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

Dr. Chris Thompson, MD, Professor of Medicine at Harvard Medical School, Chief of Interventional Gastroenterology at Mass General Brigham in Boston, and Co-Director of the Center for Weight Management and Wellness, is a world-renowned expert on gastroenterology, metabolism, nutrition, and obesity medicine. He explains how your GI tract regulates hunger, fullness, and blood sugar, as well as the gut microbiome, metabolic health, and weight loss. We also discuss common GI tract issues and which particular tests or interventions are actually useful. We discuss both GLP-1 medications and non-GLP-1 approaches to weight loss. Given that gut health is vital to all the organs of the body, overall health, and longevity, our discussion ought to be of interest and practical value to everyone, including, of course, those struggling with gut health or weight loss challenges. Show notes: https://go.hubermanlab.com/moMYULJ Thank you to our sponsors AG1: https://drinkag1.com/huberman Function: https://functionhealth.com/huberman Lingo: https://hellolingo.com/huberman LMNT: https://drinklmnt.com/huberman Our Place: https://fromourplace.com/huberman Timestamps 00:00:00 Dr. Chris Thompson 00:02:16 Digestive Tract, Gut Hormones & Nutrient Absorption 00:08:06 Colon Microbiome & Colon Cancer Screening 00:11:13 Sponsors: LMNT & Lingo 00:13:40 Swallowing Problems & Zenker’s Diverticula 00:16:08 Bowel Movements & Constipation 00:18:28 Fiber, Resistant Starch & the Gut Barrier 00:21:50 Intermittent Fasting & the Gut Microbiome 00:23:38 Fermented Foods, Microbial Diversity & Butyrate 00:27:12 H. pylori, Stress & Stomach Ulcers 00:30:20 GLP-1 Medications: Benefits & Limitations 00:33:42 Lower GLP-1 Doses, Weight Regain & Muscle Loss 00:37:35 GLP-1 Side Effects, Food Noise & Apathy 00:39:49 Bariatric Surgery & Medical Innovation 00:46:07 Sponsor: AG1 00:47:44 Hunger & Satiety: Ghrelin, CCK, GIP & GLP-1 00:50:01 Retatrutide & Combining Hormonal Targets 00:52:55 Ultra-Processed Foods, Overeating & Leptin 00:55:32 Incretin Discovery, Exendin-4 & the Gila Monster 00:59:35 Endoscopic Ultrasound & Pancreatic Biopsy 01:07:40 Early Metabolic Markers, CGMs & Fasting Insulin 01:13:06 Insulin Resistance & Metabolic Flexibility 01:15:53 Sponsor: Function 01:17:35 Patient Data, Screening & Treatment Adoption 01:26:31 AI, Robotics & Improving Procedures 01:29:27 Choosing a Surgeon & Measuring Procedure Quality 01:35:29 Image Guidance & Hyperspectral Imaging 01:37:19 Sponsor: Our Place 01:38:56 Diagnostics & Targeted Metabolic Treatments 01:42:45 Gastric Bypass, Foregut Exclusion & Diabetes 01:47:59 Duodenal Liners & Mucosal Resurfacing Research 01:52:58 Gut Permeability, Inflammation & Fatty Liver 01:59:39 Artificial Sweeteners, Fructose, Fats & Omega-3s 02:05:00 Resistance Training, Zone 2 Cardio & Intervals 02:06:31 Weight Set Point & Metabolic Adaptation 02:08:13 Endoscopic Sleeve Gastroplasty & Fundus Ablation 02:10:30 Magnetic Intestinal Connections & Combined Treatments 02:16:52 GLP-1 Gene Therapy Research 02:22:13 Innovation, Problem Solving & Teamwork 02:25:58 Zero-Cost Support, Sponsors & Neural Network Newsletter #hubermanlab #science #guthealth Disclaimer & Disclosures: https://www.hubermanlab.com/disclaimer

Dr. Chris ThompsonguestAndrew Hubermanhost
Sep 21, 20262h 27mWatch on YouTube ↗

EVERY SPOKEN WORD

  1. 0:00 – 2:16

    Dr. Chris Thompson

    1. CT

      There's all sorts of evidence that if you don't have a lot of fiber, your microbiome's not healthy. Feed your microbes, you know? They need to be fed. And what they eat is fiber, okay? That's what you want them eating. You want them eating fiber. And if you're not feeding them fiber, they'll eat your mucus layer, okay? And we already talked about how thin that barrier is, and now all of a sudden they start eating your mucus layer. They're, they're not producing the butyrate you need, and the butyrate's needed to maintain the tight junctions, right? So there's layers to this. It's like a snowball effect.

    2. AH

      Mm-hmm.

    3. CT

      That if you're not feeding those micro- the microbiome and keeping it healthy, you're gonna run into all sorts of-

    4. AH

      Hmm

    5. CT

      ... all sorts of trouble.

    6. AH

      Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. [upbeat music] I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Chris Thompson. Dr. Chris Thompson is a professor of medicine at Harvard Medical School. He is also the chief of Interventional Gastroenterology at Mass General Brigham in Boston. He is a renowned expert on the intersection of gastroenterology, metabolism, nutrition, and obesity medicine. And in today's episode, Dr. Thompson explains how to improve your gut health, including the roles of your diet, gut microbiome, and gastrointestinal motility, as well as how your gut communicates with the rest of your body, which of course includes the gut microbiome, but as you'll learn today, much more. Dr. Chris Thompson is a guest on this podcast because he's not just a GI tract and obesity medicine expert, he's also credited with having created an entire new field of treatments and perspectives on GI and metabolic health. So the knowledge he shares today is truly at the cutting edge and applicable, which is why by the end of today's episode, you will have a clear understanding of how your gastrointestinal system works, and you will have a set of new, modern, evidence-based tools for improving and maintaining your gut health. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Chris Thompson. Dr. Chris Thompson, welcome.

    7. CT

      Thanks so much. Good to be here.

  2. 2:16 – 8:06

    Digestive Tract, Gut Hormones & Nutrient Absorption

    1. AH

      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 and just educate people a bit on what happens that stimulates them to want to eat, why perhaps for certain periods of t- 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. This is such a critical part of our biology and our lives.

    2. CT

      It's becoming more and more complex all the time, right? The gut. And it does a lot of things. So i- it's obviously involved in digestion, but it's also an endocrine organ. You can hear it called the second brain, right? So there's a lot of different ways we, we think about, about the gut. And it is compartmentalized, and each, each area has a different job. So at first you have, you know, the esophagus, and its job is to just kind of move the food into the stomach safely. And it's thick, right? It has different lining, so it can handle things that might be a little rougher. And, uh, it pushes sequentially, you know, down into the stomach. So it's taking that food bolus and driving it into the stomach. And you can have all sorts of problems in your esophagus, right? So each one of these organs has, you know, 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 it's just the bottom of the esophagus doesn't relax, right? And so 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, you know, a few millimeters. You can tunnel down into there and cut that muscle to relieve the obstruction, so.

    3. AH

      What are the symptoms of that?

    4. CT

      So inability to swallow.

    5. AH

      So what, what do they do? They choke?

    6. CT

      So, yeah, they feel like they're choking. So they'll, they'll swallow food, it'll get down and stop, and then they'll feel pressure. They'll feel really uncomfortable. If they've drank some fluid with it, it might start coming back up. It'll just stay there. And then sometimes they'll have to, you know, in- induce vomiting to remove it. It's very uncomfortable for them. And it's not a terribly common condition, but it's becoming more and more frequent. I see it every week, right?

    7. AH

      Hmm.

    8. CT

      So that inability to swallow. And you can get that inability to swallow for other reasons, actually, that are far more common. Chronic heartburn. If someone has reflux, you know, that burning sensation, uh, that can damage the lining of the esophagus and it can lead to precancerous conditions called Barrett's esophagus, which is something that, you know, needs to be treated, looked at, and, and, and, uh, kind of followed. Uh, but with time it can actually cause scarring, so you get a stricture. So it's kind of very fibrotic tissue there. That's another reason why people might have difficulty swallowing. There's other reasons as well that are more obscure. But, so and that's the job of that esophagus, just to move the, the food down safely, and a lot of times it, it doesn't work. Then you have the stomach next, right? First, what the stomach does is, is it stretches to accommodate and accept a meal, right? So it stretches. Normally it's like a tube in your, you know, in your, in your abdomen. But then when you start to smell food, it starts stretching and becoming more like a bag.

    9. AH

      Really just the, the odor of food.

    10. CT

      Yeah. It can, it can stretch, relax to accept that meal. And if it doesn't do that properly, it's, it causes symptoms like nausea, right? So, uh, so then it accepts the meal, and, uh, it has to do its job, which is to break it down and pass it on. So that the stomach now isn't just transporting, it's breaking it down. And it does that mechanically. So in, in the, the fundus, the top of the stomach is holding that meal. That's what kind of stretched up to hold it. And then the rest of the stomach's working on it. So the body of the stomach, the next segment, is breaking it down, it's grinding the food-

    11. AH

      Mm-hmm

    12. CT

      ... into smaller bits. Acid is part of this as well. The stomach secretes acid. And then the bottom of the stomach, called the antrum, will push the food out slowly into the duodenum, right? That's the first part of the small bowel. Satiety, satiation all becomes part of this because the stomach's what secretes ghrelin. And we'll talk about that probably more later, but the stomach secretes ghrelin. And so this is part of your satiety signaling. All sorts of problems with the stomach, right? So similar to the esophagus, food might not leave Uh, you know, as it should in the right, in the right timing. So it can happen due to ulceration in the stomach, scarring, or something called gastroparesis, where, uh, for a variety of reasons, it might be post-viral, it might be due to diabetes, uh, neural hormonal, um, kind of origins of this. The stomach just doesn't empty as it should. People have nausea and vomiting with that and other problems, so. Then you get into the small bowel, and the small bowel's job now, typically you do a little digestion still early on 'cause you have pancreatic and biliary secretions going in there. But its main job's gonna be to absorb calories, right? So that's absorbing calories and moving it down. It's very thin. It's one cell thick. Has about the surface area of, like, a pickleball court, right?

    13. AH

      One cell thick?

    14. CT

      Yeah, it's one cell thick. The lining is one cell thick. That's the barrier.

    15. AH

      What's the cell type? Just to-

    16. CT

      Entero- enterocytes. Yeah, so columnar.

    17. AH

      Those are-- Those must be some really sturdy cells.

    18. CT

      Columnar epithelium. Yeah. [laughs] So they're pretty sturdy. Uh, they, they rely on more than just the cell itself to, to, to maintain that barrier. Um, there's certain cells called goblet cells that produce mucin, and that creates a nice thick layer there, uh, that help as, as, as another part of the barrier. They have something called tight junctions-

    19. AH

      Mm-hmm

    20. CT

      ... right between the cells, which are complex little structures that are part of that barrier as well. And there's immune cells in there. There's other elements to that barrier, but it is one cell layer thick. So that's why the stomach's-- You know, the esophagus and stomach got a good job of processing that, processing that food so that it's, it's safe to go down through the small bowel and be absorbed. All sorts of issues with the small bowel. Similarly, you can have different diseases that, uh, uh, affect that, you know, select disease, uh, Crohn's disease, et cetera, different inflammatory conditions. Um, and, uh, what we're learning now and we'll hopefully get, get into is it plays a central role, we think, in metabolic disease, and that's kind of what's very exciting is, is its role in obesity, diabetes, and other similar conditions.

  3. 8:06 – 11:13

    Colon Microbiome & Colon Cancer Screening

    1. CT

      And then eventually you have the colon, and that's where your microbiome is the star, right? The, the colon, uh, its job is to usually just absorb water. Most of the nutrients are gone by then. But it does play an important role, um, as well, and it is working hand-in-hand with your microbiome to, uh, you know, to, to make sure that, um, you're producing... It really is-- It's, it's mostly butyrate, I think, that's mostly involved there, where the microbiome is producing short-chain fatty acids, and one of them, the most important probably, is butyrate that has a, a, a lot to say about your metabolism as well. That's involved in satiety signaling. And you have a lot of GLP-1 produced from the colon again, so you're, you're getting these kind of, uh, endocrine function of your colon that's very involved, and then it passes. So and again, diseases in the colon. Colon cancer is a big one, right? So colon cancer screening is important. People-- Typically now I think they moved the age back to forty-five. Everyone should start getting screened, uh, to make sure, you know, they don't have, uh, cancer. You can do it different ways. There are genetic tests you can do, like Cologuard, and if you do that, you have to do it every, every few years, but you can do that. Uh, you can do screening colonoscopy every ten years if it's normal, and there's other things you can do as well. CT colonography is not as common in other tests, but those are the two most common. It's important, important to do that.

    2. AH

      How common is, um, colon cancer?

    3. CT

      In our line of work, it's the, it's the most frequent-

    4. AH

      Mm-hmm

    5. CT

      ... cause of, of cancer, unfortunately.

    6. AH

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

    7. CT

      The survival rates are definitely improving due to screening programs, right? So that's, that's important. So it is definitely important to get screened. Also, screening earlier helps. So for instance, starting at forty-five is better than many people who started at fifty and they wouldn't get till fifty-five or sixty, right? But also, if you have a family member that has had cancer, you wanna start at forty, or if they were younger, you wanna start ten years younger than when they were diagnosed, right? So you wanna start that screening process early. It's very effective, um, you know, and, and, uh, it's import- important to do. And I think that things like Cologuard and other genetic tests are gonna keep getting better and help because you don't have to have that kind of very uncomfortable screening procedure. Colonoscopy is not, it's not a great way to do screening, right? You shouldn't have to have a relatively invasive procedure to be screened for something. You know, it should be something you do just to a blood test or a stool study or something like that. And I think we're getting there with technology, and that will definitely show dividends 'cause you can have the colonoscopy to remove the lesion, which is something that we can do. It's, it's a newer technique where we can actually go in and remove these very early cancers endoscopically, so we call it organ-sparing surgery. So you don't have to actually remove a piece of the colon anymore. You can just kinda, you know, take a, take the lining where that pre-cancer is residing. It's a complicated procedure, but it's easy for the patient. You know, they keep their colon, they go home the same day. And these tests, you know, are, are easy ways to, to diagnose those patients and, and get them in for proper care. So very important. So that's pretty much the quick overview-

    8. AH

      Mm-hmm

    9. CT

      ... of, of the gut. And, uh, it plays-- One thing we haven't touched on too much yet is its role in, in really, uh, you know, satiety and, and kind of how it's involved in processing of food, uh, in detail and the kind of en- enteroendocrine system that's involved.

  4. 11:13 – 13:40

    Sponsors: LMNT & Lingo

    1. AH

      I'd like to take a quick break and acknowledge one of our sponsors, LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes, sodium, magnesium, and potassium, all in the correct ratios, but no sugar. Proper hydration is critical for brain and body function. Even a slight degree of dehydration can diminish your cognitive and physical performance. It's also important that you get adequate electrolytes. The electrolytes, sodium, magnesium, and potassium, are vital for the functioning of all cells in your body, especially your neurons or your nerve cells. Drinking LMNT makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes. My days tend to start really fast, meaning I have to jump right into work or right into exercise. So to make sure that I'm hydrated and I have sufficient electrolytes, when I first wake up in the morning, I drink 16 to 32 ounces of water with an LMNT packet dissolved in it. I also drink LMNT dissolved in water during any kind of physical exercise that I'm doing, especially on hot days when I'm sweating a lot and losing water and electrolytes. LMNT has a bunch of great-tasting flavors. In fact, I love them all. I love the watermelon, the raspberry, the citrus, and I really love the lemonade flavor. So if you'd like to try LMNT, you can go to drinklmnt.com/huberman to claim a free LMNT sample pack with any purchase. Again, that's drinklmnt.com/huberman to claim a free sample pack. Today's episode is also brought to us by Lingo. Lingo is an everyday wearable that tracks your glucose 24/7. Glucose drives a lot of key processes that support energy, body composition, and long-term health. When glucose is constantly spiking and crashing, that's where we can start to see metabolic dysfunction, and over time, that can even progress to prediabetes. Right now, about 115 million adults in the US have prediabetes. Most don't know it, and a higher percentage of men have it than women do. Often, there aren't clear symptoms of prediabetes early on, so people don't tend to look into it. But the fact is that metabolic health is shaping how your body functions every day, whether you feel it or not. Tracking your glucose with Lingo can help you see how food, activity, and stress impact your glucose throughout the day. I personally have used Lingo, and it's been an invaluable tool for improving my metabolic health. If you would like to try Lingo, Huberman Lab listeners in the US and UK can save 10% on a four-week plan. Just visit hellolingo.com/huberman for more information. Terms and conditions apply. Again, that's hellolingo.com/huberman.

