with less nausea. GIP plays that role. It has a role in insulin sensitivity as well, and it does some of the same stuff GLP-1 does — it's synergistic. But what's interesting about the glucagon is the potential for muscle sparing. Glucagon is usually up when your insulin is down and vice versa. Its main job is to say "burn fat." It also causes you to dump your glycogen out of your liver a little bit, but the main job with glucagon being up is to say burn fat. It's kind of nice that they're adding that as a muscle preservation mechanism as well as a way of helping to burn some of the fat.

Andrew Huberman: These pharmaceutical companies — however many people might hate "big pharma" — they're putting hundreds of millions of dollars into the research. Twenty years ago there was nothing druggable for obesity as I understand, and what was there was mainly stimulant-based.

Dr Chris Thompson: Like phentermine, which was a sympathomimetic really — basically speed. And nicotine. Some people think that when we basically abolished smoking, people started eating more and then America got fat. Now nicotine is back in oral forms in a big way, mostly with men but also with women. A lot of people like it because it's an appetite suppressant. I'm not a fan for a bunch of reasons — raises blood pressure, highly addictive, and so on.

Andrew Huberman: It's interesting, right? People have struggled forever with how to enjoy food but not eat too much — whether it's a drug that increases a compound we already make, like GIP, or something to make us move around more like stimulants. It's like a human obsession. Why can't we just eat enough and not too much?

Dr Chris Thompson: I think it's metabolic dysregulation, and there are many causes. The processed foods certainly are an element. There was a study done — I believe it was an NIH study in Bethesda — where they had about 20 subjects randomized and crossed over. They could either have whole foods or processed foods, and the people eating the processed foods were eating like 500 calories more a day. Not only are you eating more of it, it's easier to digest — you're getting bigger glucose spikes and you have a lower thermogenic effect of food. It's probably also not doing great for your microbiome because there's less fiber in it. So that is playing a big role.

Then you have your peptide YY and your GLP-1. GLP-1 is triggered by anything, but glucose tends to trigger more of it. Peptide YY is more triggered by proteins and fat. It does something similar — you stay full longer with a big heavy fat and protein meal, probably because of the peptide YY. That's been very hard to drug — they didn't have a Gila monster to solve the problem the way they did with GLP-1. But it's also very potent. Both come from the L cells in the distal small bowel and the colon.

You also have leptin in the background. That's more of a thermostat — it's involved in set point and things like that. It's secreted from your fat cells, almost proportionate to fat. So if it's high, generally you're going to eat less. If it's low, you're going to eat more. But there are all sorts of problems with leptin resistance and other things that complicate it.

Andrew Huberman: I remember coming up through science — leptin was all the rage. Its discovery, its cloning, and everyone thought drugs are going to come along to mimic or stimulate leptin and we're going to solve the obesity issue. But it didn't really pan out. Why was that?

Dr Chris Thompson: I think leptin never panned out in large part because of leptin resistance. The hypothalamus and the brain itself just become resistant to it because it's so high in people with obesity for so long. The receptors are saturated. There's low-grade inflammation in those tissues and eventually you just don't respond to it anymore. So the drugs just didn't pan out.

With the GLP-1s it's another story. The concept of incretins first came about in the 1930s in London. They were basically grinding up animal duodenums, emulsifying it, and injecting it back into the animal's vascular system. The idea for that was secretin — someone had found secretin, a hormone produced in the duodenum that goes to the pancreas and says "secrete fluids for digestion." This person thought, well, if the duodenum secretes secretin, maybe it secretes something else. They did this study and in the animal the blood glucose fell. Something in the duodenum is causing glucose to fall. They called it incretin because they had secretin — they'd call it incretin.

Then there's another lab — Sheila Sherlock's lab in London. She was famous for being one of the founding physicians who started the field of hepatology. They had access to a new tool — a way of actually detecting and measuring insulin. They did a very interesting study where they gave subjects a set amount of glucose intravenously and measured the amount of insulin produced. Then they gave them the exact same amount of glucose orally and found they produced much more insulin. They coined this the incretin effect. They thought it was probably coming from the duodenum based on that old 1930s study.

Then other studies came after that, getting closer and closer. Eventually, at Lilly Labs I believe, there was a physician named Bell who cloned the pre-pro-glucagon, and from that you get GLP-1 and GLP-2. Now we had GLP-1 identified. Then there was a physician — Bloom, I believe — in London again, who did some phenomenal work. He found GLP-1 was in the bowel where they thought it was. He found that when you gave glucose, GLP-1 increased in the blood. Then he actually infused GLP-1 and found that when he infused it, insulin went up and glucose went down. So now all of a sudden we had a real sign of what this incretin was, and it was GLP-1.

The problem was you had to infuse it for it to work because it gets chewed up really quickly by dipeptidyl peptidase. There's something on the end terminus of it that is susceptible to that, and that's the part that binds the receptor so you can't really get rid of it.

Then in the Bronx in the 1990s, there was a Dr. Eng who was studying Gila monsters. In the Gila monster he found something in the venom that looked very much like GLP-1 — had one substitution, the second amino acid in, otherwise looks just like it and will bind the receptor. The C-terminus is a little longer and different, but this is exendin-4. Basically this is the molecule he discovers, and this is what ends up becoming all the GLP-1s. Gila monsters don't have to eat very often, so it makes a good candidate to stay in the system.

Dr. Thompson's Path to Innovation: From Biopsy Needles to Endoscopic Procedures

Andrew Huberman: You do surgeries of various kinds. People are coming to you — they've all tried GLPs and don't like them or they're not working, or they'll micro-dose but it's not solving the problem. What sorts of surgeries were you trained to do, and at what point did you become the doctor who seeks out IRB approval to build something better?

