215 - The gut-brain connection | Michael Gershon, M.D.

1. 0:00 – 0:11

   Intro

   1. PAPeter Attia0:01

      [upbeat music]

2. 0:11 – 3:49

   Setting Expectations and Introducing Dr. Gershon

   1. PAPeter Attia0:11

      Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you wanna take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you wanna learn more now, head over to peterattiamd.com/subscribe. Now, without further delay, here's today's episode. My guest today is Dr. Mike Gershon. Mike is a Professor of Pathology and Cell Biology at Columbia University, where his research focuses on the neural control of the gastrointestinal tract and the role of serotonin in the gut as a neurotransmitter. Mike earned his medical degree from Cornell University, followed by a postdoctoral fellowship at Oxford. Mike has received numerous awards and honors over the years, published hundreds of peer-reviewed papers on the nervous system, and even authored a book on the role of the brain and the GI system. This episode's different from, I think, a lot of our episodes. A-and truthfully, I think it comes across more as a bit of a med school lecture, which is kinda how it felt to me. It was, you know, really interesting but I think at the surface doesn't really come across as highly applicable. And I think the reality of it is you just sort of have to get through some of the embryology, anatomy, and neurophysiology of the gut and the brain to kind of understand how these things coexist. So I just wanna be honest and set expectations. If you're coming into this thinking that this is going to be a podcast that's about how to eat this and not that and affect your gut biome, i-it's really not about that. This is a much more basic discussion, and I mean basic not in simple, but I mean basic in more elemental explanation of how this system works. And truthfully, I learned a lot in this episode, much more than I normally do. A lot of times I go into podcasts kind of knowing the subject matter pretty well and maybe increasing my knowledge by 20% or something like that, but I think this was pretty different. So I think what I would just say is rather than give you a blow-by-blow of everything we talked about here, which would probably take me [chuckles] 20 minutes, I would say go into this assuming you're not gonna know much of what we talk about, and you'll come out of this with a much greater appreciation for how your gut and your brain are connected. And unfortunately, I think we're only now beginning to think about how to translate that to clinical utility. So in other words, I think that we don't yet have all of the insights. I don't come away from this episode saying, "Oh, all you need to do is eat this and your gut's gonna be healthier, and if your gut's gonna be healthier, then your brain's gonna be better," or vice versa. So maybe you'll come out the other end of this podcast feeling like you've got it figured out. I certainly don't. But nevertheless, I feel like I have a much better foundational knowledge to evaluate half of the snake oil stuff that is out there, which, I mean, I gotta be honest with you, most of what's out there on this topic is utter nonsense. Commercial tests that promise miracles that don't make any sense and supplements that just don't make any sense, and I, I think you'll come away from this kind of understanding how difficult it is to try to make the claims that are out there. So without further delay, please enjoy my conversation with Dr. Mike Gershon. [upbeat music] Hey, Mike. Thanks so much for making time to speak with me today about a, a subject matter that I know very little about but know enough to know that it probably matters, and I think that's why we're gonna talk about it.

   2. MGMike Gershon3:47

      Okay. I'll do my best.

3. 3:49 – 12:54

   The Gut as Internalized Outside Space and Its Embryology

   1. PAPeter Attia3:49

      Let's kinda start with what is it that has brought you so much curiosity in an area over what I'm guessing 60 years now is probably how long you've been studying the GI system?

   2. MGMike Gershon3:59

      Yes. I guess that shows you it's a very difficult subject because I've been studying it for 60 years and there's still more to study. In other words, I haven't gotten very far. [chuckles]

   3. PAPeter Attia4:10

      Or as the saying goes, the further you get from shore, the deeper the ocean gets, right?

   4. MGMike Gershon4:15

      I love that. Yes. I haven't heard that before.

   5. PAPeter Attia4:18

      You know, this is one of those subjects that-- and I've been thinking a lot about this in trying to figure out how to frame our discussion today because there's just so much fundamental foundational knowledge that I think is necessary to at least have a basic understanding of before we can get into kind of the nuanced stuff around the GI system. So does it make sense to maybe just start with some of the real basics of the human GI system, including, frankly, its embryology, anatomy, vascular supply, and ultimately I think we're gonna wanna talk, of course, about its nervous system, which is quite distinct and unique relative to even the peripheral nervous system. Would that be a reasonable place to start?

   6. MGMike Gershon5:05

      Absolutely it would.

   7. PAPeter Attia5:07

      All right. Well, let's start with the embryology of this. So what is it that takes place during our development as embryos that leads to this system of the gut?

   8. MGMike Gershon5:18

      Well, before I mention exactly what that is, let me just define it because I think that some people don't really know what we mean by the GI system. So basically, it's a tube. It begins at the mouth, and it ends at the anus. And as T.S. Eliot said, "We are hollow men," and I will add, "And women." So the inside of the GI tract is really outside the body. It's internalized external space. If you bleed into your GI tract, you lose blood. It's no longer in you even if you can't see the blood. So one of the major crises in medicine is hidden bleeding in the GI tract. Which can be very damaging even if you don't see any blood. The inside of your gut is outside of your body, and as such, you can have, and you do have inside the gut, space for the existence of a community of extra organisms that is immense. And so the inside of your gut is dangerous and has to be kept separate from you. So it's a major problem for the GI tract to keep a barrier and a surface to defend the body and yet allow food to be digested and absorbed and foodstuff to come in. So it has to maintain a communication with the lumen, which is what we call the inside of the GI tract, and yet at the same time be protected.

   9. PAPeter Attia7:08

      That's a really good point, Mike, which is that we think about this all the time when we think about our skin, which is the other part of us that is exposed to the outside world, and I think most people would be familiar with how many bacteria we have colonizing our nasal passages, skin surface, et cetera. I guess most people would probably understand that bacteremia is a bad thing. When bacteria enter our body, and they can do so through many of these pathways, it's problematic. But you're right in that the GI tract has a particularly unique challenge, which is it must still do a lot of transmission across its surface, obviously all of nutrients. In that sense, for example, the respiratory system only has to be serving for gas exchange. And not to minimize that, but you could make a case that that's an easier problem to solve to allow gases to exchange but not to allow organisms to go through. So I think that's a very interesting way to begin this discussion.

   10. MGMike Gershon8:13

       Of course, I don't want to denigrate the importance of the respiratory tract in an age of COVID. Let me tell you, it's important that gas exchange be easy and proper. Anyway, to get back to the GI tract, the gut has a further problem in that the food we eat is not ready for absorption. It doesn't come in. Food that you eat has to be digested, so that you eat complex products, and then you have to digest it into small molecules that can be absorbed, so that not only does the gut have to absorb a variety of things, it has to have a particularly awful witch's brew to turn the same kind of thing that we're made of into juice, essentially break it down without dissolving the body. The lining of the gut is absolutely remarkable.

   11. PAPeter Attia9:10

       So it's complex molecules that are not sterile as well entering a non-sterile environment, and somehow we have to only allow sterile nutritional building blocks to move across the border.

   12. MGMike Gershon9:23

       Yes, and those nutritional building blocks have to be made from the same kinds of things that we're made out of, which we have to break down and digest.

   13. PAPeter Attia9:33

       Without breaking down ourselves.

   14. MGMike Gershon9:34

       Correct. So we don't want to self-digest. It's a major problem, and the gut-

   15. PAPeter Attia9:39

       Yes

   16. MGMike Gershon9:39

       ... manages to solve all that. Now, you asked where it comes from. Well, during development, the body forms a disc, a flat disc, and that disc undergoes a series of folds from head to toe and from side to side. And the lateral or side folding produces the tube from which the gut forms. And so the flat disc folds around to create an internal space, and that tube becomes the gut.

   17. PAPeter Attia10:15

       How many weeks, can you remind me, Mike, post-fertilization does that fold take place?

   18. MGMike Gershon10:20

       The folding takes place during the first trimester, and the gut is fully developed during the second trimester and is between s- the second and the third trimester when you're born. The gut is modeled and achieves its ability to do the kinds of thing that we were just talking about, digest and absorb. The first part of development is called embryogenesis. That is the fertilized egg forms the disc, the disc folds, the organs of the body form, and that's the embryonic period. The fetal period follows that, and the fetal period models the organs into their final, or not necessarily final 'cause some development continues to take place after birth, but appropriate development so that it becomes functional enough to support a baby.

   19. PAPeter Attia11:26

       In my recollection, which is about 26 years old now, is that when that tube, that fold turns into the tube which will become the entire length of the GI system from, as you said, mouth to anus, there are also these little out-pouchings that come along later that become things like the pancreas and the bile duct and things like that, which form other things that drain into the GI system that obviously perform essential functions for digestion.

   20. MGMike Gershon11:53

       Yes. That same fold gives rise to lots of things, some of which drain into the gut, like the pancreas, the gallbladder, which you mentioned, but it also forms the lungs, which do not drain [chuckles] into the GI system, and the liver Which has a component that drains into the gut through the bile system, but those are all derivatives of the gut. So the foregut forms the stomach, the first part of the small intestine, the lungs, the pharynx, pancreas, gallbladder. The midgut is the business of small intestine and the first part of the large intestine, and the hindgut is the end of the large intestine.

   21. PAPeter Attia12:40

       And my recollection, Mike, was that the foregut, midgut, hindgut basically tracked with the three vessels coming off the aorta, the celiac, the superior and inferior mesenteric. Is that correct?

   22. MGMike Gershon12:53

       That is correct.

4. 12:54 – 16:26

   Blood Supply and the Portal System

   1. PAPeter Attia12:54

      So maybe tell folks a little bit about that blood supply, what makes it unique, which is, of course, we have a portal system, which is very important. We'll go from there into the nervous system, which is perhaps the most complicated of the bunch.

   2. MGMike Gershon13:07

      As you said, the foregut is defined as the part of the gut from the celiac artery. The celiac artery is the first of the, or the most rostral or anterior or-

   3. PAPeter Attia13:21

      Closest to the head.