  5. 13:40 – 16:08

    Swallowing Problems & Zenker’s Diverticula

    1. AH

      A couple questions that, uh, no doubt will resonate with people because they're fairly common, and, uh, you'll tell me if they're of concern or not, uh, depending on the frequency. We'll start at the, the top of the, the GI tract. People will say sometimes that they eat and some of the food seems to go up their nose. They know this because if they blow their nose, they might get some food particulate. It, it sounds like something that's not entirely uncommon based on the number of questions I get about it. What's going on there? Why would... You know, I get asked a lot of questions, some of them truly weird and rare-

    2. CT

      Mm-hmm

    3. AH

      ... and some of them, um, weird and less rare, and I would put it in the second category.

    4. CT

      That could be a variety of different things.

    5. AH

      Mm-hmm.

    6. CT

      And this is the area that I do work in, right?

    7. AH

      Mm-hmm.

    8. CT

      So it can be an oropharyngeal transfer problem, where the, the hypopharynx is transferring food into the esophagus. That can be, you know, an E- ENT thing. It can actually be functional medicine as well, where you can work with a speech pathologist that teaches people how to swallow better. They might have to change the c- the quality of the food they're eating to thicker food. They might have to turn a certain way to swallow, and there's ways they can actually train people with, with kind of biofeedback to, to learn how to swallow better, 'cause that part's still under your control a little bit.

    9. AH

      They're not swallowing well.

    10. CT

      Yeah. And with age, that can happen, right?

    11. AH

      Mm-hmm.

    12. CT

      With age, that can happen. Now, the next thing that can contribute to that is if they have high tension in the first sphincter up above, which is the upper esophageal sphincter. That's the, the sphincter that separates the top of your esophagus from your mouth, basically.

    13. AH

      Mm-hmm.

    14. CT

      And that can be, have high tension.

    15. AH

      Mm-hmm.

    16. CT

      And what I see a lot is something called Zenker’s diverticula, which we haven't talked much about. There's a few different little pockets that can form high up-

    17. AH

      Mm-hmm

    18. CT

      ... in your esophagus near that sphincter. Uh, there's different names for how they, you know, kind of where they, where they exactly occur. And with time and with age, this, this, this is like a herniation of mucosa through the muscle, and it creates a pocket, and that can actually trap food.

    19. AH

      Hmm.

    20. CT

      So when people are eating, the food goes into the pocket and then comes back up and can go out their nose or, or sit in there, which is very uncomfortable for them, right? That's another way you can have problems swallowing.

    21. AH

      Mm-hmm.

    22. CT

      And that can be fixed very easily. We go in through the mouth, actually make a tiny incision, and just kind of take down the septum that, that's part of that pocket, opening up the pocket so that the food can leave. So it's important to do it early too, because people can actually... This, it looks like an inconvenience initially, right? It's, you know, you're not swallowing well. Food's, you know, is, is not where it's supposed to be necessarily. The problem is when people then aspirate and that food goes in the lung, and then it can lead to scarring in the lungs, and eventually it can really cause problems. So it is something that should probably be taken seriously and looked at, even though it sounds funny, you know?

    23. AH

      Mm-hmm.

    24. CT

      It, it is something that can be

  6. 16:08 – 18:28

    Bowel Movements & Constipation

    1. CT

      a real problem.

    2. AH

      There's a weird thing about GI tract and bowel movements in particular, which is the following: with babies, with puppies, and to some extent with ourselves, but especially with babies and with, uh, puppies, we sort of, because they can't speak, we have a couple of, like, key readouts that we intuitively understand reflect their health. One is the, uh, pallor of their skin, the eyes, like if eyes are looking glassy or tired, you know, um, and their... and the, uh, quality or lack thereof of their bowel movements, quality, frequency, et cetera. But then something happens where speech comes online and we get, uh, you know, uh, uh, toilet trained, and then everyone's responsible for, like, understanding, like, their own bowel movements, right? And then we're never really told, like, what's healthy bowel movements. We, but we all kind of know what's normal for us or not normal. I'd be lying if I didn't say, like, these are important metrics of health.

    3. CT

      Yeah. Well, there's so much you can tell from bowel movements, okay? So the rule of thumb is, you know, 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. So that's kind of the general rule. And you want it to be one formed bowel movement, you know, or, or a couple. You don't want little tiny pebbles. That's called scidula stool, and that's, that's a sign something's going on. But there's a lot you can tell. How much are they taking enough fiber, right? The World Health Organization, um, uh, published something in The Lancet years ago on, on fiber, a fiber synthesis I think they called it, and they found that, you know, the vast majority of the population really doesn't, especially Western countries, just are not getting enough fiber, which is obviously concerning because it, that, that causes a lot of issues long term, right? Which, which w- we'll get into. But if you're having these scybalous stools, if you're, if you are constipated, meaning you're, you're having a bowel movement more than once every three days, and they're hard stools, that's a sign you're not getting enough fiber. So that's one thing you really have to, to, to think about, right? Additionally, there's other things you can tell after procedures, you know, if a s- if a proced- if a, if a bowel movement's very dark, tarry, and shiny, that's a sign you have blood in your GI tract, right? So there's different things you can tell from, from, from, from the stool that are important to keep an eye on. But in general, that's kind of the rule of thumb, uh, you know, uh, with, with, uh, with bowel movements. You're having more than three a day is probably leaning towards being too loose, right? And if you're not having one every three days, you're probably bound up and, and then you really have to think about

  7. 18:28 – 21:50

    Fiber, Resistant Starch & the Gut Barrier

    1. CT

      fiber.

    2. AH

      As I recall, the recommendations were for adult men, 35 grams of fiber per day, and for women, 25. And obviously, that's not accounting for variations in body weight and height and all the rest. So, um, does that sound about right?

    3. CT

      Yeah. That's, that's about right. And it kinda depends on the quality, too. There's a couple other really interesting studies that came out recently, just within the last few years, uh, looking at the importance of fiber related to certain conditions. Like, one was fatty liver, right?

    4. AH

      Mm-hmm.

    5. CT

      And fatty liver was a interesting, interesting study. They were using resistant starch, like level two, so basically raw powdered, um, potatoes-

    6. AH

      Mm-hmm

    7. CT

      ... something like that, right? Uh, um, and they were supplementing it, I think it was at 40 grams, and they found that when they did that, they actually saw significant improvement in fatty liver, which is phenomenal, right? And it was, you know, relatively weight stable. So it has important treatment effects. Another group actually, um, uh, studied it and looked at insulin, uh, sensitivity. So they did clamp studies, you know, where they, they would, um, kind of really be able to detect insulin resistance and kind of try to, uh, look at, um, kind of glucose utilization and clearance. And they found that with this RS2 type, you know, resistant starch two, they were able to improve insulin resistance-

    8. AH

      Hmm

    9. CT

      ... and insulin sensitivity as well. So fiber i- is very important. It's not just about the bowel movements, right? It's also about, you know, really just having, you know, health. It probably helps the microbiome. There's, there's all sorts of evidence that if you don't have a lot of fiber, your microbiome's not healthy, right? You get less diversity in your microbiome. There's different studies that have looked at that. It is important to have that fiber, and that constipation is an early window into it, right? It's an early sign maybe you're not getting enough, enough fiber.

    10. AH

      Mm-hmm. Yeah, I make it a point to eat fruits and vegetables because I like them, but recently I started supplementing with a powdered psyllium husk that... and some of them actually taste pretty good. And the... my expectation is I was gonna feel really bloated. It was quite the opposite. It, it... not that I had gut issues before. If it was normal, it kinda like hyper-normalized things. Actually, it made, uh, post-meal, um, subjectively, the sensation just to, like, feel good, feel great. Um, and 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.

    11. CT

      Mm-hmm.

    12. AH

      And I think that's a... that might be true for some people, but it certainly wasn't my experience, and I think that if... I feel like the messaging on fiber to the general public is pretty lousy. What-- Meaning, people are told to take it. That's great.

    13. CT

      Mm-hmm.

    14. AH

      They're told all the time. But I think people think, "Oh, if I have a lot of fiber, I'm gonna be really gassy, I'm gonna be really bloated." But as you pointed 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.

    15. CT

      Totally. It's like, feed your microbes, you know?

    16. AH

      Yeah.

    17. CT

      Or they're gonna eat you, right? [laughs]

    18. AH

      Yeah.

    19. CT

      And, and it's kinda true, right?

    20. AH

      Yeah. Yep.

    21. CT

      'Cause i- they need, they need to be fed.

    22. AH

      Mm.

    23. CT

      And what they eat is fiber, okay? That's what you want them eating. You want them eating fiber.

    24. AH

      Mm.

    25. CT

      And if you're not feeding them fiber, they'll eat your mucus layer, okay? And we already talked about how thin that barrier is, and they'll all of a sudden they start eating your mucus layer. They're, uh, they're not producing the butyrate you need, and the butyrate's needed to maintain the tight junctions, right? So there's layers to this. It's like a snowball effect-

    26. AH

      Uh-huh

    27. CT

      ... that if you're not feeding those micro- the microbiome and keeping it healthy, you're gonna run into all sorts of-

    28. AH

      Hmm

    29. CT

      ... all sorts of trouble.

  8. 21:50 – 23:38

    Intermittent Fasting & the Gut Microbiome

    1. AH

      Raises some, um, interesting questions about, uh, intermittent fasting. I think very few people are doing long-term fasts of more than a day or so. I mean, it does happen, but most people, a lot of people do sort of time-restricted feeding, or they're s- they'll skip breakfast. Uh, you know, I'm, I'm one of those people most days just by default. Uh, I had a, a colleague friend at Yale who studied microbiome, and I said, "Oh, so does fasting improve the gut microbiome?" And he said, "No, actually, during the fasting period, your microbiome starts eating up your, uh, your digestive tract," which is what you're saying. But then he said, "But then the rebound often is im- puts you at a slightly better place afterward." So it's tricky. Should people avoid intermittent fasting if they're having gut issues? Uh, I know we don't want to make any broad recommendations. It's highly contextual, but based on what you said, it, it seems that it stands to reason that you might want to avoid having your stomach empty for t- very long periods of time outside of sleep.

    2. CT

      I don't see it as being a major issue. I think there are benefits of intermittent or time-restricted eating, intermittent fasting, probably would outweigh that risk. You know, you need to give your pancreas time to relax. You know? You need to have insulin come down. If you're eating frequently, your insulin levels are already up, alw- always up, and that, that causes problems. So I do think the benefit of, of, of the, the time-restricted eating definitely outweighs that, that potential risk.

    3. AH

      Uh, great to hear. Um, especially as somebody who just by default doesn't eat breakfast or, and just don't get hungry till 11.

    4. CT

      I skip breakfast as well, but there's studies, 'cause initially they actually used to say, "Well, you have a cortisol spike in the morning, and, you know, y- you know, you're more likely to star- uh, store the, uh, the food you take in if you, if you, if you eat in the morning." Turns out maybe that's not so true.

    5. AH

      Mm-hmm.

    6. CT

      It might be better to actually have... you know, eat earlier and then have your fasting window start in the afternoon.

    7. AH

      Right.

    8. CT

      I think doing is better than not doing.

    9. AH

      Yeah.

    10. CT

      And I still, I still skip the breakfast.

  9. 23:38 – 27:12

    Fermented Foods, Microbial Diversity & Butyrate

    1. AH

      The topic of fermented foods, low-sugar fermented foods as a possible benefit for gut health has come up, um, since Justin Sonnenburg and colleagues have published that, the, the study at... There's a small number of people in that study, admittedly, but, um, that taking in some low-sugar fermented foods really helped lower the inflammatome. They didn't look specifically at, as I recall, uh, uh, symptoms of gut irritabil- ir- irritation or things of that sort. But what are your thoughts on fer- low-sugar fermented foods? So we're not talking beer.

    2. CT

      Yeah.

    3. AH

      We're, we're talking, uh, kimchi, sauerkraut, brine, uh, you know.

    4. CT

      I think they're, they're important, um, and they're missing in the Western diet, which is an issue. And I think there's... The study you referred to, actually, I think they compared it to, to fiber, right?

    5. AH

      Mm-hmm.

    6. CT

      It was-

    7. AH

      Mm-hmm

    8. CT

      ... it was fermented foods to fiber. And with the fermented foods, you had, uh, reclaimed some diversity in, in the microbiome, which was great, as well as the, the reduced inflammatory markers, where the fiber didn't seem to do that. And you saw all these benefits in these other f- other fiber trials that we're, we're talking about with the resistant starches, right? So it stands to reason that we'd probably see that as well as we do more research into the fermented foods. They're, uh, beneficial for a variety of reasons, you know. One, they're prebiotic, right? So you're feeding your microbiome things they want, which is phenomenal, and it's already kind of started. It's a little partially digested, which is really helpful. And, um, and they're also a little bit of a probiotic as well because you do have some, you know, some live cultures in there, right? And, um, you usually have bifidobacterias or lactobacillus or something like that in, in them and a variety of other things as well. So it gets the ball rolling, right? So it's sort of like when you're, you're trying to grow something. You want to plant the seeds but also have the fertilizer and whatnot, and this, this is what, um, fermented foods do for you. So I think, you know, that, that's, that's very helpful. And it's all about maintaining this, this kind of healthy microbiome that can produce things like butyrate, which have a lot of, a lot of benefits we can talk about. You can't just take butyrate and then... I- it's not gonna make it to the colon, right? It needs to be in the colon to have its, to have, to have its effect. And so what these bacteria do is they kind of... They, they will, um, uh, kind of cross-feed, in a sense, right? So you have those first layer of bacteria that will take the fiber and break it down, and they create acetate and lactate and whatnot. And then that can then be used by other bacteria, so you're feeding the other, the other bacteria that can then turn that into butyrate.

    9. AH

      Mm.

    10. CT

      You know, and, and things like that. The butyrate is magical, right? So that will feed your colon cells. Your colon cells live on that with butyrate's needed for those tight junctions. Butyrate, you know, does all sorts of things via GLP-1 pathways and satiety pathways. So it has a lot of different, uh, a lot of different roles that it's playing. Additionally, it keeps your bowel acidic, right? So, like, these short-chain fatty acids and, you know, uh, acetate and whatnot, and that's great to, to make sure you are, uh, protected from certain pathologic organisms that might wanna take, take root, right? So, uh, the aerobic organisms and the, the other organisms that you don't want don't survive as well in an acidic environment. So really important to, to, to take these fermented foods in addition to fiber.

    11. AH

      Do you make it a point to consume them?

    12. CT

      I do.

    13. AH

      Yeah.

    14. CT

      Yeah. I, I, yeah, I like kefir or kefir.

    15. AH

      Mm-hmm. Yeah.

    16. CT

      I never know how to say that, right?

    17. AH

      Yeah.

    18. CT

      I, I like, I like that.

    19. AH

      Yeah, it's tasty.

    20. CT

      I think it's phenomenal. Yeah, it's good.

    21. AH

      Yeah.

    22. CT

      Kimchi is good, you know. Sauerkraut. Um, there's all different types. Yogurt, you know. Um, there's, there are different types, I think, that everyone should be able to find. K- kombucha, you know.

    23. AH

      Mm-hmm.

    24. CT

      Um, and it's certainly missing in our diet, so I think it's, it's important to, to, to, to, to, to recommend that the folks do.

  10. 27:12 – 30:20

    H. pylori, Stress & Stomach Ulcers

    1. AH

      Canker sores and ulcers, uh, my understanding for a long time is they were caused by stress or wounds to the mouth. And then, you know, a couple folks won a Nobel Prize for identifying a soil-based bacterium that causes ulcers. And I loved that Nobel Prize year, you know, as a scientist. Like, some people watch the Super Bowl. Like, you know, we're like, "Who w- you know, who won the Nobel Prize?" And it's never surprising who wins. It's, at least for the sciences, right? Um, it's often surprising who doesn't, but let's leave aside that, uh, that component. But that was a very surprising set of findings, right? Like, a gut bacterium is causing ulcers. And I, I love the findings but at the same time, I think m- many, many millions of people, hundreds of millions, billions across history would say stress gives people ulcers. So there's something going on there that's more than soil-based bacterium, right?

    2. CT

      Yeah, definitely.

    3. AH

      You know? And, and that, that's the problem with these... You know, the way the media covers these findings. Like, it's not all that you ingested the wrong soil. I mean, stress can give you ulcers, right? Or am I-

    4. CT

      Yeah

    5. AH

      ... am I missing something?