Dr Chris Thompson: For me it really started in fellowship. I moved to Boston to learn interventional gastroenterology — not colonoscopy and whatnot, but doing procedures mostly focusing on pancreatobiliary conditions. The big problem at the time was really pancreatic cancer diagnosis. I was moving there to learn a new procedure called endoscopic ultrasound. You'd be able to put a scope in the mouth into the stomach and small bowel and then use the ultrasound probe embedded in its tip to see the structures just outside the lumen and gain access to them. You could put a needle in them, and that held a lot of promise.

Andrew Huberman: So you're feeding a needle through a tube, watching it on a screen. You're not opening up the abdominal cavity.

Dr Chris Thompson: Right. You can do it through the mouth — a natural orifice. For pancreatic cancer, a lot of times they would go to surgery, open the belly up, and get the biopsy. It's really hard to make the diagnosis. I wanted to learn this new technique where the patient goes home the same day and doesn't feel anything.

When I got there, I'd done a master's in health evaluation science at Penn State before going, and I thought I would be doing epidemiologic research. But my mentor, Bill Brugge at the time, was a pioneer in this ultrasound. He gave me a needle and said, "Hey, this thing doesn't work to make the diagnosis of pancreatic cancer. I need you to try to fix this." And he was right — we had about a 50/50 chance of getting a diagnosis with the needle. It was designed like a hypodermic needle — designed to atraumatically split the tissue, not take chunks of tissue out of you.

Andrew Huberman: Designed to deliver stuff, not take stuff.

Dr Chris Thompson: Exactly. I kind of figured out what the problem was. The company thought it'd be too expensive to fix. But a couple of years into practice on faculty, we still had the problem — people wouldn't want to have a major surgery having their pancreas taken out without an answer, and then they'd have worsening cancer and by the time you'd be able to make the diagnosis it'd be too late. That's where I started the entrepreneurial stuff. My first company was based on that. I needed a team — one of the engineers had the brilliant idea of how to change the bevel design. I knew what the clinical problem was, but you needed a team to fix it. We hired engineers, got together, and came up with a needle that could biopsy the pancreas without causing pancreatitis or any problems. That really became very instrumental in helping a lot of people get the diagnosis earlier. Now we have preserved cellular architecture, so you can do precision medicine — test different drugs on the tissue and see what it's going to respond to, do immunostaining. It's a lot better than just having a few shaved cells.

That was the first time I got involved in trying to solve a problem like that, and that was before I started diving into metabolic disease, where I've spent a large part of my time.

The Sequence of Metabolic Dysfunction and Early Detection

Andrew Huberman: Let's talk about metabolic health in more detail. You mentioned the sequence of metabolic dysfunction. Can you walk us through that?

Dr Chris Thompson: Metabolic dysregulation follows a fairly predictable sequence. First, it's calorie excess. In the western diet, it's usually glucose — you have too much glucose around, too much saturated fat, but primarily too much glucose. You could catch that by doing a CGM — a continuous glucose monitor. You can see if you have particularly glucose spikes to certain foods. If your glucose is shooting up to 200 with certain meals, you know you're sensitive to that and maybe you should change how you're eating it.

This goes back to the Whitehall 2 study on British civil servants — a prospective longitudinal study. They found that if someone had high fasting insulin, they were more likely to get diabetes long term. They could detect this thing 15 years earlier. They could do something about it. But no one does because no one looks for fasting insulin.

The other thing that's very relevant is the NHANES study — a large database looking cross-sectionally at a point in time. They found that less than a third of people who are lean are metabolically healthy. That's crazy. 12% of the whole population, less than a third of lean people, are metabolically healthy based on their parameters — waist circumference, glucose, blood pressure, and so on.

So the word there is: start looking early and don't look with the traditional things. We have to look at other things. First, you could check for glucose — a CGM can do that. I wouldn't say wear it all the time. Get one for a month or two, learn what spikes your glucose, and adjust.

Next, you have fasting insulin. The next thing that happens is high insulin levels — fasting insulin goes up. You can get a fasting insulin level. It's an inexpensive test and you can see if you've evolved into that problem where now you have chronically high insulin levels. Part of that is due to eating too frequently and eating things with a high glycemic index or load that's going to cause your sugar to spike. If you're eating every few hours, insulin goes up and spikes. It drives the glucose out of your blood, but then the insulin stays high for a few hours. If you're eating every few hours, you always have this high insulin, and that's going to lead to other problems.

The next thing that happens is ectopic fat. You have subcutaneous fat — that's where it's supposed to be, your depot for energy. Then you have visceral fat, which is in your omentum, in the abdomen around the bowel. Then you have organ-associated fat — some fat around the heart, around the kidneys. The last bucket is ectopic fat, where you have fat in cells that is not their job to store fat — like liver cells, muscle cells, or pancreas cells. That becomes a problem.

Andrew Huberman: It's like Wagyu beef.

Dr Chris Thompson: Yeah, it's like Wagyu beef. Those cows are overfed and don't move. And that's another problem. So that's the next phase of metabolic dysregulation. Fatty liver is very bad. And then that is what goes on to insulin resistance.

For the fat, how can you look for that? You can do a waist circumference measurement, waist-to-height ratio. You can get a DEXA scan that'll tell you if you have visceral fat. A CT scan, MRIs, other things will do it too. Or an ALT — look at a liver test measurement. That's alanine aminotransferase in your liver, and usually that'll signify some inflammation.

Then you have insulin resistance, which is a little harder to check. There's a formula — you take a fasting blood glucose and a fasting insulin level, multiply those, and divide by a constant. If it's greater than two, you have insulin resistance.

And then finally, you have metabolic inflexibility. Your body is supposed to change between what it's burning. If you're fasting, it's supposed to be burning fat. If you're eating carbs, it should be burning the carbs. You can develop metabolic inflexibility once you have insulin resistance — when you're fasting, you're not really accessing your fat anymore. And when you eat, it doesn't shift over to burn the carbs well either. It kind of just doesn't know what to do.