   4. MGMike Gershon13:22

      Yes. I'm trying to put it into terminology that the entire world can understand. There is also the terminology that the aficionados understand. So the celiac gives rise, or the foregut, the celiac branch supplies the pancreas, the stomach, the first part of the duodenum, and the liver, and the gallbladder. The superior mesenteric artery supplies the midgut, and that's the longest part of the gut, and that goes roughly to the mid-transverse colon. The colon has three parts. It folds. It has an ascending colon, a transverse colon going sideways, and a descending colon, which goes down to the rectum and anus, which is out. The inferior mesenteric supplies the end of the gut. When the celiac gives rise to the stomach and first part of the small intestine's arterial supply, that then breaks into capillaries, absorbs materials from the gut. Those capillaries drain into veins in the gut, and in a unique way, those veins then form large vessels, which then move into the liver. They then break into capillaries, small vessels within the liver called sinusoids. So the venous system that supplies the liver is actually acting like as if it were an artery, but it begins in the gut. And so the liver depends for its oxygen on blood that the gut has had a first crack at. And to keep the liver going, it gets a second arterial supply from the hepatic artery so that it gets a little bit of arterial blood. And basically, the liver is perfused with blood coming from the gut, and when it's about to asphyxiate, a sphincter shuts that down, opens up, and it gets a breath of fresh air or fresh blood and gets some oxygen, and then it goes back to dealing with what it gets from the gut. And the reason it does that is the liver is the first step in the body's ability to use the nutrients that the gut absorbs. So when the gut absorbs fatty acids, the liver turns them into chylomicrons, which can go out and supply energy to the body. So the liver is a major center of metabolism working on products from the gut, so it gets the first crack at what the gut has absorbed.

5. 16:26 – 26:56

   The Enteric Nervous System: The Second Brain

   1. PAPeter Attia16:26

      Now how about the nervous system of the gut? How is the gut innervated?

   2. MGMike Gershon16:31

      Well, as you said, and I'm glad you've given your audience a warning, it's complex and different. The gut has its own intrinsic nervous system, and I've called that the second brain, and that's the title of the book, by the way. And the reason I called it the second brain is that like the brain in the head, the nervous system of the gut is able to function and control reflexes and behavior independently of any influence from the brain or spinal cord. So it is the only nervous system of the body that can work on its own. So if you completely isolate the gut from the brain and the spinal cord, it will function. You're not dead. Years and years ago, in the days when peptic ulcers were thought to be psychogenic, surgeons used to cut the vagus nerves, which are the major conduits that connect the brain and the gut. And after they cut the vagus nerves, the gut continued to soldier on, as it would have to. Unfortunately, it never did all that much to fix peptic ulcer disease, and that turned out to be because peptic ulcer disease is mostly an infectious illness caused by Helicobacter pylori.

   3. PAPeter Attia18:07

      So you're saying before the discovery of H. pylori, it was believed that stress was driving peptic ulcer disease. And the idea was that the central nervous system would communicate the stress to the gut via the vagus nerve.

   4. MGMike Gershon18:25

      That's correct. Now, that wasn't all wrong. The central nervous system can communicate stress to the gut via the vagus nerve, but that was not the cause of peptic ulcer disease, and it did help to show that the gut could, in fact, be cut off from the brain and still work. But that observation was made long ago. The nervous system of the gut has been known to be present for a long time. It was discovered about the time of the American Civil War. Auerbach in Germany noticed this extremely large nervous system in the human gut at that time. He didn't know what it did, but later, around the turn of the last century, that is 19th to 20th, in what I know to have been a very cold, chilly laboratory in England. And the reason I know that is I've worked in England. I did my post-doctoral training there. Laboratories were not heated even when I was there. We used to crack the ice off the organ bath to get started in the morning, [chuckles] and I'd wear gloves with just the fingertips open so you could do experiments. Anyway, at that time, Bayliss and Starling cut all the nerves to the intestine of a dog.

   5. PAPeter Attia19:52

      This is the same Starling from whom we have Starling curves in cardiac physiology?

   6. MGMike Gershon19:57

      That's the Starling. And so when they cut all the nerves to the gut and then increased pressure inside the gut in the lumen, the gut would respond with the stereotypic behavior of oral contraction, anal relaxation, that they called the law of the intestine, which was a name that I liked very much. It sounded very poetic in a, in a sense. Seventeen years later, while armies were paralyzed during the First World War across trenches that cut Europe from the Swiss border all the way down to the, uh, English Channel in France and Belgium, behind the lines in Germany, another German scientist by the name of Trendelenburg had tuberculosis, and that kept him out of the army, even the German army at that time. But he had to keep busy, so he strung up a loop of guinea pig intestine in vitro, that is in a test tube, on a J-shaped tube, and he blew into the J-shaped tube, which raised the pressure inside the intestine, very much like Bayliss and Starling had done. And he found that even in a test tube, when he did that, the gut blew back at him. And it was a very profound observation because it showed that with nothing there but gut, the gut could respond, sense the pressure, and show a coordinated wave of activity in response to it, indicating that the intestinal nervous system is able to function independently of the CNS, of the central nervous system. No other nervous system outside the CNS can do that, and even the spinal cord can't do that. It works in conjunction with the brain.

   7. PAPeter Attia21:59

      How preserved is that, Mike, across other species? Is that kind of a universal finding?

   8. MGMike Gershon22:05

      Yes. It begins with a little organism called amphioxus, which undergoes metamorphosis, turns into a vertebrate. So it's a vertebrate invention, and all vertebrates have it. You do not find it in invertebrates. So it's a vertebrate invention, and it gets more complex as vertebrates become more complex. So a fish has only one layer of enteric nervous system. Humans have two. Actually, some people would say three.

   9. PAPeter Attia22:39

      And the two that we have are between which layers? I guess we didn't really finish our GI anatomy. So when you go from the lumen at the very inside all the way out, you have a mucosal layer, a submucosa, a muscular layer. Is that where these different bundles live?

   10. MGMike Gershon22:57

       Yeah. So the lining of the gut is called the mucosa. It has a superficial lining that is in contact with the lumen called an epithelium. Underneath that is a loose nervous system called the lamina propria, but together, that's the mucosa. Below that, there's a dense layer of connective tissue, which allows gut to be used for stringing tennis rackets, allows gut to be used as suture material. It's tough. You can't pull it out. The next layer is a circular layer of smooth muscle, another layer of smooth muscle, a second one called the longitudinal layer, and then if it's in the peritoneal cavity, another layer of very thin epithelium. The major parts of the nervous system of the gut are the submucosal plexus, which has the eponym Meissner, but it's submucosal plexus, and that's in that dense layer of connective tissue, and that's the smaller of the two. The larger one, by far, is the myenteric plexus, and that is in between the two layers of smooth muscle on the outside of the gut. The two plexuses communicate with one another, and they both really do get input from the central nervous system and speak back to the central nervous system. So although they can function, as I've been emphasizing, independently of control by the brain, in practice they don't. They communicate, and there is constantly a bipolar or two-way communication between the brain and the gut. The gut receives input from the brain and sends back information to the brain. And in that function, bidirectional communication, the brain acts very much like a CEO. That is, it gives general commands. The detail of what the gut actually does, that behavior is controlled by the bowel itself.

   11. PAPeter Attia25:24

       Let me try to summarize that. You have these two muscular walls. One of them runs longitudinally, so runs in the direction of the lumen, and one runs orthogonal to that. It runs circularly. This is one of the things I remember from anatomy was that you have these things where if the circular inner layer contracts, that shrinks the lumen, and the longitudinal one, as it contracts, shortens it along its long axis. And I think that's what permits this remarkable peristaltic rhythmic contraction of the gut.

   12. MGMike Gershon25:58

       Yes. I can talk to you about the behaviors of the gut, but the behavior of the gut is not so simple as to have just one peristaltic movement. When you look at it, it seems to be moving rhythmically, but it's much more complicated than that. It doesn't do that all the time.

   13. PAPeter Attia26:17

       Interesting. So that first part of the enteric nervous system, which is the myenteric plexus, sits between those two layers, correct?

   14. MGMike Gershon26:26

       That's correct, yes.

   15. PAPeter Attia26:28

       And then beneath those muscular layers is when you get into that very tough submucosal layer, and it's between that circular muscular wall and the submucosa that you have the submucosal plexus.

   16. MGMike Gershon26:43

       That's absolutely right.

   17. PAPeter Attia26:44

       And then, of course, inside the submucosa you have the mucosa and then ultimately the lumen on the very inside with the enterocytes that form the endothelial lining of the gut.

6. 26:56 – 34:26

   Epithelial Turnover, Colon Cancer and Cholera

   1. PAPeter Attia26:56

      Give me a quick sense of the epithelial turnover. What is the, I don't know, median residence time of an epithelial cell in the gut?

   2. MGMike Gershon27:04

      They vary depending on the type of epithelial cell, but it-- you turn the gut, the epithelium over about once a week.

   3. PAPeter Attia27:12

      Interesting. And when you say it varies, I assume you mean from, say, the proximal jejunum to the ileum to the colon. Is that what you mean in terms of location?

   4. MGMike Gershon27:22

      No. What I was talking about is that you have certain cells in the lining of the gut, such as a cell called the Paneth cell, which is in the base of the crypt, which is getting into the weeds here, but it's a part of the folding of the lining of the gut. But the Paneth cell has two major functions. One is that it's defensive, and it puts out a number of antibacterial proteins that keep the lining, particularly of the small intestine, sterile or close to sterile. Only a few thousand microorganisms [chuckles] per cubic milliliter. But the, um, large intestine doesn't have those, but it has cells that put out the equivalent kind of antibacterial product that helps to fend off the bacteria from getting too close to the lining of the gut. The other function of the Paneth cell is to nurse the stem cells that turn over all of the cells. So the Paneth cell lasts perhaps three weeks. You also have in the gut endocrine cells. These are enteroendocrine cells that produce hormones that are in the lining of the gut, and they're a little bit longer-lasting. The enterocytes that you talked about turn over very rapidly.

   5. PAPeter Attia28:52

      Well, we're gonna come back to those endocrine cells pretty soon, 'cause that's a very big part of this gut-brain connection I want to explore. I do have kind of a random question for you though, Mike, which is in some ways it's not surprising that the colon is so susceptible to neoplasia, to the formation of cancer, because it has at its surface a cell that turns over so frequently, and therefore it's turning over constantly, and as a result you probably have more and more chances for genetic errors of replication that produce mutations that are oncologic. I find it interesting that the small intestine, which presumably turns over at roughly the same pace, is almost void of cancer. Do you have a thought as to why that's the case?

   6. MGMike Gershon29:43

      Well, people have speculated on that. One part of the answer is that microbiome to which the large intestine is exposed is orders of magnitude larger than that of the small intestine. And the other part of it is that the products that sit in the lumen of the large intestine sit there for much, much longer. Small intestine digests food, and it just goes by very fast. So in terms of being exposed to environmental toxins or toxins produced by organisms or toxins that are split off from what you eat, the large intestine, which acts as a sewer, really is exposed to very much more.