    6. CT

      Stress can play a role. Um, you know, it, it is, it is certainly complicated. So Barry Marshall was phenomenal in Australia, and he found H. pylori could cause gastric ulcers, right? And he had to consume... No one believed him. He had to consume himself, consume it, and, and then he had gastric ulcers and-

    7. AH

      I love it when scientists do self-experimentation.

    8. CT

      Right? That's crazy, right?

    9. AH

      Yeah.

    10. CT

      So but that was phenomenal, right?

    11. AH

      Yeah.

    12. CT

      And he, he proved H. pylori, and we need to treat that, right?

    13. AH

      Yeah.

    14. CT

      And, uh, and that, that... Actually, H. pylori was actually found even in Ötzi the Iceman. I don't know if you remember Ötzi the Iceman. He was this, uh-

    15. AH

      Oh

    16. CT

      ... like, 5,000-year-old, you know, homo sapien in the, in the Italian Alps. He was found frozen, right? So you could actually get into his stomach and see what was in there.

    17. AH

      He died stressed. No, I'm joking. [laughs]

    18. CT

      He died stressed. [laughs] He had H. pylori in his stomach.

    19. AH

      Poor guy.

    20. CT

      That thing's been around a long time.

    21. AH

      Yeah. Yep.

    22. CT

      It's kind of interesting. There's other lessons there, like, like, l- uh, a loss of, of, of diversity of the microbiome, right? You know, with industrialization, we have far fewer species and less genetic diversity in our microbiome. But regarding, regarding ulcers, [laughs] so I, I actually did a study of this in gastric bypass patients a good bit, right? And, uh, it, it was not a bacterium that was causing it, right? Sometimes it was a relative ischemia. Type 2 diabetes causes, uh, kind of microvascular ischemia. Smoking can cause microvascular ischemia. In gastric bypass patients, the small bowel doesn't, uh... It's, it's a distal part of the small bowel from lower down that's connected to the stomach, and it doesn't have bicarbonate, uh, that's being secreted from the pancreas in, in the area. So there's no way of neutralizing acid. So you have the pouch- Which, you know, we can get into the anatomy here, but if the pouch of, of the gastric bypass is too large and makes acid, the duodenum now has no-- or the, the jejunum actually has no natural defense against that. So acid clearly plays a role, and if you're stressed, you can produce more acid, right? So generally, there's probably multiple hits. We don't fully understand things, but clearly it's not just an infectious organism, and it kind of depends on individual circumstances, um, and susceptibilities. But ulcers are certainly something that can occur short of a bacteria.

    23. AH

      So important for people to hear that, you know, because one thing can cause something, it doesn't mean it's the-- always the case that-

    24. CT

      Yeah.

  11. 30:20 – 33:42

    GLP-1 Medications: Benefits & Limitations

    1. AH

      So let's talk about metabolic health, hunger, obesity, weight loss. These are areas that when, you know, square in your wheelhouse. Can't have this conversation without talking about the GLPs. Um, most everyone has heard of these things nowadays. Millions and millions of people I've heard, I don't know if this is true, as many as twenty percent of, of a, uh, people eighteen and older have taken or are currently taking a GLP or either, you know, Ozempic, Mounjaro, soon Retatrutide will be out to market. What's your thought on these compounds? Are they the perfect solution to weight loss?

    2. CT

      I'm grateful we have them, right? Um, obesity is, is a serious problem, and all the, all the metabolic issues that, that are kind of there with obesity, uh, 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, you know, there's limitations, but they're m- it's much better to have them than not have GLP-1s for sure. There's issues with, with certainly, um, adherence, unfortunately, right? So there's a, there's a number over a million people a month are coming off GLP-1s, right? And it's for a variety of reasons. About thirty percent come off GLP-1s in the first month and then fifty percent or so by, by the end of the year, right? So and it's not specific to GLP-1s. You see that with any medicine. You see that with, with blood pressure medicines. You see that with cholesterol medicines.

    3. AH

      Well, what's the-- Can we say what the primary driving force is in the case of GLP-1s? Is it the side effects? Is it they don't like having to pin themselves?

    4. CT

      I, I think 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.

    5. AH

      That tracks. Yeah.

    6. CT

      That might be part of it. I think that, you know, sticking yourself is, is a, is probably for some people, they don't want to jab themself once a week. That might be something. They get needle fatigue. That's probably there. I think when you take a medicine orally every day, it gets hard to remember to take it. And then I think there are issues with, with how you ramp them up to the effective dose and side effects. I think there's ways you can do that, you know, safely going step by step. But nausea is an issue with some of these. You know, muscle loss is an issue. There's different features there. And then additionally, you know, long term this, this is, you know, 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, right? You're treating obesity. We know obesity is a problem. We don't know, you know, GLP-1s will be a problem long term. That does weigh heavy on some people's minds, and that might be why they stop as well.

    7. AH

      Hmm.

    8. CT

      So in my practice where we do endoscopic therapies, uh, over eighty-five percent of people have already been on a GLP-1, and either they're struggling on or they've come off.

    9. AH

      Eighty.

    10. CT

      Eighty-five percent.

    11. AH

      Oof! Wow. Yeah, um, and we-- again, we don't want to get too far into the sociology and psychology of, of, uh, uh, medication adherence, but it is interesting that so many people come off meds. But then there are meds like SSRIs and things like that, which I think can benefit certain people, like people with, like, full-blown clinical OCD, the extreme, they save lives, right? But, but then they're overprescribed. I feel like especially in the United States, people like their prescription drugs. So if they're stopping, I feel like there's got to be a reason. I mean, aren't we the biggest consumer of prescription drugs in the whole world?

    12. CT

      [laughs]

    13. AH

      Like, people love their drugs. Like, I, you know-

    14. CT

      That's true.

    15. AH

      I've heard about the nausea. I, I don't--

  12. 33:42 – 37:35

    Lower GLP-1 Doses, Weight Regain & Muscle Loss

    1. AH

      There are a number of people now who are quote unquote microdosing the GLPs and finding that they're getting some benefits without taking the, the, the prescribed amount. I'm not recommending people do that. Uh, you know, I guess talk to or don't talk to your doctor. They probably won't approve. But I know people are doing that. I think initially it was because of cost and actually pen sharing. Um, but also people feeling like, oh, I get the same effect. So is your sense that when-- because the way clinical trials are done, there aren't-- often there aren't, like, really nice dose responses that you're just kind of comparing. They're so expensive to do these trials that they're going, you know, two doses, you know, moderate high versus placebo, and then the-- that's what the doctors have to work from. Do you have any knowledge of whether or not the lower dosing p- brings-- takes people away from side effects, and then you're seeing fewer of them?

    2. CT

      I think it's actually very useful. So that's, you know, the approved dosages are kind of just, uh, an effect of our regulatory system as, as you've alluded to, right? And it's too expensive to do different, different doses. Plus it takes a, it takes away personalization. You know, we're all trying to get to precision medicine and personalized medicine, and that's what microdosing allows you to do. And the first time I, I, uh, I heard about microdosing was one of my patients, and he was a physician, and he came in and he, he said, "You know, I, I-- A, it's too expensive, you know. B, I don't feel great on it, and C, I'm doing this thing where I take the pen and I inject it into a sterile vial, and I use a, an insulin syringe, and I'll take a small amount out and I'll give it to myself." And he said, "I'm doing great, you know. I don't feel nauseous. My weight is staying off." And, you know, he was a physician, so he's, he's familiar with, with, you know, the, the equipment, if you will. And that was the first time I came across it. I was like, wow, that's actually-- that's a great idea. So a lot of my patients actually do microdose these things.

    3. AH

      Hmm.

    4. CT

      Uh, and you know, generally you get up to the, the, the point where you want to lose weight, you get to that dose, you're losing weight, you're losing weight. And then for maintenance, rather than just stopping it, 'cause if you stop the GLP-1s, there's problems, right? This is not meant to, to be stopped. These are kind of lifelong medicines. Instead of stopping it, just go to microdosing, and you'll find a spot, hopefully. You know, not everyone does. But you'll find a spot where, uh, you keep the weight off, you feel good, and you're not, you're not taking as much of the med. Now- The problem with coming off of them is, especially with the, the, the original drugs, you know, like semaglutide's an example, right? Where when you lose weight, about a third of the weight you lose would be lean mass, right? So most muscle, right? Maybe some bone, et cetera. And the problem is when you cycle on and off, right? So say you come off of it and you put your weight back on, you're not putting the lean mass back on, okay? You're putting the fat back on. So now you've shifted your body composition to be less favorable than before you were on the GLP-1. And then you go on it again, and you lose weight again, and you lose a little more muscle. And then you go off, and you put more fat on, not more muscle. So now basically you're taking your, your, your body composition and shifting it, you know, worse every, every cycle. So there has to be a game plan. If you're coming off the GLP-1, you need either to microdose it or have a bridging plan to a procedure or something else which, uh, you know, will, will keep the weight off for you.

    5. AH

      Are there any good studies, um, showing that resistance training can offset the muscle loss, um, from a standard or microdose of, of one of these GLP drugs?

    6. CT

      Yeah, resistance training definitely. I, I'm not familiar with one that where that was the primary outcome or the focus, right? But you can actually see that that does play a, a major role in maintaining muscle. And that's with anything. It's not just GLP-1 medications. It's with the first generation medications. It's with any surgical procedure or endoscopic weight loss procedure. You know, y-y- if you're doing resistance training, you tend to maintain your muscle because the body realizes, "Hey, I need this muscle. I'm not gonna, I'm not gonna get rid of it as the person's losing weight," right? So when there's a caloric deficit, the body's looking for what it can do to, you know, uh, you know, to, to, to, uh, maintain, you know, energy levels, if you will.

    7. AH

      Mm-hmm.

    8. CT

      And you don't want it chewing up the, the muscle to do that.

  13. 37:35 – 39:49

    GLP-1 Side Effects, Food Noise & Apathy

    1. AH

      The side effects that I see getting the most coverage are, um, increased feelings of apathy. Um, general-- you know, food noise is down. Alco- alcohol appetite is down. Appetite for life is down. You hear this, but I don't know that-- how accurate that is, right? Social media is a weird place 'cause certain things get amplified it, um, out of proportion to the, the real data often. The other one is that, uh, GLPs, um, can, can cause blindness, these GLP drugs. But turns out that's in a very, very rare set of individuals that have this, uh, optic nerve head kind of ischemic opportunity. So like-- so yes, the GLPs can make certain people blind, but yes, also it's a very small number of people, so you wanna get screened for this, um, structural thing in the eye. But it's not true that, like, GLPs are making people go blind all over the place. So what I'd like to ask is, like, when patients come to you and they say, like, "I didn't like the GLP," or, "It wasn't working for me," are they telling you why? Are they saying, like, "It made me feel nauseous"? Certainly you'd know if it-- they lost their vision because of it. But is there some resounding themes there?

    2. CT

      There are. I think that muscle loss, honestly, is, is one of the bigger ones, right? Um, and it might just be subtle, like Ozempic face, Ozempic butt, right? You're losing some muscle in places where it's noticeable. Other people actually truly develop sarcopenia, I think, right? Where you have significant loss of muscle. It's rare, but it-- those are people that they're not really exercising a whole lot when they take it.

    3. AH

      Mm-hmm.

    4. CT

      And they, they might have had a predisposition to it in the beginning, right?

    5. AH

      Mm-hmm.

    6. CT

      Just to start with. So in people that I'm concerned about that, it's good to get a DEXA scan beforehand, right? Make sure you have adequate muscle mass, and if you don't, you really have to think twice about if you want to do the GLP-1, right? Or if you want another, another avenue to try to lose the weight. And you definitely have to start hitting the gym. I think that's the most common thing is, is muscle loss in obvious places or sarcopenia developing. The other one's nausea. A lot of folks do get nausea on the higher doses. And they will not lose weight on the low dose, right? And if they go on the high dose, they feel nauseous. So that's another issue. Some people say it stops working, and that might be because, you know, of, of that, of that similar issue. They don't tolerate the higher doses. Those are the primary reasons that I, that I

  14. 39:49 – 46:07

    Bariatric Surgery & Medical Innovation

    1. CT

      hear.

    2. AH

      Mm-hmm. Uh, maybe we can move a bit towards some of the surgical procedures, and, um, I always, uh, like to remind people there's basically two ways you can affect your, your brain and body. You've got chemical methods and mechanical methods. So, uh, you know. Um, and when I think of quote-unquote stomach stapling, I think of that purely as a mechanical thing. You're making the stomach smaller. Make people feel full earlier in the meal is my naive view of this, right? But of course, it stands to reason that you're also removing tissue, and so you're gonna change the chemical milieu of the environment. I'm sure that you'll tell us that the, you know, both things are involved and, and what. We had this thing called stomach stapling for a long time. Why did we need the GLPs? Now, some people say, "Well, that's a surgery," but I think in today's conversation, hopefully we'll convince people that, uh, surgeries can be done less and less invasively now and can be done with tools that make it seem a, a lot more like a, a dental cleaning, maybe a bit more, than the idea that, you know, you're cutting open the body and taking things out, laying them out on a table, putting them back in, this kind of thing, 'cause people's minds go all sorts of crazy places, trust me, including mine when we hear surgery. Why did we ever need the GLPs? We had stomach stapling.

    3. CT

      So surgery, it really started back in the '50s. University of Minnesota I think was the first place they did it. And the first procedures were focusing on malabsorption, right? So the idea was they're gonna bypass a portion of the small bowel so that you don't absorb your calories, okay? And it was called a, a jejunoileal bypass. But this procedure was awful, right? So the people did lose weight, but the problem was it created a long blind limb. So there was, there was no actual food going through the limb.

    4. AH

      Mm.

    5. CT

      Okay? So you connected the je- jejunum, which is the, the kind of early small bowel, to the very bottom small bowel. And the rest of the small bowel was still in there, but it wasn't-- no food was going into it.

    6. AH

      Hmm.

    7. CT

      So you had bacterial overgrowth in there.

    8. AH

      Mm-hmm.

    9. CT

      You had all sorts of problems. You had the fat that was being malabsorbed was binding calcium. And so calcium, you didn't have calcium in the bowel, so what happens is the oxalate, which normally binds calcium, gets absorbed, and then it binds calcium in the body and the kidneys. So you're having all sorts of renal failure issues, and it was a disaster. It went on for years, right? 'Cause, you know, people were desperate, but it was a very bad procedure, and it was replaced by something called gastric bypass, and I think that came about probably in the, in the mid to late '60s. And Mason, I think, was the, was the surgeon that came up with this. So his goal was to avoid the problems with the GI bypass and, um, you know, still get a treatment effect. And he did, right? So he thought of this as restriction. So when you eat stomach stapling, 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 really, but that's what he thought was going on.

    10. AH

      Hmm.

    11. CT

      And then from there, you keep moving forward. You have all these other procedures, lap bands, adjustable gastric bands. That was just purely restrictive. It, it worked. True stomach stapling, which was I think the VBG, and now the sleeve gastrectomy. So these are the real surgeries. And, you know, they were created at the time just conceptually thinking about either restriction or thinking about malabsorption, but they work entirely different than what they thought.

    12. AH

      I have a question about your profession generally. I'm guessing there are not large scale clinical trials of each of these surgeries, like they're doing, you know, 5,000 of these surgeries comparing to the existing surgery. So how much license do physicia- do surgeons have to say, "You know what? I'm, I'm very familiar with this tissue. Maybe I just, like, graft these two, cut out the middle. That's the part that absorbs stuff. Oops. Okay. Actually, big problems and modify."

    13. CT

      [laughs]

    14. AH

      And then 'cause I mean, there's, there are other things, but there are few things greater in terms of trophies for a physician, knowing some physicians, aside from the great feelings they get from healing patients and saving lives, let's, let's be fair, having a procedure named after you that saves lives. Like, that seems to me like that's, like, the ultimate thing. So there's gotta be a huge incentive for, um, physicians to do it on that basis, which might sound all, like, ego, but there's another facet to this, which is no- and we know this from science, too, like, you can read about the brain, but if you get your hands on brains, record from them, slice them up, look at them under a microscope, y- you just, like, a familiarity with the tissue of interest, especially in the context of the whole person who's coming back and saying, "I don't know. I'm still hungry, less hungry, but I got this pain on my left side." You know what that pain could be. Are there any procedures that you would love to be able to do 'cause you have the sense that it could really help people, but the red tape is just too thick that it doesn't even make sense to try and develop that procedure?

    15. CT

      I don't think so.

    16. AH

      Okay, that's good.