Once you have a loss of metabolic flexibility, studies have shown you're more likely to gain weight and develop obesity. You're more likely to start losing beta cells — they become apoptotic and you lose beta cell mass — and you start having all sorts of other problems. This is a very typical sequence backed by science and different clinical trials. And at each step of the way, you have a study you could do to find out about it.

The last one, metabolic flexibility, is a little harder because you have to do a breath study where you're looking at gas exchange. It's very accurate because we know there's a respiratory exchange ratio. It's a ratio of volume of carbon dioxide divided by volume of oxygen. When you eat carbohydrates, carbohydrates have an equal number of carbon and oxygen, so it doesn't require much oxygen to burn them. When you burn fat, it requires more oxygen. If that ratio is around 0.7, you're using more oxygen, meaning you're burning fat. If it's one, you're burning carbs. You sit in a chair and breathe for half an hour. There are companies developing at-home methods for this too.

So there's a lot of things we should be doing before we do the standard test of looking at your fasting glucose and hemoglobin A1C.

The Case for Early Metabolic Testing and CGMs

Andrew Huberman: It's gratifying to hear that you put the CGM pretty early on that list. I've gone public many times saying that as the cost of blood testing comes down, this is awesome — you get a window into lipids, hormones, things that can be very informative whether you have issues or not. And the pushback from the medical community — many of them will quietly say, "Yeah, I totally do that test," but many of them just say, "Oh great, now patients are going to be coming to me worried about everything." I actually put a post out recently about whole-body MRI as the cost comes down. There's a celebrity who took one of these types of scans and identified a malignant issue that could be cut out and very likely saved their life. I get it on one hand why a lot of physicians are worried about people walking around with a lot of data. But now that CGMs have been out for a couple of years, I don't hear much pushback. Somebody wants to use a CGM for a couple of weeks and see how they react to different foods — cool. So it's kind of wild to me that physicians don't want patients to have data. But here I'm hearing something very different.

Dr Chris Thompson: The problem with medicine is it moves very slowly. A lot of people are going to want a randomized control trial, another randomized control trial, maybe a few more, and then a meta-analysis. But from a patient perspective, people want data now if they can get it inexpensively. And these are elective procedures — no one's saying you have to get this done.

It's unfortunate that there's a reason for it — do no harm — but by the same token, it does not necessarily do the patient any favors by waiting for something that is logical and makes sense. There's enough evidence for this sequence of events for metabolic illness all the way back to Syndrome X in the 1980s. We know there's this constellation of things. And we also know that if you don't act early, you're much less likely to have a good treatment effect. If you start treating someone once they have diabetes, it's much harder to get them back to healthy and normal. They've already lost beta cell mass, or they could have loss of sensation in their fingertips and toes.

Now, if you don't get the CGM and you have fasting insulin, and the fasting insulin is normal, you don't know if the step before that is a problem. If it's abnormal, you need the CGM to learn how to eat — because that fasting insulin is high for a reason. You're spiking your insulin and you've got to figure out why. So you go back to the CGM and you learn how to eat to not spike your insulin. I do hope physicians are more open to encouraging this as well, where we start acting earlier. It's going to be better for the population in general.

Andrew Huberman: Well, even when you have procedures that have gone through rigorous evaluations and have FDA approval, you have so many people who are reluctant to send patients for them. Why is that?

Dr Chris Thompson: I think it's in the culture. Some of these procedures, you can't learn them in a weekend course. You have to spend a year or longer learning some of these things. And so for a physician who wants to add something to their practice, they're not going to dedicate a year to it. They might do a weekend course, realize it's too hard, and then don't adopt it. The problem is the people that do adopt it and they're not ready. So then doctors who are referring go, "This procedure's been around for six months or a year, it really has great data in the clinical trials, but does the guy down the street know how to do this after doing a weekend course?" And so they're reluctant for that reason. Or insurance isn't covering it yet. It just moves slowly.

AI and Robotics in Endoscopic Medicine

Andrew Huberman: I have to imagine that there are good surgeons, mediocre surgeons, and exceptional surgeons. Are there places where you've brought in devices or machines that could offset the mediocre ones?

Dr Chris Thompson: Most devices we see are kind of incremental improvements — a little bit of better wire, devices a little more ergonomic. But what I see happening more recently is AI starting to have an impact where it can actually coach you through procedures. You have a heads-up display on the screen. It will actually give you information — it can highlight certain structures you want to work on, point to something where you want to put your stitch, count the stitches as you're placing them and tell you if they're close enough together. It can change the shape of the stomach as you're working on it to let you know if you're having a good treatment effect. This is something we never could have done before in real time. Right now it's not widely available — this is in research centers — but you can actually see this happening in real time, and it's phenomenal.

Additionally, there's the hope for robotics to help as well. We've done a lot of research in our lab on robotics and how it can take trainees learning a very complicated procedure and shorten the learning curve dramatically. We'll randomize the trainees — this is usually resecting a tumor from the colon leaving the colon in place, a very complicated procedure. The fellows will struggle horribly with the original way, which is why it takes two or three years to learn. They'll sit down with the robot and be almost as good as an expert. And in the future, when you start layering on AI and automation with the robots, you might have a big win. We've seen this before with different surgeries — with Intuitive Surgical's robots when they first came out years ago. It democratized the field. It took mediocre surgeons and made them excellent, and the excellent surgeons were still excellent.

Andrew Huberman: How do I know if I'm getting a truly exceptional surgeon?

Dr Chris Thompson: That's a good question. Understanding whether you're getting the best physician for something is really hard to determine. Some things we rely on are volume — case volume and historic case volume. How many procedures do they do? That's important. And probably more important, how many have they done over the course of their career. Volume is important — it's not the whole story, but it's important.