   7. PAPeter Attia30:32

      My recollection is most of the nutrient absorption is taking place in the small intestine and that the large intestine is mainly reabsorbing water. Is that right?

   8. MGMike Gershon30:42

      Yes, but not quite, because what the large intestine does is conserve sodium. So it absorbs sodium and secretes potassium, and water follows the sodium as it's coming back into the body. So the colon acquired that function, and it enables organisms to live on land. When organisms lived in the water, conserving sodium and water was not such a problem. Living on land makes it so. The bulk of the water that the gut absorbs, however, is not in the large intestine. It's done in the small intestine together with the bulk of most of what else you absorb. Still, the final hundred milliliters or so per day of what you absorb is polished off in the colon, and it is important in maintaining the body's fluid content. If you lose it, as one does in cholera, where cholera toxin turns sodium absorption into chloride secretion, water flows out, and you can die of dehydration in about four hours, and people do with cholera. So it's a great plague. Perhaps three million people a year die of cholera even today.

   9. PAPeter Attia32:10

      Three million people a year die of cholera today?

   10. MGMike Gershon32:13

       Correct.

   11. PAPeter Attia32:14

       I had no idea. Where is this primarily happening? Is this in Africa and Asia?

   12. MGMike Gershon32:18

       At the moment it is, but there have been major league outbreaks in our hemisphere. One began off the coast of Peru with contaminated crab. That led to cases that were as far north as New Jersey as people ate contaminated crab. Haiti, of course, is the most famous one. There was a great earthquake in Haiti.

   13. PAPeter Attia32:44

       Yep.

   14. MGMike Gershon32:45

       Destroyed a lot of their infrastructure. They had a group of peacekeepers from the United Nations from Nepal that was stationed there, and they brought cholera with them, put it into the water system of Haiti. It got into the rivers and streams and is now endemic in Haiti. So it reduced the population of Haiti considerably. But it is mostly in Asia and Africa.

   15. PAPeter Attia33:12

       Are there direct treatments for it, or is the only treatment supportive care to prevent dehydration?

   16. MGMike Gershon33:17

       Well, it's a very simple illness. All one has to do is keep track of the water. So you put a patient on what is known as a cholera cot, a gurney with a hole in the middle for the anus to be positioned over. You put a bucket under it. The nurse puts a ruler into that bucket periodically to see how much fluid is coming out. You replace it intravenously and orally. The great life-saving discovery was that although cholera blocked the absorption of sodium, it does not block the absorption of glucose in the small intestine. And so adding a little bit of sugar to the fluid that you're using for oral rehydration has saved countless millions of lives, just that simple thing. So antibiotics have no use at all in cholera. Zero.

   17. PAPeter Attia34:15

       Does the immune system basically, if given enough time, fight it off, and all you're doing is just supporting the hydration status of the person until their immune system kicks in?

   18. MGMike Gershon34:25

       Correct.

7. 34:26 – 43:33

   Intrinsic vs. Extrinsic Innervation, Pain and Gut Behaviors

   1. PAPeter Attia34:26

      I want to go back to something you said earlier. You made a point to talk about the intrinsic innervation, and I realize that there are gonna be people listening who might not know the difference between intrinsic and extrinsic neurons. Can you explain what that means in the context of the gut, please?

   2. MGMike Gershon34:42

      So the intrinsic nervous system of the gut is a term representing the nerve cells that live within the gut. We've described them, the two plexuses. The extrinsic innervation includes the brain, which sends fibers to those neurons, and the sympathetic nervous system, which projects from outside the gut into it. And it also includes the spinal cord and the ganglia associated with the spinal cord, sensory ganglia, and dorsal root, which provide a sensory innervation of the gut. So those are all extrinsic nerves. Intrinsic means that the cell body of the nerve cell resides within the gut. Extrinsic means that the cell body is outside the gut, wherever.

   3. PAPeter Attia35:40

      Mike, one of the things I'm sure anybody listening to this can appreciate is the incredible pain that one experiences with distension of the bowel. I used to be a general surgeon, so when patients present with bowel obstructions, it can be as painful as a bowel perforation, and it's so important to be able to put a nasogastric tube in them and decompress them. And again, even if you haven't had a bowel obstruction, just if you're bloated or something like that, it can be incredibly uncomfortable. So explain to people how that pain of distension in the gut is being communicated to their brain, where they're obviously conscious of the discomfort.

   4. MGMike Gershon36:17

      Let me make two points. One is that essentially pressure of the kind that which you're speaking, whether very severe, as you've mentioned, or much less so, the only way the gut feels pain is in response to dilatation or pressure. You can cut the inside of the gut with impunity. So surgeons are constantly doing that, taking biopsies from inside the gut, and that can be done without anesthesia. So it's differently innervated from the point of view of pain than the skin, for example. The skin feels pressure, but it's much less of a painful stimulus than cutting. The gut is exactly the reverse. Most of the fibers that get excited when you press increased pressure are located in the dorsal root ganglia. Those are pain fibers that relay the signal to the brain by way of the spinal cord. The vagus nerve has some pain, but not much. Mostly, the vagus nerve carries information back to the brain that has to do with signaling what is called homeostasis, which means we don't know for exactly what it all is, but you need it.

   5. PAPeter Attia37:44

      [chuckles] Before we leave kind of the anatomy and innervation of the gut, you mentioned the CNS functions kind of like the CEO, providing broad instruction, but not necessarily minutia-driven operational instructions. Can you give an example of what type of information is conveyed by the CNS and how that information is enacted locally?

   6. MGMike Gershon38:12

      Let me give you an illustration this way. One of the things we do as scientists is depend for our funding on the NIH, and we send in grant applications in which we try to give our research its best look, undergoes peer review, and then the government decides on the basis of the peer review on two levels whether to fund it or not. So when I wait to hear how my grant has done on peer review, I become acutely aware of the kind of effect the CNS can have on my gut. And after three trips to the john, I will go and open the computer and find out. So what I'm saying is most people can resonate with that because they felt it, this feeling of butterflies, this feeling of tension-induced diarrhea. That is all coming by way of the CNS. Similarly, some people, when they're frightened or traveling, just completely lose the ability to defecate. They become constipated.

   7. PAPeter Attia39:29

      I always assumed that that was due to the dehydration of air travel, but it sounds like you're saying there's more to it.

   8. MGMike Gershon39:35

      There may be, yes. I think there is. Well, what it seems to come to is, for example, the sympathetic nerves can slow the gut and make it less likely to defecate, and that is in response to, as opposed to anxiety, to true fright. So for example, if you're fleeing a foxhole because the enemy is coming, it's best if you don't have to stop to defecate along the way.

   9. PAPeter Attia40:07

      You've alluded now to the sympathetic and parasympathetic overtone of the CNS. So it communicates that via acetyl-CoA and acetylcholine, things like that. But at the local level, how does the gut receive that message? And then let's use the example of anxiety in-induced diarrhea. The actual action taken by the gut is presumably more rapid peristalsis and less absorption.

   10. MGMike Gershon40:34

       That's correct, and that's all has to do with the enteric nervous system functioning. One theory, which I believe, is that there are nerve cells in the gut called command neurons, and they receive the input from the CNS. So it turns out that the number of fibers in the vagus nerve that are running to the gut are pretty small in humans, three to five thousand, it's been estimated. And the number of nerve cells within the gut are in over a hundred million.

   11. PAPeter Attia41:11

       So the intrinsics outnumber the extrinsics by three orders of magnitude, if not more.

   12. MGMike Gershon41:17

       So that raises the question, how do these nerve cells control it? As I've said, as a CEO, they can get to command nerve cells and start reflexes going, keep things moving more rapidly. The gut has a number of different behaviors. It's not just propelling at all time. If the gut were propelling, as I described it, with oral contraction, anal relaxation, as it's capable of doing, then social discourse of the kind we're having right now would become impossible. The gut has to sometimes stop.

   13. PAPeter Attia41:54

       Mm-hmm.

   14. MGMike Gershon41:55

       And so one type of behavior is just essentially paresis. The gut stops moving. A second type of behavior that the gut shows is mixing, in which it allows the enzymes that it puts out to do digestion. And anybody who's ever taken time in an organic chemistry laboratory will tell you nothing very much happens unless it's stirred. So the gut has a mixing process in which it's just goes back and forth, back and forth, no propulsion. And then it's able to sense what goes on, and when digestion has occurred sufficiently, it propels it on. It can also, during night while you're sleeping A cleaning process goes through the gut in which a wave begins at the stomach, goes down [chuckles] the small intestine, down the large intestine, and cleans the gut out. Opens sphincters so that things that are-- would ordinarily be much too big to pass can go through. So a little kid can swallow a paper clip, a dime, sometimes an open pin, and all those things are passed. And miraculously, I don't know how the gut manages it, but if an open safety pin goes in, somehow it manages to propel it all the way down [chuckles] with the small end down, and it almost never gets stuck.

8. 43:33 – 51:14

   Appetite, Satiety, Ghrelin and Gastric Emptying

   1. PAPeter Attia43:33

      So let's pivot a bit to appetite. Obviously, the gut plays a very important role in the regulation of our appetite, and this, I suspect, is an area where the gut and the brain are in a high level of communication. Can you walk us through what that looks like? And let's assume we're talking about this in a non-pathologic state, 'cause obviously there's gonna be things that I assume can hijack this process.

   2. MGMike Gershon43:58

      A number of factors play into it. Distension of the stomach being one, so that as the stomach is pushed out, it tends to cause satiety and decrease your urge to eat. Another factor is not the level of blood glucose, but the rise of blood glucose, the ascent of it. And these factors are sensed, one, by receptors within the gut, which send signals to the brain, and the other are cells within the brain that are chemosensitive and detect nutrients within the gut. Another factor which you alluded to before are the enteroendocrine cells within the gut, which make hormones such as cholecystokinin, which can signal to the brain by going through the blood-brain barrier to be received by neurons leptin within the gut. So there are a large number of hormones, hormone receptors in the brain that can trigger your urge to eat, as well as nutrients that you absorb, as well as distension of the bowel itself, so that the gut has receptors in it and the brain has signals within it that trigger the urge to eat.

   3. PAPeter Attia45:32

      So basically, mechanical and chemical are the two big means through which this is communicated?

   4. MGMike Gershon45:37

      That's correct. That summarizes it well.

   5. PAPeter Attia45:39

      So the mechanical are both in the actual stomach but also in the small bowel?

   6. MGMike Gershon45:46

      Yes, to a lesser extent.