    17. CT

      Um, I think y- the proper channels are workable. I do think that there are compassionate use cases where you need to make exceptions, and then they have expedited protocols for that. I remember one time I had p- a person that was bleeding, and it, it was, was bleeding that was chronically going on and couldn't be stopped, and we needed something that was not yet approved in the United States. It was approved in Canada. And the person, they had no other option, right? And so we were actually able to get within, you know, 12 hours approval-

    18. AH

      Yeah

    19. CT

      ... to use it as compassionate use, and it worked for the patient. So there's even pathways for that, right? So I think there's always, you know, there's always a way to use that. It, it slows it down. Yeah, you're excited to do something, right? And it, it does slow things down, but, um, but I think it's always workable. Now, there are other examples of where you have a device that's approved for one thing that the, the company doesn't want to get it approved for everything 'cause they have no money to do that, so you use it off-label. That happens every day in every hospital.

    20. AH

      Just like drugs are used off-label.

    21. CT

      Yeah, right. Same thing, right? So, so, um, like, we use wires when we're, when we're accessing a bile duct to remove a, a stone, right? That wire has not been approved for that. It was approved for some vascular indication, right? And we've been using it that way forever because no company ever went through and did it. So the whole field's based on this, but it was never approved for that. So, so there are examples where you use your clinical knowledge and you use a device that's approved, it's approved, but just not approved for that indication necessarily. And so there's, there's that, um, and that does require medical judgment. It happens on a daily basis. Um, 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? Like, if you're doing this, check this gut hormone." Right? So they have, uh, you know, a lot of times they, they give good feedback that helps the study, um, you know, improves the study.

  15. 46:07 – 47:44

    Sponsor: AG1

    1. AH

      I'd like to take a quick break and acknowledge our sponsor, AG1. AG1 just launched their newest formulation called AG1 Pro, and right now you can get an extra 20% off your first subscription. AG1 takes the clinically backed AG1 formula, which is a blend of vitamins, minerals, probiotics, and adaptogens, and adds three important new ingredients, creatine monohydrate, calcium HMB, and zinc carnosine. It has five grams of creatine monohydrate to support muscle strength and performance, along with brain health, calcium HMB to support muscle recovery and reduce muscle breakdown, and zinc carnosine to support and improve the lining of your gut. Some of these ingredients I personally was already taking separate from the AG1 formula, so it's great to see all three of them now in the new AG1 Pro. As you may know, I've been taking AG1 every single day for about 14 years now. That means I discovered it and started taking it daily long before I even knew what a podcast was. I continue to take it and back it here on the podcast because it is an excellent formula, and it's now even better with the AG1 Pro formula. For a limited time, you can get an extra 20% off your first subscription to AG1 Pro by going to drinkag1.com/huberman and using the code BACK2ROUTINE, so that's with the numeral two, BACK, numeral two, ROUTINE. Just go to drinkag1.com/huberman. When it comes to the chemicals associated with hunger and satiety, maybe we can just kinda, like, list out the, the big players. Uh, we're talking about the GLPs, which obviously play a role in satiety-

    2. CT

      Oh, yeah. Yeah

    3. AH

      ... and other things, hence the side effects.

    4. CT

      Oh.

    5. AH

      So what are some of the big ones that we don't hear about so, so much anymore because of the GLPs?

  16. 47:44 – 50:01

    Hunger & Satiety: Ghrelin, CCK, GIP & GLP-1

    1. AH

      Like-

    2. CT

      Yeah.

    3. AH

      Yeah.

    4. CT

      Well, it starts with... ghrelin's a big one. That's the hunger hormone, right? So that goes up, and it k- is produced in the fundus of your stomach, and, uh, when that-

    5. AH

      The, the fundus is the, uh-

    6. CT

      The very top of the stomach.

    7. AH

      Mm-hmm. Yeah.

    8. CT

      The top thin part of the stomach.

    9. AH

      Mm-hmm.

    10. CT

      Right? The, the kind of where the esophagus comes in, and it, a lot of the ghrelin's produced there, and when that's high, you're feeling hungry.

    11. AH

      So it leaves the gut, travels to the brain-

    12. CT

      Yeah

    13. AH

      ... and stimulates hunger.

    14. CT

      Yeah, it's a hormone.

    15. AH

      What a beautiful mechanism. You're the top of the gut. You're like, "I haven't seen food in a while."

    16. CT

      [laughs]

    17. AH

      I'm still... You know, I, I have to say, uh, I'm perseverating in the background about this, this thing that the gut expands in anticipation of food and that that's odor-based. So does that mean that the olfactory neurons are communicating with the gut directly, or are they talking to insulin goes up and then the gut expands? Does anyone-

    18. CT

      Insulin actually does go up, too.

    19. AH

      Yeah.

    20. CT

      So insulin is before you eat, you'll have a little spike in insulin too, right?

    21. AH

      Mm-hmm.

    22. CT

      So I don't, I don't know if they ever figured out exactly that mechanism by which, uh, smell, you know, tasting food early on-

    23. AH

      Mm-hmm

    24. CT

      ... um, uh, you know-Triggers seeing food potentially, right? Triggers this whole process to start.

    25. AH

      Right.

    26. CT

      But before you swallow any food, right, you already have insulin coming up a little. Your stomach's already starting to stretch to accommodate the meal. So maybe some of it's learned as well.

    27. AH

      Mm-hmm. Mm-hmm.

    28. CT

      I don't know. But I'm not sure of those mechanisms, but it's very interesting how it's a critical role, right? It certainly is involved.

    29. AH

      When was ghrelin discovered? I, I should know this.

    30. CT

      Oh, man.

  17. 50:01 – 52:55

    Retatrutide & Combining Hormonal Targets

    1. CT

      right?

    2. AH

      People might, um, be curious to know that this drug retatrutide that the more cavalier peptide-curious folks are already getting off from compounding pharmacies in the gray market, black market. Retatrutide, as I understand, promotes GLP, GIP, and glucagon. Um, to... I think the clinical trial Lilly ran showed a 30% reduction in body weight, which is really striking. So it's kind of curious that this GIP never really took off as a drug, a druggable thing. But, you know, GLP seems to be, like, the heavy gun. But now by combining with other things, maybe you actually get some synergistic effects.

    3. CT

      It does help. I think it helps with nausea.

    4. AH

      Mm-hmm.

    5. CT

      So it allows you to have higher doses potentially of GLP-1-

    6. AH

      Mm-hmm

    7. CT

      ... with less nausea.

    8. AH

      Interesting.

    9. CT

      So GIP, I think, plays that role.

    10. AH

      Mm-hmm.

    11. CT

      It has a role in insulin, insulin sensitivity as well. And it does some of the same stuff GLP-1 does, and it's synergistic, I think. But what's interesting about the glucagon is potential muscle sparing there, right? So glucagon, among other things... You know, glucagon is usually up when your insulin is down, and vice versa, right?

    12. AH

      Mm-hmm.

    13. CT

      And its job is to, is, is to say burn fat, right?

    14. AH

      Mm-hmm.

    15. CT

      That's its main job. It also causes you to, to dump your, your, um, glycogen out of your liver a little bit. But the main job with glucagon being up, it says burn fat, right? So it's kinda nice that, uh, they're adding that as a muscle preservation as well as-

    16. AH

      Mm

    17. CT

      ... as a way of helping to burn some of the fat potentially.

    18. AH

      Yeah, these, uh, pharmaceutical companies, however a bunch of people might hate quote-unquote big pharma, I mean, they're putting hundreds of millions of dollars into the, the research. Kind of an amazing case of, of, like, 20 years ago there was nothing for, uh, for druggable for, for obesity, as I understand. And what was there was mainly stimulant-based-

    19. CT

      Yeah

    20. AH

      ... like the fenfluramine and, like, this kind of thing.

    21. CT

      Well, yeah, the valve issues.

    22. AH

      Yeah.

    23. CT

      But you had... Well, you had phentermine, right, which was a sympathomimetic really. Um, and-

    24. AH

      Speed.

    25. CT

      Yeah, basically. [laughs]

    26. AH

      Mother's little helper type thing, right? I, right? I mean, and nicotine. You know, there's a whole set of conversations there. Some people think that when we, you know, basically abolished smoking, um, people started eating more, and then America got fat, and then snack foods and highly palatable. There are a lot of things, right? Moving more, eating more, highly palatable foods and less fiber. But, um, now nicotine's back in oral forms. It's back big time, mostly with men, but also with women. And, um, a lot of people like it because it's an appetite suppressant. I'm not a fan for a bunch of reasons.

    27. CT

      Yeah.

    28. AH

      Raises blood pressure, highly addictive, and so on. But it's interesting, right? Like, people have struggled for forever to, like, how can I eat, enjoy food, but not eat too much? Whether it's a compound what we norm- you know, a drug that increases the compound we already make, like GIP, or we're taking something to make us move around more and, like you said, sympathomimetics.

    29. CT

      Mm-hmm.

    30. AH

      It's like stimulants. It's like a human obsession. Why can't we just eat enough and not

  18. 52:55 – 55:32

    Ultra-Processed Foods, Overeating & Leptin

    1. AH

      too much?

    2. CT

      I think it's, uh, obviously metabolic dysregulation, and there are layers of it. The processed foods, which you touched on, certainly is an element to it, right? There was a study done, I believe it was in Bethesda, an NIH study, when they had, like, 20 subjects, and they randomized and crossed it over, and they could either have whole foods or they could have processed foods. And the people that were eating the processed foods, they could eat at will. They were eating, like, 500 calories more a day. So it is something that you do in, in your normal environment. If you're eating stuff in a wrapper and you're eating it, you're inclined to eat more of it. And not only are you eating more of it, right, it's easier to digest, right? You're getting bigger glucose spikes, and you have a lower thermogenic effect of food, right? So it really is... It's probably also not doing great for your microbiome 'cause there's less fiber in it. And so that is playing a big role. Start, start, starting the ball rolling for sure.

    3. AH

      Yeah.

    4. CT

      And then there's different, there's different layers to it. Then you have your, your PYY and your, and your GLP-1, which the GLP-1, um, you know, it, it's triggered by anything, but glucose tends to s- trigger more of it, right? And then the PYY, um, that's more, you know, your proteins and your fat. It does something similar. You stay full longer, I think, and with a, with a big, heavy fat and protein meal probably 'cause of the, the PYY. Um, uh, that something's been very hard to drug, right? They, they didn't have a Gila monster to solve the problem that, uh, the GLP-1 did.

    5. AH

      Mm-hmm.

    6. CT

      But, uh, it's, it's also very potent, and they both come from the L-cells in the distal small bowel and the colon. And, uh, you know, those are, those are kind of all the, the, this, the major players. You also have leptin in the background. Now, that's more of a thermostat, if you will. It gets involved in its set point and things like that, and it's, that's secreted from your fat cells. Uh, and if it, it's in almost in proportion to fat. So if it's high, you know, generally you're gonna probably eat less. If it's low, you're gonna eat more. But there's all sorts of problems with leptin resistance and other things like that too that complicate it.

    7. AH

      I remember coming up through science, like leptin was all the rage, um, its discovery, its cloning. A-and everyone thought, okay, there are drugs gonna-- are gonna come along to mimic or stimulate leptin, and we're gonna solve the obesity or overweight issue. But it didn't really pan out. Why was that?

    8. CT

      I think leptin never panned out in large part 'cause of lec-leptin resistance, right? I think the hypothalamus and the, uh, uh, the brain itself is, is just becoming resistant to it because it's so high in people with obesity for so long, right? And, and, uh-

    9. AH

      So they're just saturated. They've got a lot of fat, a lot of leptin. Receptors are, are clogged.

    10. CT

      There's a little grade inflammation, we know-

    11. AH

      Uh-huh

    12. CT

      ... in, in, in, in those tissues, and, and you eventually just, yep, you don't respond to it anymore.

    13. AH

      Mm-hmm.

  19. 55:32 – 59:35

    Incretin Discovery, Exendin-4 & the Gila Monster

    1. CT

      And so, so the, the drugs just didn't pan out. I think that, um, with, with the GLP-1s, it's another story, right? I think, you know, incretins in, in general-- We've talked about incretins. We've been talking about these, these hormones that are produced in the gut. They go into the blood, and they do something. So the concept first came about in the 1930s, and it was in, it was in London. And they basically were, um, grinding up animal, um, duodenums, okay? And they were emulsifying it and injecting it back into the animal in the vascular system.

    2. AH

      Science in its not crudest form-

    3. CT

      [laughs]

    4. AH

      ... but history-- This is 1930s, so science is not that old, you know? Real science.

    5. CT

      Right? Right?

    6. AH

      That's pretty crude.

    7. CT

      That's, that's, that's nitty-gritty, right?

    8. AH

      That's pretty crude.

    9. CT

      And the idea for that was secretin. So someone had found secretin, right? And that was-- That, that's a hormone produced in the duodenum that goes to the pancreas and says, "Secrete fluids for digestion." So exocrine function of the pancreas. So this person thought, "Well, wow, if the duodenum secretes secretin, maybe it secretes something else." So he-- they, they did this study, and in the animal, the blood glucose fell. And they're like, "Holy cow," right? "This-- something in the duodenum is causing glucose to fall. Phenomenal. I'll call it incretin because you have secretin. I'll call it incretin." So that was, that was where it started in 1930s, right? And then there's another lab, uh, uh, Sheila Sherlock's lab in, in London, and she was famous for being one of the kind of, you know, founding physicians that, that, that started the field of hepatology. And she was trained in some medicine and some in, uh, some internal medicine, some surgery. And they had this concept, but what they had access to was this new tool, which is where you obviously innovation, right? They had acc-access to this way of actually detecting and measuring insulin. And so they did a very interesting study where they gave subjects a set amount of glucose intravenously, and then they measured the amount of insulin that was produced. Then they gave them the exact same amount of glucose orally, and they found they produced much more insulin. All right? So this was something they cl-- they, they coined the incretin effect.

    10. AH

      But is that based on taste?

    11. CT

      So they had no idea, right? But they knew the insulin was going up, and they thought it probably, 'cause the only other research that was out there was from this, this old nineteen thirties study where it was coming from the duodenum. It was probably due to that incretin. Then there's other studies, you know, that come after that. They, they get, get closer and closer to it, right? So eventually, what ends up happening is, uh, in, in the, uh, um, Lilly Labs, I believe it was, there was a, there was a physician named Bell who actually-- he, he, he had a pre-pro, uh, glucagon. He ends up, you know, cloning that. And then from that, you get GLP-1 and GLP, GLP-2, right? And so he, he now is-- he now-- we now have GLP-1. We've identified it. And then there was this, uh, physician, um, uh, Blossom, I believe was the name, in, in London again. And this guy did some phenomenal work. So what he ended up doing is now we had GLP-1, so he could actually study it. He found GLP-1 was in the bowel where we thought it was. He also, um, found out that when you actually gave glucose, GLP-1 increased in the blood. And then he actually infused GLP-1 and found that when he infuses it, insulin goes up, glucose goes down. So now all of a sudden, we had a real sign that what, what, what this incretin was, and it was GLP-1. Very exciting work. The problem was you had to infuse it, right, for it to work 'cause it gets chewed up really quickly by, uh, uh, dipeptidyl peptidase. It chews it up. There's, uh, something on the N-terminus of it that is susceptible to that. And, uh, that's the part that binds the receptor, so you can't really get rid of it. Uh, and then it was in the Bronx in the nineties when there's a Dr. Heng, and he's studying Gila monsters. And in the Gila monster, he finds this thing in the Gila monster's venom that looks very much like GLP-1. It has one, uh, substitution, like second, second, uh, uh, amino acid in from the inside. Otherwise, it looks just like it'll bind a receptor. The C is a little longer and different. But this is, um, you know, uh, Exendin-4, uh, and basically this is the, the molecule he, he discovers, and this is what ends up becoming all the GLP-1s.

  20. 59:35 – 1:07:40

    Endoscopic Ultrasound & Pancreatic Biopsy

    1. AH

      These Gila monsters don't have to eat very often, so makes a good candidate to, to study. So you do surgeries of various kinds. Um, the people who are coming to you, they-- have they all tried GLPs and they don't like them or they're not working for whatever reason? Or they'll microdose it, but it's not solving the problem? And, um, what sorts of surgeries were you trained to do, and then at what point did you become the doctor I referred to earlier, uh, who seeks out IRB approval to build something better? Like, like, I'm a-- I guess if there, there are multiple themes in today's discussion, but one of them is if the really great physicians look at a problem, they look at the tools they've got to solve that problem, and if they're not working for any number of patients, they build something better or different, or they inc- they increase the array of, of tools. So tell us that story. How does that-- Where, where did that start, and where are we at-- where are you at now with that?