We need in medicine to move more towards objective metrics, and this is one thing AI can do for us. I'm involved in a healthcare delivery platform called Everself. What it does is the doctors doing these procedures are held to a certain metric. It starts with just collecting the data — finding out what their weight loss outcomes are, how many stitches they place per procedure, looking at their procedure time, looking at their complications. But the next layer is putting AI on top of it where the AI, not only can it coach you through the procedure, it can give you a grade at the end. It can tell you: you placed this many full-thickness sutures versus this many — you want 100% of your stitches to be full thickness. Maybe the doctor's putting in 70% full thickness. That's not good. This number of sutures were close enough together, some were too far apart. It will give you a grade. This is the pattern used. This is the volume of stomach you reduced it by. And that grade is incredibly important.

The idea next would be to share that data so people know what grade you're getting. It'd be great to share that with governing bodies that do credentialing, so people who are truly underperforming get a refresher. It would be nice for patients to be able to select who they're going to go to based on objective metrics. AI can do this probably across the board with other things as well.

We've seen this a little bit with adenoma detection rates in colonoscopy, where they used to publish that. Doctors were expected to have a certain number of polyps they'd see per colonoscopy and they'd report that. But then the problem was all the patients wanted to go to the one or two doctors with the highest rates, and their wait times became enormous. There should be a reasonable cutoff where a certain level of expertise is required, and I think AI hopefully will help us get there.

When you're doing these procedures where you tunnel in between the layers of the esophagus, there are vessels in there that are hard to see. AI can actually see those vessels because it's got pattern recognition and color them for you so you don't hit them as you go, reducing your chances of hitting a blood vessel. That's just one example of something that's a very complicated procedure where you're making certain aspects of it a little easier.

Additionally, there's something called hyperspectral imaging being done in surgery. One group in London is doing phenomenal work. They're using all these narrow bands of wavelengths — tons of wavelengths — and finding that each tissue actually has a fingerprint. You can use this hyperspectral imaging to fingerprint tissue and actually see margins of tumors with this, without giving a dye anymore. It's just with light technology. With LEDs being able to fluctuate the wavelengths of light and chips being able to read it faster and better, we're able to make better diagnoses.

The Duodenum's Role in Metabolic Disease

Andrew Huberman: So you do these surgeries of various kinds, and you started to understand the gut hormones. Tell us that story — how did you get from closing a fistula to understanding the role of the duodenum in metabolic disease?

Dr Chris Thompson: I saw a patient with a gastric bypass anatomy — a small gastric pouch and a bigger stomach. A patient was sent to me who had bad reflux, weight gain after the gastric bypass, and their diabetes had come back. The surgeon said, "Take a look at this patient. See if they have an ulcer. Find out what's going on." So I went and looked, and there was this little hole between the pouch — the new stomach — and the old stomach. I thought maybe the acid was produced in the other side and coming up through that fistula. We had a new suturing device that you could put in through the mouth and put stitches in. I thought maybe I could use it to close that hole.

I waited until I was on faculty a few months, talked to the surgeon, he was supportive. We talked to the patient, told them we weren't sure if it was going to help or not, they were willing, and we did the procedure and closed the fistula. I was hoping the reflux would stop. The reflux stopped, but the person started losing weight and their diabetes went away almost immediately again. And that was for me — this was 2003 — I was flabbergasted. Was it a coincidence? Why is closing that little hole so important?

So that's what got me involved in understanding the gut hormones. Because if I learned about the gut hormones and why we saw this treatment effect, we could potentially manipulate them to get better results.

Shortly after that, one of my friends and colleagues did some animal work. He had a rat model — GK rats, rats with diabetes that don't have obesity. They were a great model because you didn't want weight loss to confound things. He did two surgeries. One basically excluded the foregut — he excluded the duodenum and the very first part of the jejunum. He did a little bypass surgery there so no food could get into the duodenum. The other one he did a gastroduodenal anastomosis — stomach to small bowel but left the rest open, so food could go either way: into the duodenum like it normally would, or down into the distal bowel. What he found was these were diabetic rats, and the ones that had the exclusion — their diabetes got much much better. The ones that didn't have exclusion didn't get better at all, even though you were dumping stuff into the distal gut. Very interesting. He hypothesized there was something called an anti-incretin in that bowel — something in there that, if you exclude it, you got a better treatment effect.

That got us going down that path. And it fed well into something done in the 1980s — a famous publication looking at the same study that Sherlock had done in London, giving glucose to look at the insulin response, but done in diabetics and in a normal healthy population. The normal population had that exact same incretin response — give a certain amount of glucose intravenously, little spike; same amount of glucose orally, big spike. Diabetics didn't do that. So maybe by excluding this foregut, you're playing a role with that.

Then I did another study where I closed those fistulas — 60% of people had resolution of their diabetes. If we didn't close it, no one got resolution of diabetes. So we learned there's some important element to foregut exclusion.

Then device companies started getting involved. A company came up with the idea of putting a liner in endoscopically — like a little sleeve you anchor in the first part of the small bowel. It covers the duodenum, protects it. It's an implant so it has to come out at some point, maybe a year later. I was part of those clinical trials and we found you had a one-point drop in A1C in diabetics — that's fantastic — and about 7% total weight loss. Clearly it's doing something. The problem is it's an implant that's got to come out.

Then there was a brilliant idea from one of my colleagues at the Brigham — a cardiologist. He knew I was trying to do something. I had traveled to Brazil and was doing endoscopic procedures there, and a doctor in a room nearby was doing a very novel experimental surgery called ileal interposition. He was taking the distal small bowel — the opposite of what Rubino had done — keeping it on its mesenteric blood flow, resecting it out of the distal small bowel near the colon, and moving it up near the duodenum. His idea was that GLP-1 was denser in that part of the bowel, and if you moved it up higher, you'd get a more immediate incretin effect from GLP-1. You'd hit GIP and then immediately GLP-1 and have this amazing effect. And he did — it was incredible. These people's diabetes went away and they didn't lose any weight because he didn't actually have any blind areas. He just moved that part of the bowel up. That was phenomenal.