   7. PAPeter Attia45:48

      And those are transmitted back from the gut via the vagus nerve?

   8. MGMike Gershon45:53

      Correct.

   9. PAPeter Attia45:54

      The glucose rate of change as opposed to absolute level, is that directly sensed in the CNS?

   10. MGMike Gershon46:02

       Yes, it is.

   11. PAPeter Attia46:03

       And that's fine because, of course, glucose easily traverses the blood-brain barrier, so the gut doesn't need to be involved in that decision.

   12. MGMike Gershon46:10

       The blood vessels that provide blood to the brain have transporters that allow certain chemicals from the gut, such as leptin and cholecystokinin, to be transported so that they can affect the CNS directly.

   13. PAPeter Attia46:29

       Where does ghrelin fit into this?

   14. MGMike Gershon46:31

       Ghrelin wor- is another hormone from the gut that works in the opposite way to what we've been talking about. I've been talking about things that decrease food absorption. Ghrelin is a gut hormone that promotes it.

   15. PAPeter Attia46:46

       So what amplifies ghrelin?

   16. MGMike Gershon46:49

       You mean what makes ghrelin be secreted?

   17. PAPeter Attia46:51

       Yes.

   18. MGMike Gershon46:52

       Well, there are certain chemicals in food that you eat that can do that. Mostly it's nutrients that come into the body that suppress, like amino acids and fatty acids can suppress ghrelin secretion.

   19. PAPeter Attia47:07

       Does that mean that ghrelin's natural state is to be secreted and it's the presence of nutrients that simply turn that down?

   20. MGMike Gershon47:14

       Yes. It's secreted at a constant rate, and it can be upped or downed so that in- inhibiting it is important to prevent the development of ghrelin effect.

   21. PAPeter Attia47:28

       And what about the type of meal? So if you took, you know, and this is the kind of stuff that's done, of course, all the time in research models. I think Rudy Leibel and Mike Rosenbaum have done a number of these experiments where you'll take mixed meal shakes versus solids. What are some of the differences in the way that those things would affect satiety, and is it all done purely through change in the speed of absorption, or are there other factors between liquids and solids that might factor into that?

   22. MGMike Gershon47:54

       Well, there are a number of factors. I just want to mention while we're on it that Rudy Leibel is just across the street. He's a colleague over here, uh, of mine at Columbia. The rate at which the stomach empties varies tremendously depending on what you put into it. So for example, if you just eat a saline meal, the stomach will empty much more rapidly than if there's protein in it, and even protein will empty much more rapidly than if there's fat in it. So the stomach senses the nutrients, and the speed at which it empties regulates the dilatation of the stomach and the signal that the stomach is sending back to urge satiety on the brain, which means that if you're eating protein and fat- You will reach satiety much sooner than if you're eating just salt and sugar. In terms of solids, solids do the same. Particles can't get through the pyloric sphincter unless they're ground down to be millimeter or less in diameter, so that only tiny things can get into the small intestine. So solids will delay gastric emptying. The stomach has a particular form of behavior which is amazing when you watch it, but one part of the stomach contracts massively and suddenly and forces the bolus that's in the stomach up against the pyloric sphincter, which is the exit of the stomach, which is shut tight, and this ramming action breaks up solids into the small particles that can get through. At the end of it, if you still have some solids that are too big to reach that level, they can get through, but during sleep when cleaning process operates and then the sphincters open. So solids will slow the emptying of the stomach, and anything that slows the emptying of the stomach will tend to induce satiety and reduce the length of time during which you feel hungry and want to eat.

   23. PAPeter Attia50:25

       The point here you make about the particles needing to be sub one millimeter to get past the pylorus is kind of remarkable and gives you a sense of how much mechanical digestion the stomach is doing. I mean, the pH must be helping that, but really there's just got to be a lot of mechanical shearing that goes on of foodstuff, correct?

   24. MGMike Gershon50:44

       Absolutely right.

   25. PAPeter Attia50:45

       The stomach doesn't get its recognition in this story. When you think about how small a sub-millimeter particle is and yet how big things of food that make it into your stomach are, and to think that it does this without fine instruments, it wouldn't be hard for me to make a bunch of one millimeter pieces if you gave me a knife, but it's doing this basically inside a soft reservoir using contraction and acid.

   26. MGMike Gershon51:07

       And some enzymes. It is a remarkable structure, but you can live without the stomach.

9. 51:14 – 54:23

   Gastric Bypass and Why Liquid Calories Matter

   1. PAPeter Attia51:14

      Given everything we've just learned about the stomach, let's talk about an operation where we bypass it, right? One of the most successful operations for the treatment of both obesity and type 2 diabetes is a gastric bypass. What happens in a patient, and this is kind of a remarkable operation in the sense that in an instant their upper GI tract is rerouted. It's not like they had months and months to adapt to something new. I mean, there obviously is an adaptation post-op, but it's an immediate change. Explain to folks what's actually happening in that procedure and how it might explain some of the benefits we see almost universally in post obesity and post type 2 diabetes.

   2. MGMike Gershon51:56

      Well, for one thing, why does the stomach just put all those little tiny particles through? That's because if they were to get into the small intestine, it would set up a lot of emergency, "Don't do this," kind of apparatus. In other words, satiety stop eating signals go into high gear, and what the gastric bypass is doing is it's triggering that emergency procedure so that you're getting that satiety signal a lot. In other words, the kind of thing that the stomach has evolved to keep in reserve is now coming to the foreground. It's no longer there as an emergency to stop eating because I'm getting overwhelmed with signals. Usually, you get this because people, as in the Roman Empire, when they would overeat, would force the system. The stomach would dilate so much, [chuckles] just overwhelmed the body, and they ignored the signals. And so the small intestine is there to back that up and get them to stop by making eating just so objectionable that it stops. What the gastric bypass is doing is to make eating so objectionable that it stops sooner, and you eat much, much less. That's the goal of it. Another way to do this is to put a band on the stomach and interfere with that process of grinding the food down, so large particles do come through the banded stomach and the same thing happens.

   3. PAPeter Attia53:47

      And that would explain, Mike, why both of these procedures can fail if a patient continues to consume very high calorie liquids.

   4. MGMike Gershon53:57

      That's right. High calorie liquids are the way around it.

   5. PAPeter Attia54:01

      One of the things I always say to people that are trying to lose weight is a pretty obvious insight, but this provides a better mechanistic explanation for why, is try not to drink any calories. Drink water, drink tea, drink coffee, et cetera, but minimize the number of calories that are coming in via liquid, which includes alcohol, by the way.

   6. MGMike Gershon54:19

      Yes. Uh, last I saw, uh, alcohol's a liquid.

   7. PAPeter Attia54:22

      [chuckles]

10. 54:23 – 1:02:48

    Varicella Zoster in the Gut and Shingles

    1. PAPeter Attia54:23

       Let's talk now a little bit about the role of neurodegenerative diseases and the gut. How long have you personally been interested in this connection between diseases of the CNS and the gut?

    2. MGMike Gershon54:36

       Oh, probably about 30 years or so. I've recently become, if I might digress for just a second, even more interested in the sense that I've discovered with my wife that the gut is the source of infection by varicella zoster virus, which is the virus of chickenpox and shingles. And so shingles of the gut can occur. That can be very, very serious.

    3. PAPeter Attia55:05

       So I've never heard of that. Let's give people a bit of background on how varicella-zoster remains dormant after you have chickenpox and comes back as shingles. I think people are probably somewhat familiar with that, but maybe worth re-explaining and then, of course, bringing in this new idea that you've just brought up.

    4. MGMike Gershon55:23

       The word that is generally used is latent rather than dormant, but people get the picture. It's because it's essentially there but not sleeping. It's just quiet. Anyway, so when you get chickenpox, you clear the virus, and it forms what is known as an episome in neurons and just sits there latent without causing infection for years and years and years. And essentially all of us die with the virus that gave us chickenpox. It just stays with you for life. For reasons that are unknown, can only be speculated upon, they reactivate, and reactivation gives rise to the reemergence of active virus, and it always starts in a nerve cell because it's been latent in a nerve cell. That's the site of latency. We know the virus becomes latent when it's in dorsal root ganglia because then it goes down the axon or the, uh, process from the dorsal root ganglion to the skin and causes a rash. And because you have immunity, it stays just in the nerve and in the skin and doesn't give you a systemic disease like chickenpox was because when you had chickenpox, you had no immunity. So it stays localized. And because the nerve cells die and become extremely active and they're pain nerve cells, it can be an extremely painful rash. In 15% of people in which that happens, there's a condition called postherpetic neuralgia or PHN in which pain persists for years that is very difficult to treat, and some people are driven to suicide because of this uncontrollable pain.

    5. PAPeter Attia57:21

       Mike, is that not something that's amenable to nerve killing? You know, for example, they can sclerose the dorsal root ganglion from which the pain is emanating.

    6. MGMike Gershon57:31

       No. That's no good at all. It's pathological pain, and the, the virus isn't there. The nerve cells are no longer causing the pain. It's coming from within the CNS. It's sort of like a phantom limb in which people cut off a limb, and people have the feeling the limb is still there, but it's not. So it's very difficult, as I've said, to treat. There are some drugs that do some good, like gabapentin, but nothing is wonderful.

    7. PAPeter Attia58:00

       What is it about the varicella-zoster virus that produces this very peculiar inability to die even after the immune system gets ahead of it? Back when I was a kid and you were a kid, we all got chickenpox. I think today they even vaccinate kids, don't they?

    8. MGMike Gershon58:16

       Yes. My wife developed that vaccine. She's famous for that.

    9. PAPeter Attia58:20

       Oh, wow. So despite either natural immunity or vaccine-induced immunity, when this virus comes into you, it stays, as you said, and remains latent in the dorsal root ganglion. Why is that the case? Why doesn't the immune system completely eradicate it like it does in virtually every other virus we encounter?

    10. MGMike Gershon58:38

        Because when the virus is in a nerve cell, the immune system can't see it.

    11. PAPeter Attia58:43

        I see. So this is more of an artifact of where this virus likes to spend its time or where it retreats to maybe is a better way to describe it.

    12. MGMike Gershon58:51

        Let's call it a sequestered virus, and it sits as a piece of DNA inside of your body, and your immune system can't see it because it's not expressed on the surface of the nerve cells that have it. The immune system has a very good look at it when it reemerges, [chuckles] and you attack it, kill the cells in which it reemerges, but pain can continue in a small number of people even so. What we've discovered, much to our chagrin, is that the enteric nervous system can be infected by this virus when you have chickenpox or when you get the live virus vaccine. It can establish latency within the intrinsic nervous system of the gut in the enteric nervous system. And when it re-arises, even if it gets killed by the immune system, it's killing nerve cells. And so you get diseases such as pseudo-obstruction in which the gut loses the ability to work and just becomes totally paralyzed or if the virus emerges and gets into the mucosa, the gut can perforate.