    2. CT

      Really, for me, it started in, in, um, fellowship. So I'd moved to Boston to, to learn interventional gastroenterology, right? So this is not, you know, colonoscopy and whatnot. It's, it's doing procedures mostly focusing on pancreatobiliary, so pancreas and biliary conditions. And the, the big problem at the time was really pancreatic cancer diagnosis. And so I was moving there to learn a new procedure, uh, that they called endoscopic ultrasound. So you'd be able to put a scope in the mouth into the stomach and small bowel, and then use the ultrasound probe that's embedded in its tip to see the structures just outside the lumen, and you could gain access to them. You could put a needle in them and, and that held a lot of promise. You could maybe ablate lesions with it. You could-

    3. AH

      So you're feeding a needle through a tube. You're watching it on a screen, right?

    4. CT

      Yeah.

    5. AH

      So you're not, you're not using the... you're, you're not opening up the-

    6. CT

      No. Yeah

    7. AH

      ... the abdominal cavity.

    8. CT

      Yeah.

    9. AH

      Okay.

    10. CT

      So you can do it through this, through the mouth. So it's a natural-

    11. AH

      Yeah

    12. CT

      ... orifice. You're going through the mouth rather than opening up, which for pancreatic cancer, a lot of times that's how they would do it. They would go to surgery, open the belly up, and get the biopsy, right? To see what it was. Uh, 'cause it's really hard to make the diagnosis. And so I wanted to learn this new technique where y- you just... the patient goes home the same day. They don't feel anything, right? So I thought that was phenomenal. When I got there I'd, I'd done a master's in health evaluation science at Penn State before, before going, and I thought that I would be doing epidemiologic research. And when I got there the... my, my, my, uh, mentor, Bill Brugge, at the time was a pioneer in this ultrasound. And, um, he, he, 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." Right? And he was right. The thing didn't work. Yeah, unfortunately, like, we had about a 50/50 chance of getting a diagnosis with the needle, and it's because it was, it was designed like a hypodermic needle, like you get an IV placed, right? The IV's not taking chunks of tissue out of you. It's designed to atraumatically split the tissue, and that's the needles we were using, right? So for the most part.

    13. AH

      Designed to deliver stuff, not take stuff.

    14. CT

      Yeah. Yeah.

    15. AH

      Yeah.

    16. CT

      So I kind of figured out what the problem was. I didn't know the solution, honestly, but I gave him my report, and the company thought it'd be too expensive to fix, and we didn't really do much with it. But it still went on. I was a couple years into practice on faculty there, and, you know, we still had the problem of, you know, you di- you, you take these FNAs, fine needle aspirations of it, and you wouldn't have an answer. And, you know, you'd have people that wouldn't want to have a major surgery or having their pancreas taken out without an answer. And then they'd have worsening cancer, and then by the time you'd be able to make a diagnosis, it'd be too late to treat them and help them. So that's where I started to kind of, uh, you know, entrepreneurial stuff, right? And so my first, um, in, in my first company, I guess you'd say, was based on that. And, uh, I needed a team, you know, and one of the engineers had the brilliant idea of how to change that bevel design, helped raise the money. I knew what the clinical problem was and, and, and that what... and, and whatnot, but you needed a team to fix it. So we hired engineers, and we got together, and we came up with a needle that could biopsy the pancreas without causing pancreatitis or any problems. And it has been wonderful because that, that really became very instrumental in helping a lot of people to get the diagnosis earlier, so we're saving lives with that. But now we look forward to the, the fact we have preserved cell- cellular architecture, so you could do, you know, precision medicine. You can actually, uh, test different drugs on the tissue and see what it's gonna respond to. You can do immunostaining, and, uh, it's a lot better than just having a few shaved cells. So that was the first time I really got involved in, in trying to solve a problem, like you say.

    17. AH

      Mm-hmm.

    18. CT

      And that was before I started diving into metabolic disease, where I've spent really a large part of my time, but that was what started off.

    19. AH

      So just like earlier, I, you know, I was saying the mechanical influences and chemical influences over our health and biology for what I call, like, reading from the body. Like, people get a sleep score or your heart rate or a blood pressure. That's reading, obviously. You're not writing to the body. But you have a structure, and you have functional readout. So, like, if, you know, someone goes, "I have a pain in my side," and you go, "Okay, well, you, you, uh, give them an ultrasound." There's a massive thing there. Like, you got a structure there that doesn't belong there, then, then you can decide to cut open, right? W- I hear biopsy, people hear biopsy and think, oh boy, you're getting poked with a needle, this kind of thing. But I might shock a few people, but if you told me that I could come into the clinic and spend one long day under anesthesia and get completely non-damaging biopsies of every single one of my major organs to grab a few cells here and there through the mouth or, heck, even if they had to make a small incision one place and then zip me back up and send me home, and I can just say, "Okay, like, I'm... Let's just look at all the cells. Let's see what's... You know? Let's see if I have any issues." A lot of people will be like, "Why would you do that?" Well, I'd rather do that than walk into the clinic at 72 and go, "I've got this pain," or, "I'm not sleeping well," or, "I'm sweating," or, "I have this bump here." I mean, in the end, we end up diagnosing ourselves. Well, we either drop dead, diagnose ourselves, or someone else diagnoses us, right? And so w- with a procedure like yours, I'm kind of inclined to say, like, would you just get it? You seem healthy. Have you done it to yourself? Can I come in and get it just for, uh, checking things out? We take blood tests now. People go, "What's my testosterone, my estrogen, my, uh, luteinizing hormone, my lipids, my, you know, small, uh, you know, LDL ApoB?" 20 years ago, if you wanted to get a blood test, 15 years ago, and you didn't have a problem to motivate that, it was thousands and thousands of dollars at best. It was very hard to find people that give you these. Now it's trivial- trivially inexpensive for most people. Um, so I feel like we're kind of going that way with biopsy. So how soon are we, um, gonna just be doing biopsies with non-damaging procedures?

    20. CT

      So I think a lot of times with biopsies, you have to be very targeted to get the tissue of interest, right? So even in the pancreas, like, like we said earlier, you know, you could be even in the area that looks like a lesion, like a tumor, and not getting cancer cells out. So I think that you have to be very, very targeted. But then once you do get the tissue, you can do all these stains, and you can really figure out what's going on. Is there a gene- genetic predisposition to it? Is there some way it'll respond to one drug over another? I think that's phenomenal. But I would like to see the diagnostic studies become less and less invasive so they can scale easily. So the, the one problem with, uh, procedure-based diagnosis... I like procedure-based treatment. I love it. It, it's better than surgery. Um, you know, going through the mouth and rather than making an incision in the abdomen I think has, has benefits for the most part. But when you get diagnostic studies similar to colonoscopy, there's a scaling problem.

    21. AH

      Mm-hmm.

    22. CT

      Right? So when, when a patient has to come in and spend an hour with a doctor or two hours, that doctor is taking care of one patient for two hours, and he's outnumbered, right?

    23. AH

      Mm-hmm.

    24. CT

      Everyone needs screening, and it becomes very complicated. So I would love to see innovation and technology go where we have- Minimally invasive ways of diagnosing things, whether it's via your smartphone and AI, or it's via minimally invasive scans and, and, uh, um, blood tests are great 'cause it, it's quick and easy to do. And we're not even doing... Talk about metabolic health. You know, there's several things we could be doing non-invasively at home right now that we're not doing to catch it much earlier. So-

    25. AH

      Such

  21. 1:07:40 – 1:13:06

    Early Metabolic Markers, CGMs & Fasting Insulin

    1. AH

      as?

    2. CT

      Well, so an example is most of the time we're waiting for hemoglobin A1C, right? And that's the, the marker of diabetes, and that's the gonna be the thing that, you know, once you have an A1C or a, a high ApoB, which you're probably not checking, maybe, you know, an, an LDL-C or something, right? Once those are high, we know there's a problem. However, there are signs much, much earlier than that. And so, so metabolic dysregulation follows a, a fairly predictable sequence, right? First, it's calorie excess, right? So it's, it's in the Western, uh, diet, it's usually glucose, right? So you have too much glucose around. You can have too much saturated fat too, but too much glucose. And then that too much glucose, uh, you could catch that by doing a CGM, right? So that's one way you could do it, a continuous glucose monitor. You could then see if you have particularly glucose spikes to certain foods. And 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. Try to eat it after having something fatty. Maybe avoid it, right? So because we know this is part of a sequence that's gonna lead to problems. And this goes back to the Whitehall II study, which, um, to, to give relevance here. So the Whitehall II, White- Whitehall II study was on British civil servants. It was a prospective kind of longitudinal thing. And they found that, um, it- they followed all sorts of metrics. One of them was insulin. Fasting insulin was one thing that they followed. They followed other things as well. And they saw that if someone had high fasting insulin, they were more likely to get diabetes long term. So, so and it was a long period of time. It was like a 10, 15-year time. They could detect this thing 15 years earlier. They could do something about it, right? But no one does 'cause no one looks for fasting insulin. And the other thing that's very relevant here is there was another study. It was the UNC NHANES study, okay? And, um, that's another large database. It's more cross-sectionally looking at, at a, at a point in time. And what they found was that less than a third of people that are lean are, 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. And their parameters looked at waist circumference and glucose and blood pressure and whatnot, right? So looking at metabolic signals. The word there is start looking early and don't look with the traditional things, okay? We have to look at other things, getting back to, you know, metabolic syndrome ideas. So first you could check for glucose. So glucose spikes. 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. See if something spikes your glucose and adjust it. Next, you have fasting insulin. Okay, so the next thing that happens is first in anybody, they have the insult of excess calories. The excess calories comes, that's what happens. Insulin's job is to take that sugar and push it into the cells 'cause glucose is really bad for the body. We know this. If you look at end-stage diabetes where they can't control their glucose anymore, they go blind, you know, they have kidney failure, it's killing the vasculature. It's sticky. Glucose is sticky. It glycates things. It causes problems. So the insulin's gotta get it out of the bloodstream. So next in the sequence of metabolic dysregulation is high insulin levels. Fasting insulin goes up. So you can get a fasting insulin level. That's the next thing you check, right? It's not a lot to ask for. It's an inexpensive test. And you can see if you're, if you've evolved into that problem where you now you have chronically high insulin levels. And part of that, honestly, is due to eating too frequently and could be eating, you know, certain things that are, uh, you know, high fructose corn syrups or things that, that basically, um, you know, have a high glycemic index or load that's gonna cause your sugar to spike. So and the problem is if you're eating every few hours, insulin goes up and it spikes. It drives the glucose out of your blood, but then the insulin stays high, okay? It doesn't go right back down. It stays high for a few hours. So if you're eating every few hours, you always have this high insulin. That's gonna lead to other problems. And the next thing that happens is ectopic fat, right? So your fat exists in different areas. You have subcutaneous fat. That's where it's supposed to be. That's your depot for energy, and, uh, it's healthy there. It has different ways of growing. Then you have visceral fat, which is really in your, your omentum. You know, it's, uh, it, it's in the abdomen and, uh, in your mesentery in the abdomen that's around the bowel, okay? So that's that kind of your visceral fat. Then you have your organ-associated fat. You have some fat around the heart. You have some fat around the kidneys, et cetera. It's kinda supposed to be there. They're all adipocytes. They're all fat cells. Their job is to store fat and release it, right? That's what they do. Then the last bucket is ectopic fat. And ectopic fat is where you have fat in cells that it's not their job to store fat, right? Like liver cells or muscle cells or pancreas cells, and that becomes, that becomes a problem.

    3. AH

      It's like Wagyu beef.

    4. CT

      Yeah. It's like Wagyu beef. [laughs]

    5. AH

      Yeah, those cows are over- they're not, they don't move.

    6. CT

      Yeah.

    7. AH

      They're overfed. It's... Yeah. Um, yeah.

    8. CT

      And, and, and that, that's, you know, that's another problem, right?

    9. AH

      Yeah.

    10. CT

      So that's the next phase of metabolic dysregulation, and they've done all sorts of great studies that have shown exactly from each step what happens and how you get there, right? And so that's when you get fat in your muscle, and you get fat in your liver, and that's bad. Fatty liver is very bad. And then that is what goes on to insulin resistance, okay? So for the fat, how can you look for that? Well, 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 or, you know, if you have a lot of subcutaneous fat. A CT scan, MRIs, other things will do it too. Um, or an ALT, look at a liver test measurement, right? Uh, that's, uh, aminotransferase in your liver. Um, and usually, you know, that'll signify some inflammation. So, you know, that's the next level, right? And then you have insulin resistance, which that's a little harder to check. That's a combination of... There's a formula that you can do to look at that. It's a, it's a,

  22. 1:13:06 – 1:15:53

    Insulin Resistance & Metabolic Flexibility

    1. CT

      a fasting blood glucose and a fasting insulin level, and you multiply those and divide it by a constant, and if it's greater than two, you have insulin resistance. So that's the next, next phase of it. And then finally, you have metabolic inflexibility. Your body is supposed to change between calories, right? What is burning. If you're fasting, it's supposed to be burning fat, and if you're eating, it's supposed to be burning some element of carbs, depending on what you eat. But if you have carbs in it, it should be burning the carbs, right? And so you can develop this metabolic inflexibility as the next phase of this once you have insulin resistance, where when you're fasting, you're not really accessing your fat anymore. Your fat's still there. It's burning more of your glycogen stores, and God forbid, it's chewing up muscle, right? But it's, it is no longer accessing the, the fat stores it's supposed to be accessing. And then when you eat, it doesn't shift over to burn the carbs well either. It kind of just, it doesn't know what to do.

    2. AH

      Mm-hmm.

    3. CT

      So that's a loss of metabolic flexibility. And by then you're getting near the time when all of a sudden something's gonna happen, 'cause once you have a loss of metabolic flexibility, they've shown in studies that you're more likely to gain weight and develop obesity. You're more likely to start losing beta cells. You start burning out your beta cells and they become apoptotic and you lose beta cell mass, and you start having all sorts of other problems. So this is a very kind of typical sequence that you see. It can happen in other ways, but that's the typical sequence that's backed by science and different clinical trials. And each, each step of that way you have a study you could do to find out about it. The last one, the metabolic flexibility is a little harder because y- you have to do, kind of go in and do a breath study for that where you're looking at gas exchange. And it's very accurate actually, because we know that, uh, there's a respiratory exchange ratio. Um, athletes do this to optimize performance. You can do this where you get a DEXA scan a lot of places. They'll tell you how many calories you're burning or what you're burning. And basically it's, you know, first law of thermodynamics and you're burning calories, but it's a ratio of, 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, to burn the carbohydrates. But when you burn fat, it requires more oxygen. So if that ratio is like .7, uh, so it's, it's volume of carbon dioxide over, um, oxygen, that means you're using more oxygen. That means you're burning fats, right? And if it's one, you're burning carbs, and then there's the in between. And so this is a great way to see if you're metabolically flexible. Eat fat, see what happens. Eat carbs, see what happens. Do it fasted, see what happens, right? And you sit in a chair and you breathe for half an hour. There's companies that are actually developing at home methods doing this too.

    4. AH

      Mm-hmm.

    5. CT

      There's a few of them. And actually one of them recently, I think now has one that does both the oxygen and the carbon dioxide.

    6. AH

      I think I've seen this, like a little box that you breathe into.

    7. CT

      Yeah. So I mean, you can do everything, right? So and then or you can just wait until you have diabetes and your A1C goes up. And so yeah, there's a lot of things that we should be doing-

    8. AH

      Mm-hmm

    9. CT

      ... before we do the standard test of looking at your fasting glucose and looking at your hemoglobin A1C.