I was trying to do that endoscopically by harvesting tissue from the ileum via colonoscopy, creating stem cells, and injecting them in the foregut — that wasn't successful. But my cardiologist colleague said, "Why don't you just burn the duodenum? Ablate the duodenum — you could do it with steam, hot water, etc. — and see if you can reset those stem cells, because the duodenum is sick."

This is very interesting research to prove the duodenum is sick. If you can reset the duodenum, it might work. And that is something we're studying more and more. Now you don't have a sleeve in place, you don't reroute any bowel — you just ablate the duodenum. What happens is your A1C drops by over a point. You don't lose a lot of weight by just ablating the duodenum, but your A1C corrects. That's a potential treatment for diabetes. They've also done some studies — I don't believe these are published yet — showing that when someone comes off a GLP-1, if you use this treatment, it keeps them from regaining their weight. So you can take a GLP-1 and then have your duodenum kind of reset — the stem cells come back, and you've maybe healed those tight junctions and other problems.

Andrew Huberman: So it regenerates?

Dr Chris Thompson: It regenerates. Yeah. It comes back more healthy and more normal.

The rationale for that comes from a lot of very good research. Studies showed that if you overfeed mice, when you take them to necropsy and look at their bowels, the bowels in the overfed mice are longer, heavier, the villi are longer — they've adapted. They've upregulated the ability to absorb calories. These studies have been repeated in humans where people getting gastric bypass are already going to be doing surgery, so they resect part of their small bowel, and someone getting cancer surgery is a control patient. The differences are extreme — the villi are longer, it's thicker, there's more inflammation in people with obesity or type two diabetes. Natural killer cells are up eightfold, macrophages up 1.5-fold. You have more inflammatory activity going on in these patients. Additionally, if you look at those patients and do immunostaining for tight junction proteins like zonula occludens, you'll see that those are much lower and disorganized.

Andrew Huberman: So if I understand correctly — if people overeat, the villi, like little finger-like protrusions inside the gut that sense things and collect nutrients, are growing to adapt to the elevated levels of calories. And so you've changed the digestive tract in a way that yes, they can make more use of those calories, but that also creates a more pro-inflammatory environment. Do I have that correct?

Dr Chris Thompson: That's absolutely correct. Also, because they're changing in configuration and using that energy, the cells are using energy to do other things, and your tight junctions are deprioritized.

Leaky Gut, Tight Junctions, and Gut Permeability

Andrew Huberman: So then there's this secondary or parallel effect on the tight junctions. My understanding is that the tight junctions — the goal is to keep stuff inside the gut, not let bacteria out. Is leaky gut a real thing? Because I've heard it's sort of like chronic fatigue syndrome — a lot of the standard medical community hears "leaky gut" and goes, "Okay, that was made up by people in the Bay Area." But we've had a fair number of people come on here and talk about tight junction deficits, bacteria getting out of the gut, inflammation going up, bacteria circulating places they shouldn't be. Is leaky gut real?

Dr Chris Thompson: Increased gut permeability is 100% real.

Andrew Huberman: But that sounds like a different language for leaky gut.

Dr Chris Thompson: Yeah, it is. So why is the phrase "leaky gut" so irritating to the medical community? I think if you say leaky gut, it could have other connotations. Someone might think that leaky gut means it's responsible for a certain constellation of symptoms — like irritable bowel or Alzheimer's. You see in lay literature they'll say leaky gut is associated with XYZ, and it's not clear that phrase is really talking about the same thing I'm talking about. The danger is calling something leaky gut when people already might have a definition for it in mind — like it's responsible for all these other problems.

But let me tell you what increased gut permeability is, and I'll tell you that it's very real and actually tied to metabolic illness. We can start with a study that used small bowel biopsies — this was recent, just last year. They did small bowel biopsies and from the stem cells grew little organoids — three-dimensional cultures that behave as they should. They had a control group and a group with MASH — metabolically associated steatohepatitis. They looked at the organoids and found that the tight junctions were far less well-developed and more disorganized in the MASH patients compared to the control patients. Additionally, they did transcriptomics on it and found that they weren't even producing the proteins — they weren't even making the RNA to produce the tight junction proteins. So clearly at the transcriptional level, they were downregulating the tight junction proteins.

Another group looked at something similar — same population, patients with MASH. They studied gut permeability using tracers. 51-chromium EDTA is one that was used in this study — it's not supposed to get into the bloodstream. In patients with MASH, it zipped right in, much higher levels than there should be. In patients without MASH, it wasn't getting in. In patients with celiac disease that was treated, it wasn't getting in. But in patients with fatty liver disease, it was getting in and it's probably playing a role.

If you think about it, the gut — the first place it goes is the liver. There's a portal circulation, and the gut goes to that portal circulation. Everything that goes through there has to stop by the liver, with the exception of fat. Fat gets into the lymphatics and dumps out of the thoracic duct — it doesn't have to actually go to the liver. So if you have bacterial products — LPS, lipopolysaccharide, a portion of gram-negative bacterial cell membrane — if that gets through these tight junctions, it causes all sorts of problems. It goes directly to the liver. They're inflammatory. They interact with toll-like receptor 4, and that starts all sorts of inflammatory cascades via NF-κB signaling, etc.

Another group proved that was problematic — they actually took LPS and injected it into healthy people and found that their inflammatory markers went through the roof. They did clamp studies in these patients and found it induced insulin resistance. So yes, I think leaky gut can be involved in all this stuff. And that gets back to our very early discussion about fiber and fermented beverages and how important it is to keep your microbiome healthy, because that microbiome and that butyrate is critical to producing healthy enterocytes, healthy tight junctions, a healthy mucin layer. And it also works together — butyrate and the microbes and the byproducts of the microbes work with your immune system, your innate immune system, and tell it what to recognize and what not to recognize, which is just as important. Your bowel is full of bacteria, so absolutely it's very important. You do see where this increased gut permeability is associated — with hardcore good science evidence — with real illness. It's just I don't want to blame it for everything.