    13. PAPeter Attia1:00:05

        And what's the frequency that this happens in?

    14. MGMike Gershon1:00:07

        We don't know. It's just been discovered. The most shocking thing that we've just published on with this is that it gets into the nerve cells and reemerges in the esophagus and causes a disease called achalasia, and the ability of the esophagus to deliver food to the stomach is lost. The esophagus can't open, so you can't swallow at all.

    15. PAPeter Attia1:00:34

        And just to be clear, this can occur during primary infection or reinfection, or is this just during reinfection?

    16. MGMike Gershon1:00:40

        Just during reinfection.

    17. PAPeter Attia1:00:42

        What triggers the reinfection? I mean, I think most people understand that-

    18. MGMike Gershon1:00:46

        If I could answer that question, I believe I could get an all-expenses-paid trip to Stockholm in December.

    19. PAPeter Attia1:00:55

        And if not there, at a minimum, you would probably get free dinner at Red Lobster every Tuesday for the rest of your life.

    20. MGMike Gershon1:01:03

        [laughs]

    21. PAPeter Attia1:01:04

        That's the second prize after the Nobel Prize. Yeah, it's interesting. I mean, we know it's a disease associated with aging, or the reactivation is associated with aging, and we know that things like weakened immune system can see it. I think in the early days of HIV, we would see patients

    22. MGMike Gershon1:01:18

        A weakened immune system is part of it, and that's how you get to aging. That sets the stage. It seems likely that the virus keeps reactivating periodically throughout your life, and that when you have shingles, just exceed a threshold because the immune system has receded just enough to let it out, reach the clinical threshold. That's the idea.

    23. PAPeter Attia1:01:47

        And the current vaccine that we have, Mike, the Shingrix vaccine, the two-shot separated by six months, this has been kind of a step forward, correct?

    24. MGMike Gershon1:01:55

        That has been a giant leap forward. That's been amazing.

    25. PAPeter Attia1:01:59

        And the purpose of that vaccine is just to prime our immune system to the virus once again to either catch it more quickly if it escapes DRG or-

    26. MGMike Gershon1:02:14

        Even more important, the enteric neurons, it's about 97% effective. Remarkable vaccine.

    27. PAPeter Attia1:02:22

        Yeah, I got mine early. I'm not quite 50 yet, but I was like, "Ah, what the heck am I waiting for?" And the other thing I'll tell you is what a kick in the chops that vaccine is. That makes you sick. So I've had my first shot. I'm dreading my second.

    28. MGMike Gershon1:02:34

        Actually, interestingly, the older you are when you get it, the less likely you are to be bothered by the injection.

    29. PAPeter Attia1:02:41

        I'm reaping the benefits of my young immune system as I get butchered by the Shingrix shot.

11. 1:02:48 – 1:09:46

    Autism, the Gut, and the Wakefield Controversy

    1. PAPeter Attia1:02:48

       What about diseases like autism? You know, children with autism seem to have, as the severity of their illness goes up, an increase in the prevalence of gastrointestinal illnesses. How well acknowledged is that? Is that kind of loosely accepted, or is that now becoming more accepted? What does that tell us?

    2. MGMike Gershon1:03:08

       It's so accepted it's right [laughs] .

    3. PAPeter Attia1:03:10

       What can we take from that? What does that suggest potentially?

    4. MGMike Gershon1:03:14

       Well, autism is a disease involving a synap-- probably synaptic transmission. It occurs in the CNS, the well-known behavioral effects. It occurs also in the enteric nervous system with small effects on the GI tract, some of which are constipation, but more frequently diarrhea.

    5. PAPeter Attia1:03:40

       There also seems to be a higher degree of food sensitivities and allergies, doesn't there?

    6. MGMike Gershon1:03:44

       Yes. That's not so well understood, but it does seem to be related to activation of mast cells.

    7. PAPeter Attia1:03:53

       Spoken with many parents of kids with autistic children, and a lot of them are pretty convinced that if they pay more attention to what their kids eat, they can reduce the severity of their symptoms. This would not seem like an entirely unreasonable idea given the simple observation of this association, correct?

    8. MGMike Gershon1:04:15

       It wouldn't seem to be unreasonable. But having said that, I would like to point out to you that there's no regularity to the symptoms that you can point to. It's hard to back it up, and there's-- people have been unable to produce any sort of rigorous background for that, so that when you put controls and constant observation, you just can't document it.

    9. PAPeter Attia1:04:43

       There must be so much variability that it almost seems like you have to be kind of empirical in approach, and probably no, hate the term, but no one size fits all here, which is stating the obvious, I suppose.

    10. MGMike Gershon1:04:56

        I should also point out that the area is a bit fraught because in 1991, a British gastroenterologist by the name of Andrew Wakefield published a study in a large number of children... Not a large number.

    11. PAPeter Attia1:05:14

        Yeah, it was actually a very small number of-- We actually did a podcast on this entire subject matter, Mike.

    12. MGMike Gershon1:05:20

        Oh, did you?

    13. PAPeter Attia1:05:20

        Yeah, yeah. But by all means, go ahead and tell the story, 'cause not everyone will have heard that podcast with Brian Deer.

    14. MGMike Gershon1:05:27

        Oh, well, he, he knows much more about it than I do. But in any case, Wakefield associated it with GI inflammation, and his idea was that if you ate gluten-containing material, you could produce from what you were eating what he called endorphins. That is, you'd eat an opiate-like material. Magically, the enzymes of the digestive tract would liberate opiate-like products. You'd absorb these opiate-like substances, and they would go to the immature developing nervous system and cause autism. That is not the case. And his idea was that if you got measles, mumps, and rubella vaccine, it would cause the defect in the gut, which could lead to the absorption of these products. That was also incorrect. You can't train an enzyme to cut something differently than the way the genes have programmed it to, so that trypsin looks for particular amino acids and cuts proteins there. It doesn't care what kind of endorphin is sitting somewhere else. Nothing can ever make it cut that out. And then when it gets peptides out, peptides are essentially not absorbed. The only thing that's absorbed are amino acids or maybe dipeptides, tripeptides. So tiny little molecules are absorbed.

    15. PAPeter Attia1:07:09

        Yeah. Let's make sure people understand the difference there. Amino acids are the building blocks of peptides. A peptide is a string of amino acids, but the amino acid is the smallest functional unit that makes up a protein. So we have these 20 amino acids, and you can string them together in thousands and thousands to make complex proteins. But a small peptide of nine to 11 amino acids, for example, would be what the immune system recognizes. And what you're saying, Mike, is from a GI standpoint, they have to be even smaller than an immunogenic peptide if they're only sort of single amino acids or maybe two peptides or two amino acids joined.

    16. MGMike Gershon1:07:48

        That's correct. That gets absorbed. But even if there was some miracle happened and they got absorbed, they couldn't get to the blood-brain barrier. They wouldn't, in fact, go past the liver. So I testified actually to Congress on that subject.

    17. PAPeter Attia1:08:04

        Yeah. It's funny. Now that I think about it, Mike, I think you were actually mentioned in Brian Deer's book.

    18. MGMike Gershon1:08:09

        I might have been. There was an exhibit at Science Museum in London called The Autism Files, and I had a section called Mike's Miracles. And Mike's Miracles had to do with the way I was phrasing it at, when I testified to Congress, and I was threatened then by, uh, Congress.

    19. PAPeter Attia1:08:31

        You were threatened?

    20. MGMike Gershon1:08:33

        Yes. I was told that if I didn't recant my testimony, I would be charged with perjury.

    21. PAPeter Attia1:08:40

        I'm not sure I understand.

    22. MGMike Gershon1:08:41

        So I testified at the Congressional Committee on Government Oversight, and the chair of the committee did not like my testimony in a major way. In fact, he had to be restrained from throwing a gavel at me. And after that, when I went cringing into the cloakroom afterward, Congressman Waxman from California came over to me and gave me a high five.

    23. PAPeter Attia1:09:11

        Remind me the name. I've forgotten now. What was the name of the congressman who was adamant that Wakefield was right?

    24. MGMike Gershon1:09:19

        You've got me. I can't believe it. I'm trying to think of the name. I was afraid you were gonna ask me that question. [chuckles]

    25. PAPeter Attia1:09:25

        Yes. Now this is all kind of coming back to me like a horrible, bad dream.

    26. MGMike Gershon1:09:30

        His grandson had autism, and he was sure he got it from his vaccine. He said he could see this wonderful child develop autism before they even got the needle out of his arm.

    27. PAPeter Attia1:09:43

        I know it'll come to one of us as we continue this discussion.

12. 1:09:46 – 1:16:51

    Serotonin in the Gut, SSRIs and the Super SERT Mouse

    1. PAPeter Attia1:09:46

       Let's talk about serotonin before we go further, because serotonin levels are higher in at least a subset of kids with ASD. And most people, when they think of serotonin, they associate it with a hormone in the brain that is responsible for mood. Can you say a little bit more about serotonin and, in particular, the role of serotonin in the gut?

    2. MGMike Gershon1:10:13

       Well, serotonin is a molecule that I've been working on since college. I did my senior thesis on serotonin when I graduated from Cornell in 1958, probably when dinosaurs roamed the Earth and I was young. [chuckles] In any case, serotonin was discovered actually in the gut. Enterochromaffin cells, which are an endocrine cell of the gut, are responsible for making about 95% of the body's serotonin. The brain produces about two to three percent of the body's serotonin. So although the brain serotonin is probably what makes life worthwhile by that is living and is responsible for happiness, among other things, in terms of amounts, it's a little afterthought of evolution. So within the gut, serotonin is made in two places. The bulk of it is made in, as I've just said, in the enteroendocrine cells, which are the small endocrine cells that are part of the GI epithelium. It's a minor component of the epithelium but a major component functionally of what the gut does. About 80% of the endocrine cells make serotonin. The other source is serotonin-containing nerve cells within the enteric nervous system. So it is a neurotransmitter and an endocrine substance in the gut. It's very important in feeling pain in the gut. It's very important in triggering nausea. So in sending signals from the gut to the brain, serotonin is an important transmitting substance. During development, serotonin is very important as a growth factor. The first nerve cells to form in the gut make serotonin. Subsequent nerve cells depend on serotonin, triggers them to develop. So if you knock serotonin out of the nervous system, the gut winds up with too few neurons. It doesn't have enough, and it doesn't work very well. If you knock serotonin out of the epithelium, then there's problems signaling back to the brain, and the peristalsic reflex is impaired. It's not stopped, but it's impaired because the enteroendocrine cells in the gut can trigger peristaltic waves that are propulsive. But it-- if you lose that, then in order to trigger it, you have to press harder and harder and dilate the gut. And get the nervous system to do this directly. It's highly involved within the gut, and it also talks to the immune system, so it triggers inflammation. As you might imagine from the amount of it that's in the bowel, it does everything. It's a pan function, multifunctional molecule.