  23. 1:15:53 – 1:17:35

    Sponsor: Function

    1. AH

      I'd like to take a quick break and acknowledge our sponsor, Function. Function provides over 160 advanced lab tests to give you a clear snapshot of your bodily health. This snapshot gives you insights into your heart health, your hormone health, autoimmune function, nutrient levels, and much more. They've also recently added access to advanced MRI and CT scans. Function not only provides testing of over 160 biomarkers key to your physical and mental health, it also analyzes these results and provides recommendations for improving your health from top doctors. For example, in a recent test with Function, I learned that some of my blood lipids were slightly out of range. As a result, I decided to start supplementing with nattokinase, which can naturally help reduce LDL cholesterol, and it did. In a follow-up test, I could confirm that this strategy worked. My blood lipids are now back exactly where I want them. Comprehensive lab testing of the sort that Function offers is just so important for health. I mean, how else are you gonna know what's going on under the hood? And while I've been doing blood work for years, it used to be time-consuming, complicated, and expensive. In fact, I used to spend thousands of dollars per year trying to get this kind of data, and the data, frankly, were not all that good. But now with Function, it's extremely easy and affordable. A Function membership is only a dollar a day, $365 a year. And if you think about the information it provides and the health challenges it helps you avoid and the proactive things that it can do for you to enhance your health, I truly look at it as a savings. To learn more, visit functionhealth.com/huberman and use the code Huberman for a $50 credit towards your membership. Again, that's functionhealth.com/huberman. It's gratifying to hear that you put the CGM,

  24. 1:17:35 – 1:26:31

    Patient Data, Screening & Treatment Adoption

    1. AH

      uh, pretty early on that list, very early, in fact. I mean, I, I don't-- I wanna be clear. I'm, I'm neither complaining about nor am I, um, trying to turn you against your colleagues, but I'm gonna just be really blunt from... And these are my words and my words only. I want people to understand this [chuckles] like... I mean, I've gone public many times saying, "Hey, like, as the cost of blood testing comes down, this is awesome. You get a window into, uh, lipids, hormones, things that can be very informative whether you have issues or not." And the pushback on that from the medical community, not all, 'cause I have friends in the medical community who will quietly say, "Yeah, I would totally do that test. I take that test," you know? But many of them just say, "Oh, great. Now patients are gonna be coming to me saying like, 'I need to-- do I need to be worried about this? Do I need to be worried about this?'" I said, I actually put a post out recently that as the, uh, cost of a whole body MRI comes out, it's gonna be interesting to see what happens. I have neurosurgeon friends who tell me about life-saving procedures they, they do all the time. The neurosurgery community was super angry. It generated some press. This l- week actually, uh, uh, this is how the, the tables kind of turned. There's a celebrity, I forget their name, who took one of these types of scans from a company I have no affiliation with, by the way. I took a Prenuvo scan and, um, identified a- a malignant issue that could be cut out and very likely save their life or at least extended it. So I get it on the one hand why a lot of physicians are worried about people walking around with a lot of data. I heard the same about CGMs. Okay, I'm gonna try not to rant here, but it was like, oh gosh, who needs to know their... Glucose goes up, glucose comes down. In the absence of diabetes or pre-diabetes, like, you can have a glucose spike. We don't want people walking around neurotically worried about eating a grape, which I totally understand. Your body can manage these things. But now that CGMs have been out for a couple of years, I don't hear much pushback. Yeah, if somebody wants to do a CGM for a couple weeks and see how they react to different foods post-exercise, post-poor sleep, et cetera, 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. You're saying, "Yeah, it's gr- I think people should pay attention to how they're regulating their blood glucose."

    2. CT

      The problem with medicine is it moves very slow, right? So a lot of people are gonna want a randomized control trial, another randomized control trial, maybe a few more, and then a meta-analysis.

    3. AH

      Understandably.

    4. CT

      And there may, there may be a guideline.

    5. AH

      Yeah, understandably.

    6. CT

      And another guideline.

    7. AH

      But, uh, from a patient perspective-

    8. CT

      Yeah

    9. AH

      ... people want data now.

    10. CT

      Yeah.

    11. AH

      And if they can get it inexpensively... And by the way, these are elec- uh, are they called elective or elected procedures?

    12. CT

      Uh, elective, yeah.

    13. AH

      They're elective-

    14. CT

      Yeah

    15. AH

      ... if they're elective procedures, so no one's saying you have to get this done.

    16. CT

      Yeah.

    17. AH

      It's an option.

    18. CT

      Yeah.

    19. AH

      I don't get it.

    20. CT

      Yeah, it's, it's unfortunate.

    21. AH

      Can't wrap my head around it, you guys.

    22. CT

      It's un-

    23. AH

      Yeah

    24. CT

      ... it's un- it's un- it's unfortunate that, um, y- th- there's, there's a reason for it, obviously, do no harm, right? So there's a reason for it, but by that same token, it does not necessarily, um, do the patient any favors by waiting w- for something that's, that, that is logical and makes sense, right? And there's enough evidence for this sequence of events, if you will, for metabolic illness all the way back to Syndrome X in the '80s, right? We know there's this constellation of things, and we also know that if you don't act early, y- 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.

    25. AH

      Or peripheral ner- I mean, they could have-

    26. CT

      Right

    27. AH

      ... loss of their-

    28. CT

      Yeah

    29. AH

      ... fingertips and toes.

    30. CT

      Right.

  25. 1:26:31 – 1:29:27

    AI, Robotics & Improving Procedures

    1. AH

      Uh, so what has come into the field that's allowed you to do your work more effectively and others to do the work more effectively?

    2. CT

      Most devices we see are kind of incremental improvements, a little bit of better wire, you know, devices are more ergonomic. But, uh, what I see kind of happening more recently is AI starting to have an impact, where it can actually coach you through procedures, which is kind of big.

    3. AH

      How does that work? Do you have an earbud in or something?

    4. CT

      Uh, on the screen itself-

    5. AH

      Oh

    6. CT

      ... it's like a heads-up display.

    7. AH

      Okay.

    8. CT

      Right? On the heads-up display, uh, it will actually give you information, so you're not just seeing the images you're working on. It can actually highlight certain structures you wanna work on.

    9. AH

      Okay.

    10. CT

      It can actually point to something where you want to put your stitch, right? And it can 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 the stomach to let you know if you're having a good treatment effect. This is something that we, we never could've, have done before.

    11. AH

      This is in real time.

    12. CT

      Real time, yeah, which is phenomenal. Right now, it's not widely available yet. This is in research centers, right? But you actually can see this happening in real time, and, um, it's, it's phenomenal. So you see that in more and more. It's happening in different surgical procedures where AI is kind of real-time coaching you and in endosco- endoscopic procedures. Additionally, there's the hope for robotics to help as well, and we've done a lot of research in our lab on robotics and how it can take trainees that are learning a new, very complicated procedure and shorten their learning curve dramatically. And we'll randomize the trainees and have them do the traditional way. Like, this is usually resecting a tumor from the colon, leaving the colon in place. That's a very complicated procedure and... or from somewhere else in the s- in the stomach or whatnot. And the fellows will learn. They'll spend a couple of weeks training in both modalities, and then they will struggle horribly with the original way. That's why it takes two or three years to learn how to do it. They'll sit down on the robot and be almost good as an expert. So robotics are very interesting. And now, in the future, we haven't done it yet, but when you start layering on AI and automation with the robots, now you may have a big win. And we, we've seen this before with different surgeries as well with the, with, you know, Intuitive Surgical's robots when they first came out years ago. It democratized the field. It took mediocre surgeons, and it made them excellent. And the excellent surgeons were still excellent, right? But it really helped the ones that were struggling perform better.

    13. AH

      How do the excellent surgeons feel about it, in keeping with our previous discussion? Seriously, like, are... Is it, is it, is part of... It's like, is it like athletics? Like, it, people want to be... They want a hierarchy of performance, um, for themselves. They don't want patients dying at the hands of poor surgeons. But-

    14. CT

      Hmm

    15. AH

      ... I would think that, um, if do no harm is really the, the, uh, the true, um, central cord of medicine, then every person in a field would want more people being healed independent of their own stature as a physician.

    16. CT

      Yeah. I think they're, um, supportive of the robots, but I think that a truly exceptional surgeon is probably just gonna be better without the robot, and just, it's, you know, the robot, it just, it's gonna m- it's gonna make you

  26. 1:29:27 – 1:35:29

    Choosing a Surgeon & Measuring Procedure Quality

    1. CT

      worse. So if you-

    2. AH

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

    3. CT

      That's a good question.

    4. AH

      Understanding, do... Am I getting the best physician for this thing is really hard to determine.

    5. CT

      Yeah. Uh, that's, uh, common across all of medicine, right? And even as I'm looking for a doctor for something, it's hard to find the right person. I'm in a massive medical center, you know, and, and have great connectivity, but knowing who truly is the best is complicated, right? So some things we rely on are volume, case volume, and historic case volume. So how many procedures do they do? That's important. And probably more important, how many have they done over the course of their career? So if you're having a procedure, you wanna know volume 'cause volume's important. It's not the whole story, but volume is important, right?

    6. AH

      Okay.

    7. CT

      And we need, in medicine, honestly, to move more towards objective metrics, and this is one thing AI can do for us, right? I'm involved in a, um, a healthcare delivery platform. It's called Everself, and what it does basically is the doctors that are doing these procedures are held to a certain metric, right? So it starts with just collecting the data, you know, finding out what their weight loss outcomes are, finding out how many stitches they place per procedure, looking at their procedure time, looking at their complications. So you're grading all that. But the next layer is putting this 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 of the procedure. It can be very specific, and it can tell you, "You placed this many full thickness sutures versus this many. You want 100% of your sutures to be full thickness." Maybe the doctor's putting in 70 that are 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." It'll give you a grade at the end of that procedure, and that grade is incredibly important. And then the i- the idea next would be is to share that data so people know kind of what grade you're getting. It'd be great to share that with governing bodies that do credentialing, so people that are truly underperforming, maybe they should get a refresher, right? It would be nice for patients to be able to select, you know, who they're gonna go to based on objective metrics. And AI can do this probably across the board with other things as well. So that's part of it. We've seen this a little bit with ADR, adenoma detection rates in colonoscopy, where they used to publish that, and they stopped doing it. So doctors were expected to have a certain number of polyps they'd see per colonoscopy, and they'd report that. That was something that was another way. But then the problem was all the patients wanted to go to the one or two doctors that had the high DRs, and their wait times became enormous.

    8. AH

      Mm.

    9. CT

      Right? And then patients couldn't get access to them. That's a problem as well, but there should be a reasonable cutoff where a certain level of expertise is required. And, um, you know, I think AI, you know, hopefully will help us get there.

    10. AH

      I'm excited by what you told me about how AI can, um, provide real-time data and prospective data about how the stomach will change shape i- in-- with the opportunity to make the adjustments as you go, as opposed to having the patient heal up and have to c- have to come back in for another surgery. Years ago, I saw something amazing. A, a, a neuro-ophthalmologist, um, friend allowed me to sit in on a, on something. He said, you know, "People forget that surgeons wear microscopes on their eyes, right?" They, they wear these, like, um, uh, optics that allow them to see things bigger, obviously. But then there are all these new tools that, you know, like a little drop of fluorescein, a little bit of, like, innocuous, uh, liquid that creates a contrast for the, for the surgeon or for the, uh, eye doctor to see what, what is what and not cut the wrong tissue. It seems like a, like such an obvious thing, but I was told that for, you know, a hundred years, the same procedure had been done without that. And so eye surgeons had to essentially guess, based on their intuition, their training of what was tissue to, uh, preserve, what was healthy, what was unhealthy tissue. I mean, these, what seem like kind of simple to us now technologies have improved the margins of safety, have, have improved the, you know, outcomes tremendously. And so the idea that you would have AI combined with really good microscopes, either worn on the eyes or you're looking down a microscope, better surgical tools, to me, it just seems obvious, like yes-

    11. CT

      Mm-hmm

    12. AH

      ... yes and yes. But a lot of people hear AI, they hear robot, and they hear surgery, and they go, "Oh, my goodness," like, "What if the..." They go to the extreme. I think with AI, people think it can go rogue. It has a mind of its own.

    13. CT

      Mm.

    14. AH

      So I don't want you to give false reassurance that that's not gonna happen. But when you sit down to do a procedure and you're getting information from AI, where does your trust come from that-

    15. CT

      Mm-hmm

    16. AH

      ... um, it's giving you good information as opposed to faulty information?

    17. CT

      Yeah. So the AI is, is trained on thousands and thousands of procedures, right? So more than I've, I've done, right?

    18. AH

      Mm-hmm.

    19. CT

      So-- Which is good. And so it recognizes patterns. So you have to use your clinical judgment, and you're not doing-- you're not using this AI kind of blindly. You're using your clinical judgment, and you might ignore it sometimes.

    20. AH

      Mm-hmm.

    21. CT

      You don't have to follow it. Now, if it come, becomes the, the time where you're automating operative robots using AI-

    22. AH

      Like suture placement, for instance

    23. CT

      ... yeah, that'd be different. If it's doing it itself-

    24. AH

      Yeah

    25. CT

      ... that's different. But for this, where it's just suggesting where you put a stitch or showing you where a blood vessel is, I think it's a huge advantage. So we do these procedures that are very technical where, where you tunnel, y- you know, you're creating a potential space in the esophagus. So back to that earlier, um, person that couldn't swallow, right? They had trouble swallowing 'cause they had achalasia. So the procedure, how we do that is we go in through the mouth, we inject a little fluid under the mucosal layer to, to lift it with a, with a pocket of fluid. We make an incision in that, and we take the endoscope, and we slide under, i- in between the mucosal layer and the muscle. We dig all the way down to the bottom of the esophagus, and then we cut through the muscle. When you're doing it, there's vessels in there, and they're 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 the vessels as you go, reducing your chance-

    26. AH

      Mm

    27. CT

      ... of hitting a blood vessel, right?

    28. AH

      Beautiful.

    29. CT

      So that's just one example-

    30. AH

      Yeah

  27. 1:35:29 – 1:37:19

    Image Guidance & Hyperspectral Imaging

    1. CT

      So now with, with endoscopic ultrasound, it's not even color. It's all gray. So when we're doing endoscopic ultrasound, we talked about looking for a pancreas tumor. It's all gray. It's just different shades of gray. There's no coloring to it. Now, you can, you can turn on a button to see if there's blood flow, right? But it's all gray. So I-- Years ago, at my lab, I was trying to use image registration, so I could take a CT pet scan, and I could link it to the, the angle of the probe, and you could see a CT scan fluctuating in the probe of the ultrasound and lay the oversound-- the ultrasound-

    2. AH

      Mm

    3. CT

      ... over it. And then you get an idea of the tumor you're looking for, the lesion you want to biopsy or whatever.

    4. AH

      Right.

    5. CT

      It was too hard to do. It would take three hours of preparation to be able to set that up. You could never scale that. Now, with AI, other groups are doing similar work now, and it's, it's almost automated. So I'm hoping that we'll see image registration with these very advanced imaging tools that are being used help us with diagnosis and hopefully even with therapy too. They're, they're doing something now called hyperspectral imaging, and they're doing it in surgery as well. There are several groups doing this. One group in London is doing phenomenal work. They're using all these narrow bands of wavelengths, just tons of wavelengths, and they're finding out that each tissue actually has a fingerprint. So you can actually use this, this hyperspectral imaging to fingerprint tissue, and you can actually see margins of tumors with this. And it's very interesting without giving a dye anymore. So you still might want to give it for lymph node testing or whatever. Sometimes they'll inject something into a tumor and then look to see if it gets into lymph nodes. That's different. But this is for actually looking for margins or for lesions, and it's just with light technology. It's amazing. So that's what LEDs are doing, right, in different-

    6. AH

      Yeah

    7. CT

      ... kind of, uh, cameras, right? So instead of CCD chips, you have CMOS, right? And so with newer technology, even though it seems incremental, with LEDs being able to fluctu-- uh, kind of fluctuate the wavelengths of light and your chips being able to read it faster and better, we're able to make better diagnosis.