Artificial Sweeteners, Fats, and Diet

Andrew Huberman: I get a lot of questions about artificial sweeteners and negative effects on the gut microbiome. It seems like there's marginal to zero effect on insulin and resting blood glucose from artificial low-calorie sweeteners. There's no reason to run out and use them if you don't want to. But the weight loss data say people who drink diet sodas instead of water actually lose more weight. Where are you at with these things in terms of their potential negative effects?

Dr Chris Thompson: I think they're better than high fructose corn syrup for sure. I think we should be treating fructose like alcohol. Fructose in fruit is fine — I'm not worried about that because it comes with a matrix around it. It's not like a rush of fructose into your liver. But fructose can only be processed by the liver, and so it's busy as it is. It's got to take the burden of a beverage which is absorbed very rapidly and goes directly to the liver. It gets trapped in the liver very quickly and that's the only place it can really process it. So I think fructose is something to watch. Again, not if it's in fruit — even in juices it can be kind of processed fruit, so it's similar. Minimally processed stuff is better.

I think the problem with artificial sweeteners is they come in foods that are highly processed as it is, and you can't separate the two. That's why for a while people were so down on polyunsaturated fats — because they'll come in a bar full of a bunch of other stuff that's not good for you. The food that it's in is bad for you, but the polyunsaturated fat has been shown to reduce LDL and has health benefits.

Andrew Huberman: Essentially, translation for people — seed oils, basically.

Dr Chris Thompson: Yeah. There's still some debate about whether the processing of them can make them worse, but it's hard to separate. Did you see this recent avocado oil thing out of UC Davis? They went and analyzed all these avocado oil-containing products that are supposed to be healthier. You know how much avocado oil these products contained? Zero.

Andrew Huberman: Oh no.

Dr Chris Thompson: The pushback has been that maybe they're looking at the wrong metabolites of avocados. I don't know how this is going to play out, but this could potentially do more damage to the non-olive-oil community. In my mind, the safest thing is you just use olive oil, a little bit of butter here and there. No one debates olive oil. Everyone knows it's good for you. No one thinks it's bad for you. But the seed oil and lard thing — they go back and forth and it's kind of like professional wrestling. Olive oil, butter — that's where I'm at.

Andrew Huberman: Am I thinking about this wrong?

Dr Chris Thompson: No, I do the same. Olive oil is the best, obviously. Then small amounts of butter. I think the problem is the overall amount of saturated fat. But polyunsaturated fats have a lot of proof that they're very safe. Where you get into problems is if you have a big container of it, you're not going to use it in a reasonable amount of time, it's sitting in the sun, and it oxidizes. That's a problem. You don't want to take an oxidized oil into your body. Or you're deep frying with it over and over again and you start generating trans fats. That's a different story. But in general, I think they're fine. And I don't even think you need this omega-3 to omega-6 ratio people used to worry about. I think you need a certain minimal amount of omega-3s. If you eat fish once in a while, you're getting all you need.

Andrew Huberman: Do you strive to get some fatty fish in your diet?

Dr Chris Thompson: I do. I love fatty fish. It's good for you. I try to do it a couple of times a week.

Andrew Huberman: I take Lovaza, the high-dose omega-3 pharmaceutical, because I don't want the mercury. What's your read of the data on omega-3s for metabolic health and cardiovascular health?

Dr Chris Thompson: It's mixed. It's probably better for Alzheimer's — if someone's starting to show signs of Alzheimer's, I think it's better for that. The problem is universally supplementing is not necessarily the way to go. You want to find a deficit and then supplement. Even with vitamin D — most people probably are deficient, so they benefit from it, but there's no point in really doing it unless you're deficient for most things. With omega-3s it's similar. You want to get your daily allowance. And if you're a vegetarian, you can do it from algae — the original source. The fish are just consolidating, right? So you don't have to eat the fish, but you can get that in some kind of supplement form.

Exercise, Set Point Theory, and the ESG Procedure

Andrew Huberman: What else do you recommend to your patients as they start to move away from obesity? Obviously fiber, some fermented foods. It sounds like resistance training might be in the list given that they're at risk of becoming thin but with more jelly tissue than lean mass. Do you prescribe resistance training?

Dr Chris Thompson: Absolutely. All my patients I ask to do resistance training, even before they start losing weight, before they go through a procedure. It's essential. Zone 2 cardio is great — you're in that zone where you're burning fat. HIIT is great for mobilizing visceral fat because your visceral fat has beta-adrenergic receptors on it. It also has gonadotropic hormone receptors on it as well. So it's responsive to acute stress. It will mobilize when you're going through the stress of high-intensity interval training. It won't be burned right away because you're burning carbs at the time — you're burning your liver glycogen and your muscle glycogen — but you mobilize the fat at least. So I try to have them do HIIT, a little zone 2, and then resistance training. I think those are the most important things long term.

Andrew Huberman: Do they do it?

Dr Chris Thompson: I think they try, and depending on how they lost the weight determines if it's effective. This is the theory of set point, which is something that's very important. It's not a point necessarily — it's a defended range. You have this defended range of what you think your weight's supposed to be. That's set by a variety of things — leptin is part of it, your thyroid hormones and whatnot.

Then what you do is a crash diet. You lose a bunch of weight. The Biggest Loser was a great example of this. Now you're fighting several factors. One factor is your body is smaller, so it burns less. You have to eat less to just maintain the same weight you're at now. You downregulate your gut hormones — you're producing less GLP-1, less peptide YY, a little less CCK. So your satiety hormones are being produced less. Your ghrelin goes through the roof if you do this with diet and exercise. In addition to that, your muscles become more efficient — they become about 25% more efficient in doing a similar task, burning less fuel to do the same task. Your non-exercise energy expenditure and your basal metabolic rate all go down. So you're burning fewer calories at rest.

Your whole body is fighting you. It wants to go back to that weight, whatever it thought it was supposed to be at. The Biggest Loser had a follow-up NIH study, and they found that participants were burning 500 fewer calories per day after that. That's why it's so important. GLP-1s help fight part of that — you're replacing the GLP-1 — but you're not addressing the ghrelin or other things.