    3. PAPeter Attia1:13:34

       Now, there's a class of medication, of course, that are used to treat the symptoms of depression and in some cases anxiety, and these medications, SSRIs, prevent the reuptake of serotonin, this neurotransmitter in the brain, presumably leaving more of it around to exert positive effects. What are the effects of SSRIs outside of the CNS? Do they impact the gut specifically?

    4. MGMike Gershon1:13:59

       Yes. They tend to cause nausea by enhancing the ability of serotonin to talk back to the brain to trigger nausea. Drugs that are used in cancer chemotherapy also trigger the release of serotonin within the gut and trigger that reflex. Same one. The SSRIs also first make the gut go a little bit faster, but then when the gut keeps doing that, the receptors, that is the molecules upon which serotonin acts, desensitize. One way they do that is to internalize, and so they can actually block the effect of serotonin in transit. So in terms of motility, they can make the gut go faster, and ultimately they stop the gut and give rise to long-term constipation and have to be stopped. So they're nauseating, they change motility, and during development, if you give them to a, a mouse during fetal development, that is given to the mother during fetal development, you get an abnormal nervous system grow in the mouse's nervous system because of the effect during fetal life.

    5. PAPeter Attia1:15:22

       Are SSRIs contraindicated in pregnancy?

    6. MGMike Gershon1:15:25

       They are used frequently and in large numbers, large amounts in pregnancy because pregnancy is very often associated with depression. Fortunately, most commonly postpartum, but even then it's a problem because SSRIs can be communicated to the, uh, child in breast milk. But there is evidence that a number of conditions are increased, such as irritable bowel syndrome, in the offspring of mothers who are treated with SSRIs during pregnancy.

    7. PAPeter Attia1:16:00

       Is that understood by the physicians that prescribe them? And, uh, obviously there are gonna be scenarios where those risks are worth it if the, uh-

    8. MGMike Gershon1:16:08

       Yeah, people worry about it, but let me tell you, depression is a potentially lethal illness, and if you've got something in which to treat it, sometimes you just have to use it.

    9. PAPeter Attia1:16:23

       Yeah, I just wonder if-- 'cause there are alternatives, right? I mean, SNRIs can also be very efficacious. Presumably, they don't have the same effect.

    10. MGMike Gershon1:16:32

        They do have some of the same effects because the SNRIs, serotonin and norepinephrine reuptake inhibitor, they're just less-

    11. PAPeter Attia1:16:41

        Less serotonin.

    12. MGMike Gershon1:16:42

        Not less serotonin, less selective for serotonin. They include norepinephrine as well, so that doesn't get you anywhere.

13. 1:16:51 – 1:30:38

    Leaky Gut, Tight Junctions and Testing

    1. PAPeter Attia1:16:51

       Let's talk a little bit about leaky gut. This is a term I think a lot of people have heard of, and I think they sort of maybe get the gestalt of. But in the context of everything we've been discussing, where we now have a pretty clear sense of what these enterocytes are up against. On their one side, on the luminal side, they've got just a never-ending barrage of toxins, microorganisms, bacteria, viruses, foodstuff that have to be absorbed. At the same time, they can't be digested by these things. We didn't talk about tight junctions specifically. Do you wanna maybe tell people what the tight junctions are that sit between these things?

    2. MGMike Gershon1:17:32

       Epithelia are the cells that line cavities. Epithelia have three types of junctions that hold the cells together. One type is called the desmosome or a spot weld, just very tenacious, hard to pull out connection between the cells. Another one is called the tight junction. Tight junction has protein in the membrane on one cell, forms a attraction to the membrane across the cell, transmembrane, and it obliterates the space between two cells. So the function of tight junctions is to prevent material going through the channel between two epithelial cells. It's a plug in the bathtub. There's another junction called an adhesion junction, which is essentially like the spot weld, but it also is contractile. But let's concentrate on the tight junction because that's what we're now talking about. And the more of these tight junctions you have between two epithelial cells, the less leaky or permeable that connection is between them. So anything that interferes with tight junctions can make the channel open and allow material from the lumen to get into the body, but at the same time allow material within the body to get into the lumen. And material going into the lumen Is very dangerous because, as I've told you, anything going into the lumen is lost from the body. And so if you open tight junctions in the lining of the gut, you can essentially flow out into your bowel.

    3. PAPeter Attia1:19:30

       And Mike, besides the obvious, which would be water or electrolytes, is there ever a scenario where nutrients that were actually absorbed now go back into the lumen?

    4. MGMike Gershon1:19:43

       Absolutely, and worse than that, protein from the body. It turns out that underneath the lining of the gut, capillaries are very permeable, and there's a lot of protein in the lymph, the fluid underneath the lining. And so if you open the lining of the gut, that protein gets into the GI tract, and that's a disease called exudative enteropathy. You lose protein, and people with that disease can blow up and look like balloons because edema goes-

    5. PAPeter Attia1:20:18

       Yeah

    6. MGMike Gershon1:20:18

       ... all over the body. It's a terrible thing.

    7. PAPeter Attia1:20:21

       So Mike, what would you say is the most common cause of leaky gut?

    8. MGMike Gershon1:20:25

       Allergy.

    9. PAPeter Attia1:20:26

       Okay. So meaning there is, um-

    10. MGMike Gershon1:20:29

        Hypersensitivity. That is the immune system is reacting and causing tight junctions to open.

    11. PAPeter Attia1:20:36

        Is this an allergy in the food specifically because the allergen is in the lumen?

    12. MGMike Gershon1:20:42

        Not always. For example, bee sting can cause this or can be injected or some other way that you can get a toxin that can do this.

    13. PAPeter Attia1:20:54

        I want to ask a question going back to something you said earlier that I never really have thought about until now, but I've never [chuckles] thought this deeply about the gut. You know when they say a shark, like great white sharks, have multiple rows of teeth so that they're kind of constantly just pushing forward, so when teeth fall off, they kind of have new ones that have already grown into place? How does this epithelial layer replace itself while preserving the tight junction? If we're talking about every week or so, these epithelial cells slough off and new ones are present. Does that mean we have several rows of them ready to sort of spring into action already tightly bound to their neighbors, or how does that happen to preserve the integrity?

    14. MGMike Gershon1:21:34

        The gut is arranged, the lining of the small intestine until lesser extent, the large intestine, so that the gut lining is highly folded. And there are projections that come up from the surface of the gut that look like fingers, and these are called villi. So most absorption occurs on the surfaces of these villi. Now, between the villi, there are clefts called crypts, and at the base of crypts, there are stem cells. And the stem cells, which live next to this other cell that I mentioned earlier called the Paneth cell, can give rise to each of the cells that form the villi or line the gut. And there's an escalation of those cells. The progeny of the stem cells keep rising, so as new ones form, other ones move up. In part, the proliferation in the crypt produces a pressure that causes cells to rise as they differentiate, but they're also mobile, so they crawl a little bit as well. And if you wound a lining of the gut, then adjacent cells can crawl over the space and cut it off. At the tips of the villi, there's a zone called the extrusion zone. And so the cells are born at the base of a crypt, climb up the crypt, up the villus, reach the tip of the villus, die, and are poofed off at that point. So they stay in contact with one another, and the tight junctions are finally lose it when the cells die, or the desmosomes, and they pop off. So the, the mechanism of death is called apoptosis. So they're programmed to die.

    15. PAPeter Attia1:23:41

        We talked about the importance of toxins, allergies, things like that playing a role in leaky and inflamed gut cells. Are there any reputable assays that can identify what these are in an individual that has otherwise vague symptoms?

    16. MGMike Gershon1:23:58

        If somebody has a substantially leaky gut, you would guess it from making a determination of the serum protein albumin. If the gut is leaking, albumin will be low. And so if you see a low albumin, you can look for it. If you think it's true, you can look for an enzyme called alpha-1 antitrypsin. Trypsin is produced by the pancreas. Antitrypsin blocks it, its action, and it gets into the lining, into the gut. It should not be absorbed. It's a measurement that will tell you whether the gut is leaking or not.

    17. PAPeter Attia1:24:45

        By the way, there's an alpha-1 antitrypsin deficiency disease, isn't there? It's a hereditary condition.

    18. MGMike Gershon1:24:50

        Yes.

    19. PAPeter Attia1:24:51

        What do those patients present with?

    20. MGMike Gershon1:24:53

        Usually vascular and lung disease because there's too much digestive action damaging in those organs. I think I said it wrong. Alpha-1 antitrypsin is on the luminal side... Sorry, on the vascular side, and if it gets into the stool, that's the problem.

    21. PAPeter Attia1:25:14

        I see. So we shouldn't be seeing it in the stool.

    22. MGMike Gershon1:25:16

        Correct.

    23. PAPeter Attia1:25:17

        Do you have to see low albumin to make the diagnosis of leaky gut? 'Cause that's a very significant leaky gut. I mean, if a person is exuding protein to the level where it shows up in their serum albumin, that would strike me as a lot of leak, correct?

    24. MGMike Gershon1:25:34

        Correct.

    25. PAPeter Attia1:25:34

        Are there milder leaks that don't allow something as massive as albumin to escape but do allow toxins and microorganisms in?

    26. MGMike Gershon1:25:44

        That is now getting onto the level of controversy, but it has probably not toxins in, at least not to a great extent. Maybe a little bit, yes. I take it back, a little bit. And you can look for those by giving various peptides or fluorescein or dyes that measure it by oral that should be excluded from the blood and seeing if the fluorescence gets into the blood. Or you can measure it with certain sugars that should not be absorbed, and if the non-absorbable sugar gets into the body, then you'd assume there's a slight leak of the kind you're talking about.

    27. PAPeter Attia1:26:33

        And do we think that there is a causal relationship between leaky gut and autism spectrum disorder, or do we think that these are things that move together for a similar underlying pathology?