  28. 1:37:19 – 1:38:56

    Sponsor: Our Place

    1. AH

      I'd like to take a quick break to acknowledge our sponsor, Our Place. Our Place makes my favorite pots, pans, and other cookware. Surprisingly, toxic compounds such as PFAS or forever chemicals are still found in eighty percent of non-stick pans, as well as utensils, appliances, and countless other kitchen products. As I've discussed before on this podcast, these PFAS or forever chemicals like Teflon have been linked to major health issues such as hormone disruption, gut microbiome disruption, fertility issues, and many other health problems, so it's very important to avoid them. This is why I'm a huge fan of Our Place. Our Place products are made with the highest quality materials and are all PFAS and toxin-free. I particularly love their Titanium Always Pan Pro. It's the first non-stick pan made with zero chemicals and zero coating. Instead, it uses pure titanium. This means it has no harmful forever chemicals and does not degrade or lose its non-stick effect over time. It's also beautiful to look at. I cook eggs in my Titanium Always Pan Pro almost every morning. The design allows for the eggs to cook perfectly without sticking to the pan. I also cook burgers and steaks in it, and it always puts a really nice sear on the meat. But again, nothing sticks to it, so it's really easy to clean and it's even dishwasher safe. I love it and I use it constantly. So if you're looking for non-toxic, long-lasting pots and pans, go to fromourplace.com/huberman and use the code Huberman. With a one hundred day risk-free trial, free shipping and free returns, you can try Our Place with zero risk and you can see why more than one million people have made the switch to Our Place kitchenware. I feel like, uh, one structure that we could, um,

  29. 1:38:56 – 1:42:45

    Diagnostics & Targeted Metabolic Treatments

    1. AH

      conceptual structure that we could put on things I'm realizing today is medicine has a, a couple of different ways to determine what's going on for better or worse. One is the stuff that comes out of the body. And we do this with babies like, "Oh, their, their, um, mucus looks really green." We do this, uh, maybe I have a sinus infection. It comes out of the body or with bowel movements or we're not so good at gauging the color of blood kind of things or then we have surface of the body, pallor of skin, how the eyes look. Do we see, you know, uh, stuff that we don't normally see? And then, you know, the age-old story where like it was like phrenology, which was like, you know, complete bogus, but it was like, oh, can we de- figure things out from the ch- way things are changing at the level of the, the shape of the skull is complete nonsense, right? But as we go in, we're still trying to do this, right? X-rays let us see, uh, you know, fractures and things with, you know, you don't want too much X-ray, uh, uh, radiation, but the, the goal has always been to get more information with, with less, uh, inv- invasive procedures. And I feel like now we have blood tests so you can pull stuff out of the body and it, it's kinda wild that in 2026 this is where we're at. I think it's super exciting, but you know, hasn't, I don't know, 50 years ago the tools were really crude there, but I think they might still be kinda crude now compared to where they are in 10 years. Are you hopeful that in 10 years you can go into a tube, 20 minutes later walk out and we might be able to scan with good enough resolution? Do you have any tumors anywhere? Compare that to a blood test and, um, you're good to go.

    2. CT

      I don't know if we'll get there. Um, I'm hoping, right? Because we are seeing capsule technology improve, we're seeing imaging technology improve and blood tests improve and there's all sorts of things you can do with, with kind of genotyping things and whatnot. I think that's exciting. But where we are seeing improvements I think are in learning about physiology and how things work and then being able to do a targeted approach. So you're not just doing that with drugs where GLP-1 is... Actually, GLP-1 isn't really targeting a deficit necessarily. There's different ways you can treat things. You can either find a pathology and treat the pathology.

    3. AH

      Mm-hmm.

    4. CT

      Right? Like cutting a tumor out is kind of like treating a pathology that's not supposed to be there. Or you can take normal physiology and augment it, right? And that's what they're doing with GLP-1. There's not like some horrible GLP-1 deficit that's, that's totally clear.

    5. AH

      But they're ramping things up thousandfold over what they would be-

    6. CT

      Right

    7. AH

      ... in even the healthiest person.

    8. CT

      Yeah.

    9. AH

      Most people don't know that by the way. They think that like the GLPs are bumping things up like two or fourfold. It's like th- n- no- never before in human history, at least to my knowledge-

    10. CT

      Exactly

    11. AH

      ... have people walked around with this level of GLP-1 circulating in their blood.

    12. CT

      Yeah.

    13. AH

      Yeah.

    14. CT

      You're supposed to have a little tiny amount that's produced in response to a meal, right? And then it goes away. You know? And it's kinda like, you know, relatively speaking, not... This is super physiologic doses. You're bathing the area postrema in this chemical, right? And it's like it's not functioning like in a physiologic way. Our GLP-1 is secreted, it's nutrient responsive, it's secreted from L cells, right? And then it does its job. It goes to the pancreas, says produce insulin. It goes to the stomach, it says slow emptying. It goes to the brain, it says you're full. It does things like that, right? And it does it in response to a meal and it's in much smaller doses like you've said. So medicines have done this for a while where they kind of see something as a mechanism they can augment or they see a pathology they can treat. But that augmenting is very interesting and surgery for a long time wasn't doing that. They were just thinking, "Oh, I'm gonna make you malabsorb calories. I'm gonna make this tight so you feel full quicker." But now that we're understanding mechanisms and there's some great research that's gone into this, we can actually develop targeted therapies and I think that's what's very exciting. It's more so even than, than a new device. It's being able to do targeted therapies and get better outcomes with that. And where I started with this is, um, in fellowship. So I saw, you know,

  30. 1:42:45 – 1:47:59

    Gastric Bypass, Foregut Exclusion & Diabetes

    1. CT

      I saw a patient with a gastric bypass. So they have a gastric bypass anatomy. They have a small gastric pouch like I mentioned and a bigger stomach and a patient was sent to me that had bad reflux. They had weight gain after the gastric bypass and their diabetes w- came back. Their diabetes was gone but now it'd come back. So the surgeon basically said, "Hey, take a look at this patient. See if they have an ulcer, what's going on. They're having all this pain and heartburn. Find out what's going on." So I went and looked and there's this little hole between the pouch, the new stomach and the old stomach and I thought, "Well, maybe the acid's produced in the other side. Maybe the acid's coming up through that fistula." And we had a new device. It was a suturing device that you could actually put in through the mouth and put stitches in. I thought maybe the suturing device, I could use it to close that hole, right? So I waited until I was on faculty a few months and I talked to the surgeon. He was supportive. So again, this is kind of that thing, are you inventing something? The procedure the FDA appro- the device is FDA apr- approved, the procedure is not. No one's closed a fistula with this. But we talked to the patient. You know, we told him we weren't sure if it was gonna help or not. We'd try to do it. They were willing and we did the procedure, closed the fistula and so I was hoping the reflux would stop. The reflux stopped But the person started losing weight and their diabetes went away almost immediately again.

    2. AH

      Mm-hmm.

    3. CT

      And that was, for me-- and this is 2003, 2004. 2003. I was like flabbergasted. You know, was it a coincidence? What the heck was that? Why is closing that little hole so important, right? So that's what got me involved in understanding these gut hormones, honestly, because we s- we were able to now... Y- if I learned about the gut hormones and h- why we saw this treatment effect, we could potentially manipulate them to get a, to, to get better results, right? So that was the beginning of it for me. And, uh, there was, uh, shortly after that, uh, one, one of my friends and colleagues actually did some animal work. He had a rat model. They're called GK rats, and they're rats with diabetes that don't have obesity, okay? And they were a great model for this because you didn't want weight loss to confound things. And so he did two surgeries of foregut and hindgut method, right? So the, the one surgery, he basically excluded the foregut. So he excluded the duodenum and the very first part of the jejunum, okay? And he did, he did a little bypass surgery there, so no food could get in the duodenum. It went from the stomach, and it went to the, the very first part of the duodenum and then boom, down into the jejunum, not touching that foregut, not touching that bowel. The other one, he did a gastrojejunostomy, so stomach to small bowel, but he left the rest open. So food could go either way. It could go into the duodenum like it normally would in the foregut or go to the hindgut, dropping down into the distal bowel. What he found was these were diabetic, uh, rats. He did glucose, uh, tolerance tests on them, and he found that 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. So he thought there was something very important about foregut exclusion, and he hypothesized there was something called an anti-incretin in that bowel that would maybe protect against hypoglycemia. But there was something in there that if you exclude it, you got a better treatment effect. So that was, you know, my fistula work and then his, his very interesting animal work got us going down that path. And it, it kind of fed well into something that actually was done, uh, in the 1980s, that, that was from, uh, a continuation of that work that Sherlock had done looking at incretins and, uh, in this famous publication by Nock. And, uh, what he did is he looked at, at the same, the same study that, that Sherlock did in London, where they were giving glucose to look at the insulin response. But he did it in diabetics, and he did it in a normal population, normal healthy population. The normal population had that exact same incretin response, where you gave a certain amount of glucose intravenously, little spike, same amount of glucose orally, big spike. Diabetics didn't do that. And they had already tied it maybe to GLP-1 and maybe in the, in the, in the bowel. So very exciting. So maybe by excluding this foregut, you're playing a role, you're having something to do with that or maybe not. So that was the beginning of trying to understand the procedures for me. And, um, with that, I then did another study where I closed those fistulas, right? And, uh, and where we closed the fistulas, 60% of people had resolution of their diabetes. If we didn't close it, no one got resolution of diabetes. So, okay, that's a good thing. So we learned there's some important element to, to foregut exclusion. Then there's various device companies that start getting involved in the space because there's this, there's this information out there that excluding the foregut might be important. And a company comes up with the idea of putting a liner in endoscopically. So it's like a little sleeve. You anchor it. It has a little stent that springs open. You anchor it in the first part of the small bowel. It covers the duodenum, protects it. It's an implant, so it has to come out, right, at some point in time, maybe a year later. But it was very interesting because, uh, I was, I was part of those, those, those clinical trials, and we found you had a one-point-- in diabetics, you have a one-point drop in A1c. That's fantastic. And you lose weight, about seven, se- 7% total weight loss. So clearly it's doing something, and it's, it's important. The problem is it's an implant. It's got to come out, but it's exploiting this mechanism potentially.

    4. AH

      So you're essentially, um, cinching down this com- partment of the, the gut, or you're cr- you're creating more compartmentalization along the, the tube?

  31. 1:47:59 – 1:52:58

    Duodenal Liners & Mucosal Resurfacing Research

    1. CT

      You have the duodenum, right? And then there's a liner that you place in it. So this is like a stent, so it springs open and holds its form inside it, and then it's a sleeve that kind of goes down. So you can still get all your secretions that go on the outside of the sleeve and track down. But it's right after the pylorus, the outlet of the stomach, so all the food's going in the tube. So the food is inside the sleeve. The digestive enzymes are outside the sleeve, and they don't mix for a few feet down. So that's very interesting, and it worked. The problem is it's, it's still in clinical trials. It's been around for a while, but it's an implant, so it's just like taking a drug. Eventually, it has to come out.

    2. AH

      Mm-hmm.

    3. CT

      But then there was a, there was a brilliant idea that came up, one of my colleagues at, at the Brigham, and he's a cardiologist, right? And he knew I was trying to do something that was... So I traveled to Brazil, right? And I was doing surgery, uh, endoscopic procedures in Brazil, and there was a doctor in a room nearby, and that doctor was doing a very novel experimental surgery called ileal interposition. And what he was doing, and this was a lean diabetic, so they, they weren't suffering from, from obesity. They had type 2 diabetes. And he was taking this, the small bowel, the distal small bowel, kind of the opposite a little bit of what Rabino had done. Took the distal small bowel, and he moved it up, kept it on his mesenteric blood flow. He resected it out of the, out of the, out of the distal small bowel near the colon, and he moved it up, and he put it near the duodenum. And his idea was, you know, the concept was that GLP-1 was denser in that part of the bowel, and it was also denser, you know, down lower. And if you moved it up higher, you'd get a more immediate incretin effect from GLP-1. So you'd hit GIP and then immediately GLP-1, and you'd have this amazing effect, and he did. It was incredible, right? These people, their diabetes went away, and they didn't lose any weight because he didn't actually have any blind areas. The food-- he didn't change anything. There's no restriction. There's no absorptive change. He just moved that part of the bowel up. That was phenomenal. So I was trying to do it endoscopically by harvesting, uh, tissue from the ileum via colonoscopy, creating stem cells, and then injecting it in the foregut and getting him to take and hopefully getting an incretin effect. That wasn't successful. But- One of my colleagues is a cardiologist, and he actually said, "Why don't you just burn the duodenum? You know, eh, ablate the duodenum." There are different ways you could do it. You could do it with steam, hot water, um, et cetera, just ablate it and see if you can reset those stem cells because the duodenum is sick, okay? And this is very interesting research that proves the duodenum is sick we should probably talk about. But, you know, the duodenum is sick. If you can reset the duodenum, it might work. And I said, "Why don't you do it?" And he did, and he started a company, and it's been great. So, and that, that, that is something that we're studying more and more of. And now you don't have a sleeve in place. You don't reroute any bowel. You just ablate the duodenum, okay? And what happens is your A1C drops by over a point. You don't lose a lot of weight by just ablating the duodenum, right? But your A1C corrects, and it's a, a potent- a potential treatment for diabetes. They've also done some studies, uh, that I don't believe these are published yet, but I think that it's showing that when someone comes off of 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, if you will. The stem cells come back, and, uh, you've maybe healed those tight junction and other problems that you're having, so.

    4. AH

      So it regenerates.

    5. CT

      It regenerates. Yeah. It comes back more healthy and more normal.

    6. AH

      Hmm.

    7. CT

      And the rationale for that comes from a lot of very good research, right? So there were studies that showed, uh, in mice that if you feed mice, you overfeed them in an overfeeding study, and you have a control group you don't overfeed, when you take them to necr- necropsy and you look at their, their bowels, the bowels in the, in the, the overfed mice are longer, they're heavier, the villi are longer. They've adapted. They've adapted it, upregulated the ability to absorb calories. And then these studies have been repeated in humans, where people getting gastric bypass, they're already going to be doing surgery on them, so they resect part of their small bowel. In someone getting cancer surgery as a control patient, they resect their small bowel.

    8. AH

      Mm-hmm.

    9. CT

      And they look at the differences, and there's extreme differences, right? The villi are longer. It's thicker. There's more inflammation in people with obesity or type 2 diabetes, a lot more inflammatory cells. The natural killer cells are up eightfold. Uh, macrophages up 1.5 fold in these studies, right?

    10. AH

      Hmm.

    11. CT

      So you have more inflammatory activity going on in these patients. The only thing that's different is really obesity, right? Additionally, if you look at those patients and you, you do a s- im- immuno staining for like zonula occludin, like tight junction proteins, scaffolding proteins and proteins, you'll see that those are much lower, and they're disorganized.

    12. AH

      Two questions. So if I understand correctly, uh, if people overeat, the villi, like basically the little finger-like protrusions inside the gut that can sense things but also collect nutrients, right? They're growing to adapt to the elevated levels of calories. And so then essentially you've changed the digestive tract in a way that, yes, they can make more use of, of those calories, but that also creates a more pro-inflammatory environment. Do I have that right?

    13. CT

      That's absolutely correct. And also because they're changing in configuration and you're using that energy, the cells are using energy to do other things, your tight junctions are deprioritized.

  32. 1:52:58 – 1:59:39

    Gut Permeability, Inflammation & Fatty Liver

    1. AH

      Okay, right. So then there's this-

    2. CT

      Mm

    3. AH

      ... um, secondary, uh, or parallel e- effect of the, the tight junctions. We haven't really talked too much about tight junctions here, but, um, uh, I'm not by no means an expert-

    4. CT

      Hmm

    5. AH

      ... but I'm familiar with them from the blood-brain barrier. They get... Like, cells need to stick together. [chuckles] And some tissues, you want things sticky but not too sticky.

    6. CT

      Mm-hmm.

    7. AH

      Some tissues, you want them really sticky. And w- my understanding is that the tight, as the name, uh, uh, suggests, tight junctions, the goal is to keep stuff inside the gut, not let bacteria out. Is leaky gut a real thing, or is leaky gut... Uh, 'cause I've heard it's sort of like chronic fatigue syndrome, that a lot of the standard medical community, they hear, uh, chronic fatigue syndrome, and they go, "Okay, that was made up by people in the Bay Area." I'm only half kidding here. I'm from the Bay Area. But th- that's how a lot of physicians react online to this phrase leaky gut. But we've had a fair number of people come on here and talk about tight junction deficits, bacteria getting out of the gut. This isn't good for the body. Inflammation going up. Bacteria circulating places they shouldn't be is not good. So is leaky gut real?

    8. CT

      Well, increased gut permeability is 100% real.

    9. AH

      But that's-

    10. CT

      And that's, that is-

    11. AH

      I mean, I'm not pushing back on you

    12. CT

      ... that is a thing

    13. AH

      That sounds like, like, that sounds like-

    14. CT

      Mm-hmm

    15. AH

      ... a different language for leaky gut.

    16. CT

      Yeah. So it is. So-

    17. AH

      So, so why, so why is this phrase leaky gut so, um-

    18. CT

      Yeah

    19. AH

      ... uh, no pun intended, so irritating to the medical community?

    20. CT

      So I think if you say leaky gut, it could have other connotations that you don't know what it means to the person. Someone might think that leaky gut means that it's responsible for a certain constellation of symptoms potentially.

    21. AH

      Like irritable bowel or-

    22. CT

      Yeah. Or, or something, right?

    23. AH

      ... or Alzheimer's. Like they can take a leap.