So that's why the ESG procedure is interesting. This is the procedure I developed in 2012. You go in through the mouth, someone's sleeping with a little scope, and you fold the stomach on itself. The goal of that was to do two things. One was to augment the stretch receptor — it's a smaller pocket, so when food hits it, the stomach stretches quicker and you have the vagal afferents that go up to the nodose ganglia and then into the hypothalamic area.

Andrew Huberman: You tell the brain we're full.

Dr Chris Thompson: Exactly. We're full. Stretch fast. Boom. And you're full. That's part of it. The other part is you suppress ghrelin because food stays in the stomach longer, so it's suppressing ghrelin. So it's doing two different things. When those people lose weight, they don't have to worry about their ghrelin going up because it's been suppressed. So it's easier to keep the weight off for 10 years or longer because you're not fighting that part of the countermeasures that the body will do to defend its potential range.

In addition to the ESG where we tighten the stomach, someone developed an idea — I think they were in Germany — where you can actually ablate those fundal ghrelin cells because they live in the mucosal layers. You can get to them. They use argon plasma coagulation — different ways to ablate it. You just kind of spray this over the fundus and it kills off the ghrelin-producing cells. They grow back, but there's not much of them. So now all of a sudden you can suppress ghrelin as well. The weight loss goes from about 18% with ESG alone in a top center up to way over 20%, maybe 25%, if you start ablating the ghrelin.

And then you add to it. Now if you've delayed gastric emptying, your CCK is not spiking as much. But GLP-1 is an issue. So what if you combine that with a small bowel procedure? There are different small bowel procedures we've come up with. Using magnetic anastomosis is one we published about 10 years ago. We did it in the Czech Republic where we used endoscopes — went from below via colonoscopy, my partner did that, I went from above. We released these two magnets and connected the jejunum — the first part of the jejunum — to the lower part of the ileum.

Andrew Huberman: We should probably tell people what anastomosis is — basically when you connect two tubes?

Dr Chris Thompson: Exactly. You're bridging two tubes. They did it originally with sutures — you cut a hole and suture the tubes together. Then they did staplers, but they're big and bulky and hard to position. So our lab developed magnets — ring magnets encased in nitinol so they can take a certain shape. You put them through a tube, in this case an endoscope. They come out and form a ring. We went from the top endoscope and formed a ring in the jejunum, and from the bottom formed one in the ileum way downstream. Then we had an anastomosis that would allow the food to directly pass there. What we found is you get these big spikes in GLP-1.

So now what people are doing — I'm conflicted and can't do this part of the procedure, but what they're doing — is they're doing that anastomosis and they're doing a suturing procedure endoscopically, and together you're really replicating a full gastric bypass. You're having GLP-1 hind-gut spikes, you're getting that sense of restriction and the vagal afferent signaling, you're getting ghrelin suppressed, and you're getting really amazing weight loss.

What we can do now is take a procedure that was really big — it started off as a big open procedure with certain risks, and we didn't know how it was working — and we're targeting different aspects of it. The goal moving forward is to be even more precise and find out what someone is going to be more responsive to, and then just do the least you need to do. Maybe they just have ghrelin that's driving them — just ablate the ghrelin. Maybe they need something more. People are actively studying that — studying the phenotyping of obesity. It's quite exciting.

Andrew Huberman: I'm sensing a theme here. This procedure that your lab developed — it's increasing GLP, but I'm guessing it's not increasing it thousandfold like a GLP drug would. It's got some other positive consequences that help address the obesity. We have these drugs like Ozempic, Mounjaro, etc. that blasted GLP through the roof, helped a lot of people who needed help, but there were a lot of side effect issues. Then along comes retatrutide — let's increase GLP but also bump up the GIP system a nudge or two, also bump up the glucagon system, and lo and behold we get a much better effect: muscle sparing and actually better weight loss. Maybe the lesson is you don't really want to push really hard on one lever in biology. The more combinatorial approach is the better approach.

Dr Chris Thompson: Oh, definitely. I think you can mitigate risk by doing that — by not giving too much of one thing. Hitting multiple levers is definitely a way to get a treatment effect without exposing the body to potentially the harms of going too big on one thing. That'd be the argument for these multimodal approaches. Then you can also combine these procedures with the drugs — do an endoscopic procedure like tightening the stomach and then give a drug and see if you get much more weight loss, or at a lower dose.

The goal moving forward is to even be more precise and find out what someone is going to be more responsive to, and then just do the least you need to do. And the treatments will fail — the endoscopic procedures, the surgeries, the medicines will fail — unless you really address those underlying problems. So even though alone they don't do it because the body has adapted, they're still important to the ultimate treatment.

Gene Therapy for GLP-1: A One-Time Treatment

Andrew Huberman: Given where things are at now, where are things headed next? You mentioned AI. What's the potential role of other technologies to improve health and outcomes?

Dr Chris Thompson: Well, one thing that's very exciting is gene therapy. We talked about GLP-1s and how it's mega-dosing, super-physiologic, not nutrient-responsive. There's a new company working on a new approach which is a gene therapy, and I was involved in the very early work for this. Basically what they've done is developed a viral vector that has the gene for GLP-1 in it, and they're using the promoter for the beta-cell insulin gene. So basically when a patient would secrete insulin in a nutrient-responsive way, this simultaneously secretes GLP-1.

Andrew Huberman: How are you getting into the pancreas? Are you injecting it through the skin?

Dr Chris Thompson: No. We're actually using endoscopic ultrasound — that same device we developed to biopsy the pancreas. We're now using something similar to actually treat. You can ablate tumors with energy as well. People are using electroporation to cause apoptosis, thermal means, but you can also do a fine needle injection. We're injecting the viruses basically into the tail of the pancreas. You wouldn't want to just take this intravenously because they end up in other tissue. We've done a lot of work to make sure those things stay in the tail of the pancreas — a lot of animal studies where we've injected it and used green fluorescent protein to make sure it doesn't end up in areas it's not supposed to be.