    28. MGMike Gershon1:26:46

        The problem in the gut in autism spectrum disorder is a disorder of the nervous system. It has nothing to do with leaky gut. That's part of the Wakefield hypothesis, leaky gut. No evidence that that's correct.

    29. PAPeter Attia1:27:02

        Let's go back and explain again now that we've talked more about serotonin. What do we think is the relationship between-- Do we see more leaky gut in ASD?

    30. MGMike Gershon1:27:12

        Not really. Let me give you an illustration. My collaborators and I have produced a mouse called G56A. This mouse has a mutation in the serotonin transporter. The serotonin transporter is the protein that you spoke of before that is the target of SSRIs. It is what the SSRIs inhibit and which removes serotonin from the circulation or from the synaptic cleft when it's a neurotransmitter. What this mutation does, though, is not inhibit SERT but make it more active. So SERT becomes what I like to call the super SERT mouse. This animal has essentially a deficiency of serotonin. It is so effective at inactivating serotonin after its release that it doesn't have a chance to act. So that animal has a smaller nervous system in the gut, too few neurons, and it has slow transit, and it has a problem in the gut. In the brain, it doesn't socially interact with other mice. If you put them in a tube, two mice convene. One with the mutation backs out and lets the other mouse through all the time. And it has repetitive behaviors. It keeps tapping its foot, hitting its head against the side of the cage. So it has central features that look like autism, and it has a GI tract which is abnormal. Abnormality is seen in about 2% of patients with ASD. So it was the human abnormality put into mouse. Now, it's not the cause of autism, but it's a sort of test case. It's one of the many genes that can give rise to autism, put into a mouse shows autism and also defect in the gut. The defect in the gut has to do with serotonin and the ability of serotonin to act as a growth factor. So there's a deficiency in terms of numbers of nerve cells in the bowel. In a patient with autism spectrum disorder, similar kinds of things happen. This, by the way, is the exactly the opposite effect of giving a mouse during development an SSRI. So if you give a mother SSRI, they get too many nerve cells growing in the gut. If you knock out the transporter, you have too many nerve cells in the gut. And if you make the transporter more active, you have too few.
14. 1:30:38 – 1:50:24

    The Gut Microbiome: Bacteria, Germ-Free Mice and Fecal Transplants

    1. PAPeter Attia1:30:38

       Let's talk about bacteria now. We very briefly touched on it earlier, and I, I knew if I started, I wouldn't stop. And the first time it came up was when we talked about the difference between the colon and the small intestine. And one of the many differences between them, of course, is the flora. Can you give people a sense of how many bacteria exist in the small intestine? And let's start-- maybe even divide them into three. Let's talk about the proximal small intestine, so the jejunum, the late small intestine, you know, the ileum before it gets to the cecum, and then the colon. What's the relative difference in bacterial colony?

    2. MGMike Gershon1:31:15

       The numbers of organisms descend, that is, or ascend as you go down the gut so that you have more of them close to the colon. And it's thought In large way, that stomach acid sterilizes to a large extent the food that you eat, although there are bacteria that can be found even in the stomach in the presence of one normal hydrochloric acid, Helicobacter pylori being the prime example of an organism that can survive. But the small intestine then neutralizes stomach acid, but benefits from that acid because very few organisms are dumped into it. The motility of the small intestine and the fact that the smaller numbers of organisms come in contribute to keeping the number down as the gut pumps its way on down. In addition, there are cells like Paneth cells, which make antibacterial proteins, which are called defensins, which help to keep the lumen of the gut not sterile, but close to it. As you get closer and closer to the colon, the mechanisms, the numbers of Paneth cells decline, gut slows down, and you're getting close to a large number of organisms which live in the colon, and they're separated by the ileocecal sphincter from the colon. When bolus of food gets into the colon, or not just food, it's by then chyme, it's been digested. When that material is delivered to the colon, it goes into a region where it will spend some time, and in the colon, there are huge numbers of organisms. Now, the numbers of organisms are about equal in number to the number of cells of the body. We're talking trillions. And you have perhaps tenfold more bacterial genes than you do your own genes in your body.

    3. PAPeter Attia1:33:30

       And what are the classes of bacteria? Are these all gram-negative?

    4. MGMike Gershon1:33:34

       No. A lot of them are gram-negative. What they do have in common is that they are almost all anaerobes. That is, they live in the absence of oxygen, and most of them are very hard to culture. And so until relatively recently, we had no idea what a teeming mass of organisms [chuckles] were in there. I mean, people all knew for a long time that the colon stool wasn't sterile, and they-- people culture stool, but most of the organisms are highly resistant to culture and have been detected through molecular biology. You look for the genes.

    5. PAPeter Attia1:34:18

       So now that that's been done, I assume we've done the, uh, equivalent of the Human Genome Project for the human colon. There tend to be a few classes of these things, right? I mean, Bacteroides is pretty common, Actinobacteria, Proteobacteria. I mean, what are the broad categories of these facultative anaerobes and such?

    6. MGMike Gershon1:34:36

       Well, there are about 16 different classes, and I can't remember them all. One of the largest of them is the Firmicutes. But Bifidobacteria and Lactobacteria, those tend to be bacteria that we think of as good. Clostridia tend to be organisms that mostly are bad, but not entirely. Some of those bacteria are related to causing cancer. Some of those bacteria are highly protective, and they do stuff for us. For example, one of the things we eat a lot of is fiber. Celery, for example, celery [chuckles] or lettuce. We don't digest that. We have no enzymes that can digest that. But we have bacteria in our gut that live on that, and they digest that, and they make short-chain fatty acids from that, and those short-chain fatty acids are absorbed by the lining of the colon, and our bac-- colonic, uh, epithelia are dependent on the bacteria to keep going, and they get the bulk of their energy from the bacteria in the gut. The bacteria also make certain vitamins that we can't live without, vitamin K being the most famous of them. So clotting of blood depends on the bacteria in it. As you probably know, they also seem to regulate things like mood and obesity.

    7. PAPeter Attia1:36:18

       It just strikes me as one of the most poorly understood connections for something that has such a high impact on human health at this point still. Obviously, we know more today than we did 20 years ago, but in many ways, it still feels like this is a bit of a black box. Is that just my ignorance or, um-

    8. MGMike Gershon1:36:38

       No, it's our ignorance. So why are we ignorant, you might ask. And the answer is, I've just told you, we can't culture most of those organisms. They are extremely difficult to study. And so-

    9. PAPeter Attia1:36:52

       And Mike, is that-- Pardon my ignorance. I'm not a cell biologist. How much of that difficulty is because they're anaerobic and just logistically it's more complicated to culture organisms in the absence of oxygen, or is there something that even goes beyond that?

    10. MGMike Gershon1:37:07

        Oh, it goes well beyond that. We don't know the nutrient nor broths and things through which they can live. It's easy enough to make an atmosphere that has no oxygen in it, but it's not so easy to figure out what they need to live. The colon produces a great environment, and how to match it is not so easy to figure.

    11. PAPeter Attia1:37:28

        This is a, a very remarkable evolutionary tale, and also perhaps the most interesting symbiosis we experience. This strikes me as a more interesting symbiosis than the one we share with bacteria on our skin. Is that a fair statement?

    12. MGMike Gershon1:37:45

        I think so because the bacteria are able to get involved with the nervous system in a way that the bacteria of the skin pretty much do not. So for example, the bacteria that are in the gut can activate lining epithelial cells or enteroendocrine cells to release serotonin or other factors, other chemicals from them, and that can signal by way of the vagus nerves to the brain or chemical products that the bacteria make can also trigger nerve signals that send signals back to the brain or even go through the blood-brain barrier to affect the brain so that experiments can be done, for example, with mice in which one can breed germ-free mice. Uh, germ-free, gnotobiotic is the term for that. Germ-free animals grow up without any contact or organisms in them.

    13. PAPeter Attia1:38:49

        I'm not trying to understand how that's possible, Mike. I mean, I've heard about it, but I've never really understood it. How do you have a germ-free animal? How do you feed it? You're feeding it sterile food into a-- And they had to have been born 'cause this would've begun gestationally.

    14. MGMike Gershon1:39:04

        That's right. So they're all born by cesarean section. They're fed sterile food, and they live in incubators, and people handle them with gloves.

    15. PAPeter Attia1:39:16

        What's the phenotype of that animal after two years relative to an otherwise identical animal that's born normally and fed normally?

    16. MGMike Gershon1:39:24

        Let's go one year.

    17. PAPeter Attia1:39:25

        [laughs] Okay, that, that tells me something really changes.

    18. MGMike Gershon1:39:29

        Yes. So for one thing, the numbers of nerve cells in their gut, their motility, the lining of the gut, they're all different. They're very much more primitive. They have almost no spleen. They have none of the Peyer's patches that we, you know, talking of the immune cells of-

    19. PAPeter Attia1:39:50

        So their immune system must be horrible.

    20. MGMike Gershon1:39:52

        Yes. They have no immune system, but they have a thymus, and so they can develop an immune system in a big hurry if they survive, when you take them out and expose them to bacteria. But what you can do with the organisms of-- with the gut is use them as vessels and recolonize the gut with organisms. So for example, if you take those animals and colonize them with bacteria derived from a strain of mice that tend to be lean, you get lean mice derived from those animals. If you colonize them with, from a strain of mouse that tends to be fat, those animals grow up to be fat, and you can cross strains. So that, that seems to indicate that bacteria can determine obesity or lack thereof.

    21. PAPeter Attia1:40:51

        Yeah. How do we think this plays out in humans, where it's not as extreme? We don't have sterile humans. But your point is, and I believe there have been some experiments done. You'll have to correct me 'cause I don't follow this literature. But haven't they done some fecal transplants from lean to obese that have at least partially addressed the phenotype?

    22. MGMike Gershon1:41:12

        Correct. And also anxiety seems to work in its very similar fashion. But what you have to take with the human is always everything with a grain of salt because the experiments are very difficult to do, and they're all flawed because you can't deal with pure organisms or pure humans, what they're retaining.

    23. PAPeter Attia1:41:37

        Do you have any idea how many such transplants have been done where they've done a fecal transplant from a lean to an obese individual? How many times has that been done-

    24. MGMike Gershon1:41:47

        Not-

    25. PAPeter Attia1:41:47

        ... under a controlled setting? Why do you think that type of research, while admittedly complicated, is technically feasible and has a potential for enormous-

    26. MGMike Gershon1:41:56

        Fecal transplantation in humans, it's not without danger.