    24. CT

      Yeah, yeah. 'Cause, 'cause-

    25. AH

      I see

    26. CT

      ... you see in, in, in lay literature, right, they'll... in other literature, they say leaky gut is associated with XYZ, right? And it's not clear that, that that phrase leaky gut is, is, is really talking the same thing that I'm talking about. Now, is leaky gut the same thing? Yes. I'm still talking about leaky gut in a sense, right? But the danger is calling something leaky gut when m- people already might have a definition for leaky gut in mind, like it's responsible for, for all these other problems, right? But let me tell you what leaky gut is to me or what-

    27. AH

      Mm-hmm

    28. CT

      ... increased gut permeability is.

    29. AH

      Mm-hmm.

    30. CT

      And I'll tell you that it's very real, and it is actually tied to metabolic illness. Uh, we can start with a study that used, uh, small bowel biopsies, right? And this was recent, just last year. And they did small bowel biopsies, and then they, they actually were able to, from the stem cells, grow little or- organoids, right? And then organoids are like three-dimensional cultures that y- they, they behave as they should. As this, the cells kind of populate out of there, they take their normal form and structure. And they had a control group, and they had a group with MASH, obesity and MASH, right? So, which is, uh, uh, a l- a metabolic associated, uh, steatohepatitis. So these two groups, they looked at the organoids, and they 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 they found that they weren't even producing it, v- v- you know, the, the, the proteins. They weren't even making the RNA to produce the, the tight junction proteins. So clearly at transcriptional level, they were down-regulating the, the, the tight junction proteins.

  33. 1:59:39 – 2:05:00

    Artificial Sweeteners, Fructose, Fats & Omega-3s

    1. AH

      um, I get a lot of questions about artificial sweeteners and negative effects on the gut microbiome. Seems like they're m- marginal to zero effect on insulin and bl- resting, uh, blood glucose from artificial slash, uh, low-calorie sweeteners in a way that, like, would lead people to say these are bad. 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 wa- water actually lose more weight. I've seen those data.

    2. CT

      Mm-hmm. Yeah.

    3. AH

      But this is not an incentive for people to start drinking diet sodas. It sounds like, you know, saccharin and Splenda are probably worse for you than stevia and aspartame. Like, w- where are you at-

    4. CT

      Mm

    5. AH

      ... with these things in terms of their potential negative effects, and if you know of any positive effects, I'd be curious.

    6. CT

      I think they're better than high-fructose corn syrup for sure, right? I mean, that I think we should be treating like alcohol, right? Yeah. I think fructose in fruit's fine. I'm not worried about-

    7. AH

      Mm-hmm

    8. CT

      ... fructose in fruit, fructose in general, because it comes with a matrix around it. It's not, you know, it's not like a rush of ca- of, of, of fructose into your liver. But fructose can only be processed by the liver, right? And so it's busy as it is. Now it's got to take the burden on of, of, uh, you know, a, a beverage which is absorbed very rapidly, goes directly to the liver, and it has to be, has to be dealt with. Um, and, you know, it gets trapped in the liver very quickly, and that's the only place it can really process it. So I think that fructose is something to watch. Um, again, not if it's in fruit. Even in juices it can be kinda... Juices are processed fruit, right? So it's similar. It's just minimally processed stuff is better. I think the problem with sweeteners, artificial sweeteners, is they come in foods that are, uh, that are highly processed as it is, right? And you can't separate the two. I think that's for a while why people were so down on, on polyunsaturated fats, right?

    9. AH

      Mm-hmm.

    10. CT

      Because it'll come in a, in a bar full of a bunch of other stuff that's not good for you. So, well, I guess the polyunsaturated fat's also bad for you in some way, right? That was, like, a n- recent phenomenon. Well, no. The food that it's in is bad for you, but the polyunsaturated fat has been shown to reduce LDL and has, has health benefits, right?

    11. AH

      So you're talking about, or essentially for translation for people, like seed oils basically.

    12. CT

      Yeah, seed oils.

    13. AH

      The, yeah. There's some-

    14. CT

      Mm-hmm

    15. AH

      ... still debate about whether or not the processing of them can-

    16. CT

      Yeah

    17. AH

      ... make them worse. But, um, yeah, it's, it, it's hard to, uh... Well, I don't know. Did you see this recent avocado, uh, oil st- thing out of UC Davis?

    18. CT

      I don't think so.

    19. AH

      Uh, this is wild. Uh, UC Davis went and analyzed, like, all these avocado oil-containing products that are supposed to be, like, healthier. You know how much avocado oil these products contain? Zero.

    20. CT

      Oh, no. [laughs]

    21. AH

      And the pushback has been that maybe they're looking-

    22. CT

      Yeah

    23. AH

      ... at the wrong, uh, metabolites of, of- of avocados. I don't know how this is gonna play out, but if it... This could, this could potentially do more damage to the, I just call it the non-olive oil, uh, community, right? 'Cause, I mean, in my mind, like the safest thing is to just use olive oil-

    24. CT

      That's perfect. Yeah

    25. AH

      ... a little bit of butter if you ha- here and there.

    26. CT

      Yeah. That's fine. Yeah

    27. AH

      Right? Like, okay.

    28. CT

      Mm-hmm

    29. AH

      No one debates olive oil.

    30. CT

      Mm-hmm.

  34. 2:05:00 – 2:06:31

    Resistance Training, Zone 2 Cardio & Intervals

    1. AH

      what else do you recommend to your patients as they start to move away from obesity? So y- uh, obviously fiber, some fermented foods. Um, uh, it sounds like resistance training might be in the list given that their, their, their risk of, uh, re- becoming, um, thin but more jelly tissue-

    2. CT

      Mm-hmm

    3. AH

      ... than, uh, f- lean, lean mass. Do you, do you prescribe r- resistance training?

    4. CT

      Absolutely. So all my patients, I ask them to do resistance training, um, even, you know, before they start losing weight, before they go through a procedure. It's essential. Uh, Zone 2 cardio is great, right? It's good for fat burning. You're in that zone where you're burning fat and, you know, not, you know, carbs as much, right? HIIT is great. So high intensity interval training is great for mobilizing visceral fat, because your visceral fat, we haven't talked a whole lot about it, but it has, uh, beta-adrenergic receptors on it. It also has gonadotropic hormone receptors on it as well. So, um, it's responsive to, to stress, like acute stress. So it will mobilize when you're going, you know, through the stress of, of, of high-high, you know, high intensity interval training. So it'll mobilize. It won't be burned right away, right?

    5. AH

      Mm-hmm.

    6. CT

      Because you're burning carbs at the time. You're burning your-

    7. AH

      Mm-hmm

    8. CT

      ... your liver glycogen and, uh, and your muscle glycogen. You're burning that. But you mobilize the fat at least, and that's kind of what it's designed for. That's why you have some visceral fat there. Um, so I include... I, I, I, I try to have them do those things, HIIT, a little Zone 2, and then resistance training. I think those are the most important things long term.

    9. AH

      Mm-hmm. Do they do it?

    10. CT

      This is very interesting. So,

  35. 2:06:31 – 2:08:13

    Weight Set Point & Metabolic Adaptation

    1. CT

      uh, I think they try, and depending on how they lost the weight determines if it's effective, right? So this, this theory of set point, right, which is something that's very important back to, back to metabolic health. So it's, it's not a point necessarily. It's a defended range, if you will, right? So you have this defended range of what you think your weight's supposed to be, and that's set by a variety of things. Leptin is part of it, right? And your thyroid hormones and whatnot, and you think you're supposed to be a certain weight. And then what you do is you do a crash diet. You lose a bunch of weight. Like, The Bigge- Biggest Loser was a great example of this, right? You lose a bunch of weight. So now you're fighting several factors, right? So one factor is your body's smaller, so it burns less weight, okay? So you have to eat less to just maintain the same weight you're at now, this lower weight. That's a bit of a problem. You down-regulate your gut hormones. We talked about a bunch of gut hor-hormones. You're producing less GLP-1. You're producing less PYY. You're pro- producing, uh, GIP is here, n-neither here nor there. 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, your ghrelin goes through the roof, right? So that, in addition to the fact that your muscles become more efficient, I think they become 25% more efficient in doing a similar task. They're gonna burn less fuel to do the same task. It's amazing, right? Your kind of non-exercise energy expenditure, right? So just kind of daily activity. Your basal metabolic rate as well. They all kind of go down. So you're burning less calories at rest. So and we've shown this study, study after study. So your whole body is fighting you, okay? It wants to go back to that weight, whatever it thought it was supposed to be at. The Biggest Loser was a great... There was a kind of an NIH, uh, follow-up study to that, and they found that they were burning 500 fewer calories per day

  36. 2:08:13 – 2:10:30

    Endoscopic Sleeve Gastroplasty & Fundus Ablation

    1. CT

      after that. So it- And there's other studies that have shown this as well if you lose weight that way. So that's why it's so important. GLP-1s help fight part of that, right? You're replacing the GLP-1 that's... You're not, you're not addressing the ghrelin or other things. So time will tell if we can have long-term weight loss, but it does, it does. So ghrelin isn't the whole story, right? So like with, with our procedures, so we're addressing these very targeted with procedures, and one bridge into that is, is the ESG procedure. So this is the procedure I, I, I, I developed in 2012. So you go in through the mouth, someone's sleeping obviously with a little scope, and you fold the stomach on itself. Now, the goal of that was to do two things. You know, uh, one was to, uh, augment the stretch receptors. So it's a smaller pocket. So when food hits that, the stomach stretches quicker, and you have the vagal afferents now that go up to the nodose ganglia and then, you know, uh, uh, NTS and then, you know, boom, into the, um, hypothalamic areas.

    2. AH

      As you tell the brain we're full.

    3. CT

      Yeah, exactly.

    4. AH

      Yeah.

    5. CT

      We're full, right? Stretch fast, boom. So when you stretch, you get that signal, boom, and you're full. That's part of it, right? That's phenomenal. The other part of it is you suppress ghrelin because food stays in the stomach longer, right? And so it's suppressing ghrelin. So it's doing two different things. Now, 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, uh, you know, of, of the countermeasures that the body will do to defend this p-potential, you know, potential range. We're not doing anything with that necessarily to, to GLP-GLP-1 and other, and other duodenal hormones. But you'll see it actually, it actually you have ways of dealing with this. So how do you augment weight loss? You have all these different targets, right? So one thing we're doing now is we talked about how ghrelin resides in the fundus. Now, in addition to that 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 'cause th-they live in the mucosal layers. You can get to them. So you can... They, they use argon plasma coagulation. There's 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, and there's not much of them, right? So now all of a sudden you can suppress ghrelin as well. So the weight loss goes from about 18% with the ESG alone in a, in a top center. Goes up to way over 20%, maybe 25% if you start ablating the ghrelin, the ghrelin producing cells as well.

    6. AH

      Are there drugs that just inhibit ghrelin?

  37. 2:10:30 – 2:16:52

    Magnetic Intestinal Connections & Combined Treatments

    1. CT

      No, not, not effectively.

    2. AH

      Hmm.

    3. CT

      Yeah. So and then you add to it, right? So now if you've delayed gastric emptying, your CCK is not spiking as much as it was, et cetera. So but you're not getting, uh, which, which is a, is a subtle countermeasure potentially, right? It will still spike, but GLP-1 is an issue. So now what if you combine that with a small bowel procedure, right? And there are different small bowel procedures that we've come up with using magnetic, magnetic anastomosis is one we published about 10 years ago. We did it in the Czech Republic. We used endoscopes. It was a hard way to do it. It went from below a colonoscopy. My partner did that. I went from above. It released these two magnets, and we connected the jejunum, the first part of the jejunum, to the, the lower part of the ileum.

    4. AH

      We should probably tell people what anastomosis is.

    5. CT

      Uh.

    6. AH

      Basically, uh, when you connect two tubes.

    7. CT

      Exactly.

    8. AH

      Right? Is that right?

    9. CT

      Yeah.

    10. AH

      You're basically just... So you're basically like ligating a tube.

    11. CT

      Yep.

    12. AH

      Or now here we're using more nomenclature. You're, you're l- bridging two tubes.

    13. CT

      Bridging them, right?

    14. AH

      Yeah. Yeah. Okay.

    15. CT

      And you-- they did it originally with sutures. You cut a hole, and you suture the tubes together.

    16. AH

      Yeah.

    17. CT

      Right? And then they did staplers, and staplers would do it. But they're big and bulky and hard to position.

    18. AH

      Yeah.

    19. CT

      So, so our lab developed magnets, right? And these are ring magnets. So they come out. They're, they're magnets encased in nitinol, so they can take a certain shape. So you put them through a tube. In this case, it's an endoscope. You can put them through a laparoscope or whatever else you want to put it through. And they come out, and they form a ring, right?

    20. AH

      Mm-hmm.

    21. CT

      So we went through the top endoscope. We formed a ring in the jejunum. In the bottom, we formed one in the ileum way downstream, and then we had an anastomosis that would allow the food to directly pass there. And 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 the GLP-1 hindgut spikes. You're getting that sense of restriction in the vagal afferent signaling. You're getting, uh, you know, ghrelin to be suppressed, and you're getting really amazing weight loss. So what we can do now is take a procedure that was really big. It started off as a big open procedure that had certain risks to it. We didn't know how it was working, and it did a bunch of different things. And we're targeting different aspects of it, and the goal moving forward is to even be more precise and find out what someone's gonna 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, right? Maybe they need something more, and people are actively studying that. Um, they're studying the phenotyping of obesity. It's quite exciting.

    22. AH

      I'm sensing another theme here. Um, this procedure that you co-developed or developed?

    23. CT

      Which one?

    24. AH

      This, this, uh, bridging of, um...

    25. CT

      So it was my lab.

    26. AH

      Yeah. So, so you-

    27. CT

      So, yeah, it was my lab. I'm the, I'm the PI, but I have a whole team obviously.

    28. AH

      So you developed.

    29. CT

      Yeah.

    30. AH

      Yeah. So it's increasing GLP, but I'm guessing it's not increasing it thousands fold like a GLP drug would. It's got some other positive consequences that help cure the obesity. I'm, I'm kind of sensing a theme here, right? Like we have this, these drugs like Ozempic, Mounjaro, et cetera, that ha- blasted GLPs through the roof, helped a lot of people that need help, but there were a lot of side effect issues. Then along comes this other drug, retatrutide, which is like, okay, well, let's increase GLP, but let's also kind of bump up the GIP system a nudge or two. Let's also bump up the glucagon system, and lo and behold, we get a much better effect, muscle sparing, and actually better weight loss. So kind of a perhaps a lesson to us that, like, you don't really want to push really hard on one lever in biology or take any one thing out without... Maybe the more combinatorial approach is the better approach.

  38. 2:16:52 – 2:22:13

    GLP-1 Gene Therapy Research

    1. AH

      So given where things are at now, the treatments, uh, that you and colleagues have, have, have developed, and when I say colleagues, I mean people within your laboratory and clinic. But, you know, clearly this is, like, a m- international thing going on trying to solve these issues. Where are things heading next? You mentioned AI. Uh, what's the potential role of other technologies to improve, um, health and outcomes?

    2. CT

      Well, I think one, uh, thing that's very exciting is, is gene therapy, right? So we talked about GLP-1s and how it's mega-dosing, super physiologic. Um, it's not nutrient responsive. There's a, a new, a, a company working on a new approach, which is a gene therapy, and I was involved in the very early work for this. And basically what they're doing is they've, they've, uh, developed a, uh, a viral vector, right, that has the gene for GLP-1 in it, and they're using the promoter for, uh, uh, the beta cell insulin gene, right?

    3. AH

      Mm.

    4. CT

      So basically, when a, a patient would, uh, secrete insulin in a nutrient-responsive way, they're simultaneously re- secreting GLP-1.

    5. AH

      These viral vectors are, um, they're a beautiful tool of vi- of, um, biology where you can put some genetic cargo into a virus that doesn't cause any problems but allows for stable expression of and the production of certain proteins in a cell. So how are you getting into the pancreas? Are you injecting it through the skin?

    6. CT

      Correct. No.

    7. AH

      Uh...

    8. CT

      So we actually are using endoscopic ultrasound. So you know, that same device we developed to actually, you know, biopsy the pancreas, we're now using something similar to actually treat. And you can, you can ablate tumors with energy as well. Uh, people are using electroporation to cause apoptosis. They're using thermal means. But you can also inject something, fine needle injection, right? So and we're injecting the, the, the viruses basically into the tail of the pancreas. Now, you wouldn't want to just take this intravenously 'cause it could end up in other tissue, right?

    9. AH

      Mm-hmm.

    10. CT

      We've done a lot of work to make sure those things stay in the tail of the pancreas, too, right? We've done a lot of animal studies where we've injected it, and we make sure. We use, you know, green fluorescent protein, make sure it doesn't end up in areas it's not supposed to be.

Episode duration: 2:27:53

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