Andrew Huberman: Is there a pancreas-specific promoter — translation: this would allow even if some got out, it could only get expressed in pancreatic islets?

Dr Chris Thompson: Very, very close. But you still just don't want it getting anywhere else. The only place it becomes active is in the beta cells. It doesn't become active in the alpha cells. And you secrete insulin into these little vesicles, so you're secreting GLP-1 into those same vesicles. So then when you have your meal, the vesicles release GLP-1 and insulin together.

Andrew Huberman: Oh, that's clever.

Dr Chris Thompson: Nutrient-responsive. You're making the drug — we were already making the drug, but now you're making it at an elevated rate. Not only that, you're not making it in the L cells where it has to go all the way up through, go to the liver, go around, do its thing. You're making it right at the place where it's needed — right at the pancreas. So it has an autocrine, paracrine function, and it's much faster.

Andrew Huberman: How often are these cells turned over? If it were brain, no problem because brain cells don't turn over. But how often does the pancreas turn over?

Dr Chris Thompson: Very important. Why you can't do it in the bowel is because they're not terminally differentiated — you're turning over your whole bowel every five days or whatever. Pancreas is terminally differentiated. So they're not going to be changing. It's a permanent — the episomal DNA stays in there, doesn't integrate into the host DNA, stays next to it and transcribes with it. And they're not going to turn over.

Andrew Huberman: I feel like there's another theme emerging. We're hearing about drugs that you can get one injection to permanently lower your LDL. We're now hearing about gene therapy to chronically elevate GLP at exactly the place and time that you want, in order to offset excess calorie consumption and obesity. Is this what we're going to see — instead of people taking drugs, they're going to take a one-time injection?

Dr Chris Thompson: That's what I'm hoping. It's very exciting. They actually just entered clinical trials in the Netherlands. So we'll see how that goes, but it looks very promising. One-time GLP-1 injection — that could be nice. Additionally, you could use it to augment other therapies. You can use it to augment the gastric procedure or the small bowel procedures. It might be another tool in your armamentarium. It might be more useful for diabetes than for weight loss. We don't know yet — it's so early right now, but it's certainly very encouraging.

Andrew Huberman: Really glad you're doing this work because I'm aware of a few conditions — rare, fortunately, but not exceedingly rare — where hyperphagia is an issue. Prader-Willi syndrome and other syndromes where these kids just can't stop eating because they lack hypothalamic signals. My read is that the traditional GLP drugs are not really working there. This would be amazing.

Dr Chris Thompson: In rodent models it's phenomenal. We did these trials where you randomize mice to get semaglutide at high dose — much higher than you'd get for a human — and then the transgene. Both groups lose weight, the transgene group loses a little more. Then they stop losing, so they don't keep losing weight forever, which is good. Then you took the group that's on semaglutide and randomized them further to get nothing or to get the transgene. They get the transgene and they go right back down to the same settling point, which is great. And the ones randomized to nothing put all the weight back on. Phenomenal. So it seems to be getting really good results from a weight loss standpoint as well.

Dr. Thompson's Background and Philosophy

Andrew Huberman: I want to take just a little more of your time. You're an interesting person. It occurs to me that you had certain solutions in hand but decided to search for better solutions. Was that always you? Are you the person who, even in high school, sees that the reason you have to keep fixing something is because the tool itself is the problem?

Dr Chris Thompson: My mother would attest to that, unfortunately. I took my motorcycle apart in high school, couldn't get it back together, had to have it flatbedded away and fixed. And I fixed some parts in my car that ended up bursting into flames. So I'm much better at dealing with patients than with machines.

I always would tinker with things for sure, and I needed to do things with my hands. That's why in medical school I couldn't be a general internist. I needed to solve problems with my hands, and I think that's fulfilling to me. I don't like managing a slow demise. I felt like internal medicine, we were giving people a reason to continue with their current life rather than addressing problems. Their blood pressure is high — well, instead of finding a way to really help them address that, you give them a medicine. Their LDL is high — instead of finding a way to address it, you give them a medicine. And you see what that gets us into — these situations where we treat high LDL and APOB really effectively and reduce mortality from that specific thing, but we took our eye off the ball and fatty liver is up and diabetes is up and people are still dying in greater numbers. We need to address the underlying problem. That's very important. But aside from that, I just like doing things with my hands, and I think that was a large part of why I was going to go into cardiology or interventional gastroenterology.

Andrew Huberman: So grateful that you're a tinkerer. It's a unique thing to find these qualities and expertise woven into the same person. The fact that you clearly have immense compassion for your patients and you're willing to come here and share information publicly — you have many important roles in your daily life, so the fact that you take the time out of your schedule to educate the public is something everyone listening has immense gratitude for. And that you're thinking about what could be done better — that's the ultimate quality in my opinion of an excellent physician or scientist or engineer. We need people who are thinking about how things can be improved. Yes, there are some solutions for some people, but we need to broaden the treatments to help many more people. So I'm very grateful to you, and thanks for coming here today and sharing this information.

Dr Chris Thompson: Well, thanks so much for having me. Very kind. It's definitely always a team effort, as you know as well as anyone. Everything is a team effort, and I think innovation is never the result of one person's work. It's a whole group, and I've been very fortunate to be surrounded by a bunch of amazing people that help us move things forward.

Andrew Huberman: Throughout today's discussion, your reflex to give proper attribution is more a testament to what you just said. It's not lost on me — nor on the people listening — that people who give credit where credit's due, it says a lot about them. So thank you. Come back again maybe in a couple of years when you've solved everything, or close to it. I'm sure you're making tremendous strides, but these things take time. Once again, thank you very much. This was very informative and has enriched my thinking a tremendous amount.

Dr Chris Thompson: Thank you.