    27. PAPeter Attia1:42:02

        For sure. Tell people how the procedure works and obviously what the risks are because I believe the only approved use of the therapy is for C. difficile. So you've already alluded to Clostridia before. Um-

    28. MGMike Gershon1:42:14

        Yeah. Let me just say Clostridium difficile is a normal component of the GI tract. Many, many people have it, and it sits there. And with your organisms, one of the major ways that you control the various bacteria is to have other bacteria. And so the bacteria control themselves. There's a, um, competition for how much nutrient is there, and they make toxins that affect one another. But people then take antibiotics, and the major effect on the human microbiome is an antibiotic. For the most part, we like to think antibiotics are used effectively and appropriately when you have an infection, and they're given to you to, to fix that. Unfortunately, that happens not to be the case. A lot of people are exposed to antibiotics because they're used in agriculture, and they're used in agriculture because it was found probably 60 years ago that giving antibiotics will cause animals to grow faster and get bigger faster. And so you can give antibiotics for that reason. You can also keep pigs more safely in small quarters by giving them antibiotics because infections are not wiping them out so badly. This profligate, if I might use the term, use of antibiotics in agriculture exposes the human population to antibiotics and changes our bacteria in ways that we would never have appreciated. Just to give you an illustration, my son, who has now just turned 60 but was young once, when he was a child, he got pneumonia. Kids do. And so culture was taken, found that it was pneumococcal pneumonia. He was two, so he was given penicillin to treat pneumococcal pneumonia. He got an exudative enteropathy for it. His skin peeled off, his teeth came in mottled, his hair changed, his fingernails changed. He was taking baths in oatmeal. We nearly lost him. So he is deathly allergic to penicillin. How the hell did he get to be allergic to penicillin at age two when he'd never had it? Well, part of the answer was that my wife had a very bad infection, and so he had to be bottle-fed after the first month of life. And so he had cow's milk for a long time. Nothing wrong with that. Kids always drink cow's milk. But cow's milk is coming now with penicillin in it because the agricultural industry treats penicillin. So he developed an allergy to penicillin. [chuckles] He then got treated with it, so now he doesn't take penicillin anymore. As it turns out, I discovered many years later, I too am allergic to penicillin. That's where he got it from. I apologized to him, but it's a gene.

    29. PAPeter Attia1:45:47

        But do you think he would have been less allergic to it despite his susceptibility genetically if he had been breastfed normally?

    30. MGMike Gershon1:45:55

        Well, if he'd been breastfed normally, the first time he got penicillin, he would have been sensitized, but he wouldn't already have had the allergy. He behaved as if he was exposed to penicillin because he had been, but in a way we never knew, and lots of kids are getting it. But the major effect of it is that it's affecting a microbiome.
15. 1:50:24 – 2:12:52

    Microbiome Tests, Diet, Probiotics and Closing

    1. PAPeter Attia1:50:24

       One of the things that's very common today is commercial home kits that they're going to tell you what your sequence looks like. This seems to be a field that's really full of a lot of nonsense. So there's been outright frauds, right? There was that company out of UCSF called uBiome that turned out to be kind of like the Theranos of this space. There seem to be a lot of companies that if you give them a small stool sample, they're going to send you a lengthy report of what your gut biome is, and let's assume that they're even able to do that accurately. Is that a fair assumption? Are they able to provide this information? Are they able to do the sequence and tell you what makes up your gut bacteria?

    2. MGMike Gershon1:51:04

       What they give you is the classes of organisms and the percentage of the total bacteria each of the classes represent, and that turns out to be remarkably unuseful.

    3. PAPeter Attia1:51:16

       Say more.

    4. MGMike Gershon1:51:18

       Well, you need to know species by species at a very, very fine level before you get to be able to really do something with it. To get this class of bacteria and proportion of it's too high in the genome, uh, too high in the, uh-

    5. PAPeter Attia1:51:37

       So far too little resolution is being provided by these tests.

    6. MGMike Gershon1:51:42

       Correct. You can say you can change anxiety, you can change body form with the microbiome, but to say that you can go look at the microbiome and then determine what that is is not yet there. You can't just go look at somebody's stool and say what that consists. The best of the kits that I know of that do this are the ones that look for cancer.

    7. PAPeter Attia1:52:10

       So like Cologuard and things like that.

    8. MGMike Gershon1:52:12

       Yes. Those are excellent. But even those kits-

    9. PAPeter Attia1:52:17

       Let's remind people exactly what Cologuard is looking for

    10. MGMike Gershon1:52:20

        ... as the cells age and undergo apoptosis, they're sloughed off into the lumen. And so human DNA is in the lumen of the gut as well as bacterial DNA. And what Cologuard does is looks at stool, and you can look at the DNA in the stool and look for the genetic signatures of a number of GI cancers. And so about 90% of GI cancer can be picked up effectively by Cologuard, which means it's wonderful and it's a great advance, but it doesn't mean you don't have to go also do colonoscopy.

    11. PAPeter Attia1:53:05

        Yeah. The goal of colonoscopy is to find it before it's cancer. It's to find the polyp that's going to become cancer, not wait until you have cancer.

    12. MGMike Gershon1:53:12

        That's a major point. But if you do have cancer and you find it early in a colonoscopy, that's great. And the problem with Cologuard is if you're missing 10% of cancer, you don't want that to happen.

    13. PAPeter Attia1:53:28

        Seems to me that Cologuard is really a great tool in areas where access is limited, where there might be hesitancy for colonoscopy and things like that. But I agree with you, it's not a substitute for a colonoscopy. So this is an interesting point, Mike, which is basically all of these commercial tests out there that are giving you information about your gut microbiome are not doing it yet at a resolution that's actionable. Is that kind of a fair synthesis of what you've said?

    14. MGMike Gershon1:53:56

        Right. And my particular quarrel with them is that because they're not doing it at a level that is sufficiently documented and sufficiently informative for you to be actionable on that information, they cost money abnormally, and they change what you do for reasons that are not well documented, and you shouldn't be following them yet.

    15. PAPeter Attia1:54:23

        Yeah, and a lot of them basically are paired with supplements or probiotics or prebiotics that are supposed to, quote, unquote, "fix the defects" that are found in the test, right? Isn't that the RxDx model?

    16. MGMike Gershon1:54:39

        That's what they're doing, but what they're really doing is making money. I think they're, uh, a con.

    17. PAPeter Attia1:54:47

        I don't know enough to draw a strong enough conclusion. I can just say based on a decade of looking at them in many, many patients who have been adamant about having these tests done, I'm still looking for a great example of where it mattered. I worry also that there is a lot of noise created without a signal. What are the most important things nutritionally that people can do to make sure that they have the optimal flora for their gut? I want to break this into two categories, Mike. The first is just as general health maintenance, and the second is after taking antibiotics. So like it or not, we're going to take antibiotics, and they're going to save our lives from time to time. I have found myself to be more and more reluctant to take them, and I generally tend to resist as long as possible until I, I have no choice. But I'm going to hold out a long time before I take a Z-Pak if I'm sick. I'm going to really try to, to make it go. But, you know, I think the last time I took antibiotics was for a dental issue where it just required something more significant. So Let's start with kind of the general maintenance principle. You're not someone who's taking a lot of antibiotics, but you want to do what's best for your gut, and I assume that nutrition is one of the most important levers we have.

    18. MGMike Gershon1:56:07

        To my way of thinking, the best kind of diet is a balanced diet, not one that tries to be like the South Beach or one of those diets to lose weight. Having a balanced diet with appropriate nutrients, including vitamin C but not in excess, although it won't hurt you to have an excess of vitamin C, but there's no reason to do it, and particularly fiber included is good for your body. So I would be opposed to having particular diets. For example, a cleanse. I like to point out to people that they should consider that the microbiome is something they live with and has evolved with human beings as long as there have been human beings, and cleansing the inside [chuckles] of the gut is not a good thing to be doing.

    19. PAPeter Attia1:57:01

        I'm not even sure I really understand what a cleanse is. I've heard so many different variants of it, but certainly one method in which we do some form of a cleanse is a prep for a colonoscopy. How much does that alter the flora of the gut, even though its purpose is really to just mechanically get rid of all stool matter so that the endoscopy can be performed with better visibility? Does that alter the gut flora in a way that doesn't return to normal quickly?

    20. MGMike Gershon1:57:26

        No, remarkably little. That doesn't kill organisms or change the balance between them. What it does is just moves the mechanical stool out, and so the gastroenterologist doing the colonoscopy can have a clear view of what's in you.

    21. PAPeter Attia1:57:42

        When people do these dietary cleanses, they're usually drinking a lot of water with pepper and presumably some nutrients, but they're kind of doing a bowel prep, aren't they?

    22. MGMike Gershon1:57:54

        Some of them are also supplementing it with enemas, and I worry about those people getting into electrolyte imbalance.

    23. PAPeter Attia1:58:03

        I see. But they shouldn't be killing the bacteria.

    24. MGMike Gershon1:58:06

        No, they're not killing the bacteria. But on the other hand, they're not doing their body a favor by eating strange foods and that kind of thing.

    25. PAPeter Attia1:58:17

        You alluded to soluble-- uh, pardon me, insoluble fiber earlier, the things that we can't digest at all in lettuce and celery and things of that nature. Tell me the importance again of that in the human diet, because there presumably are people who don't eat much or any insoluble fiber, and that's going to clearly change their gut bacteria. Is there evidence that that is impacting their health negatively?

    26. MGMike Gershon1:58:39

        Not that much has been done on low fiber for negative impact as so much as to show that there are health benefits of fiber. One of the benefits is that fiber can absorb toxins so that it can decrease, it's thought, carcinogen effects long term. It also provides the colon something to chew down on and is good for motility, keeping the bowel going in, in shape, and it also provides a substrate for the bacteria of the colon for them to chow down on and produce short-chain fatty acids, which are good for the lining of the gut and provide it with its energy metabolism.

    27. PAPeter Attia1:59:29

        By the way, do any of those short-chain fatty acids, Mike, make their way into the person to provide ATP or energy there beyond just the epithelial cells?

    28. MGMike Gershon1:59:40

        Less so, but the answer is yes. They are absorbed, and so to some extent, they can get into the body.

    29. PAPeter Attia1:59:47

        Directly through chylomicrons as regular fatty acids would or, or-

    30. MGMike Gershon1:59:51

        No. No, no. They're s- very short, and they're soluble, and they tend-- Like acetic acid is a short-chain fatty acid. That would be a one carbon.

Episode duration: 2:12:52