The Peter Attia Drive - #215 - The gut-brain connection ｜ Michael Gershon, M.D.

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.320 now, head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.740 here's today's episode. My guest today is Dr. Mike Gershon. Mike is a professor of pathology

00:00:54.940 and cell biology at Columbia University, where his research focuses on the neural control of

00:00:59.520 the gastrointestinal tract and the role of serotonin in the gut as a neurotransmitter.

00:01:03.980 Mike earned his medical degree from Cornell University, followed by a postdoctoral fellowship

00:01:07.820 at Oxford. Mike has received numerous awards and honors over the years, published hundreds

00:01:12.340 of peer-reviewed papers on the nervous system, and even authored a book on the role of the brain

00:01:18.460 and the GI system. This episode's different from, I think, a lot of our episodes. And truthfully,

00:01:23.400 I think it comes across more as a bit of a med school lecture, which is kind of how it felt to

00:01:27.160 me. It was, you know, really interesting, but I think at the surface doesn't really come across

00:01:32.980 as highly applicable. And I think the reality of it is you just sort of have to get through some of

00:01:37.460 the embryology, anatomy, and neurophysiology of the gut and the brain to kind of understand how these

00:01:44.160 things coexist. So I just want to be honest and set expectations. If you're coming into this thinking

00:01:49.700 that this is going to be a podcast that's about how to eat this and not that and affect your gut

00:01:54.020 biome, it's really not about that. This is a much more basic discussion. And I mean basic, not in simple,

00:02:01.180 but I mean basic in more elemental explanation of how this system works. And truthfully, I learned a lot

00:02:08.000 in this episode, much more than I normally do. A lot of times I go into podcasts kind of knowing

00:02:11.960 the subject matter pretty well and maybe increasing my knowledge by 20% or something like that. But I think

00:02:17.780 this was pretty different. So I think what I would just say is rather than give you a blow by blow of

00:02:23.200 everything we talked about here, which would probably take me 20 minutes, I would say, go into this

00:02:28.580 assuming you're not going to know much of what we talk about. And you'll come out of this with a much

00:02:33.360 greater appreciation for how your gut and your brain are connected. And unfortunately, I think we're only

00:02:40.080 now beginning to think about how to translate that to clinical utility. So in other words, I think that

00:02:47.740 we don't yet have all of the insights. I don't come away from this episode saying, oh, all you need to

00:02:53.900 do is eat this and your gut's going to be healthier. And if your gut's going to be healthier, then your

00:02:58.360 brain's going to be better or vice versa. So maybe you'll come out the other end of this podcast feeling

00:03:02.880 like you've got it figured out. I certainly don't. But nevertheless, I feel like I have a much better

00:03:07.460 foundational knowledge to evaluate half of the snake oil stuff that is out there, which I mean,

00:03:13.580 I got to be honest with you, most of what's out there on this topic is utter nonsense, commercial

00:03:18.180 tests that promise miracles that don't make any sense and supplements that just don't make any sense.

00:03:22.860 And I think you'll come away from this kind of understanding how difficult it is to try to make

00:03:27.060 the claims that are out there. So without further delay, please enjoy my conversation with Dr. Mike

00:03:30.660 Gershon. Hey, Mike, thanks so much for making time to speak with me today about a subject matter that

00:03:41.540 I know very little about, but know enough to know that it probably matters. And I think that's why

00:03:46.000 we're going to talk about it. Okay, I'll do my best. Let's kind of start with what is it that has

00:03:51.680 brought you so much curiosity in an area over what I'm guessing 60 years now is probably how long

00:03:57.280 you've been studying the GI system? Yes, I guess that shows you it's a very difficult subject

00:04:02.700 because I've been studying it for 60 years, and there's still more to study. In other words,

00:04:08.240 I haven't gotten very far. Or as the saying goes, the further you get from shore, the deeper the

00:04:13.700 ocean gets, right? I love that. Yes, I haven't heard that before. You know, this is one of those

00:04:19.400 subjects that, and I've been thinking a lot about this in trying to figure out how to frame our

00:04:24.080 discussion today because there's just so much fundamental foundational knowledge that I think

00:04:31.260 is necessary to at least have a basic understanding of before we can get into kind of the nuanced stuff

00:04:39.700 around the GI system. So does it make sense to maybe just start with some of the real basics of

00:04:46.160 the human GI system, including, frankly, its embryology, anatomy, vascular supply, and ultimately,

00:04:54.500 I think we're going to want to talk, of course, about its nervous system, which is quite distinct

00:04:59.720 and unique relative to even the peripheral nervous system. Would that be a reasonable place to start?

00:05:05.100 Absolutely, it would. All right. Well, let's start with the embryology of this. So what is it that

00:05:11.420 takes place during our development as embryos that leads to the system of the gut? Well, before I

00:05:19.160 mention exactly what that is, let me just define it because I think that some people don't really know

00:05:26.660 what we mean by the GI system. So basically, it's a tube. It begins at the mouth and it ends at the

00:05:34.460 anus. And as T.S. Eliot said, we are hollow men, and I will add, and women. So the inside of the GI tract

00:05:45.360 is really outside the body. It's internalized external space. If you bleed into your GI tract,

00:05:55.200 you lose blood. It's no longer in you, even if you can't see the blood. So one of the major crises

00:06:02.780 in medicine is hidden bleeding in the GI tract, which can be very damaging, even if you don't see any

00:06:10.420 blood. The inside of your gut is outside of your body. And as such, you can have, and you do have

00:06:19.880 inside the gut, space for the existence of a community of extra organisms that is immense.

00:06:29.860 And so the inside of your gut is dangerous and has to be kept separate from you. So it's a major

00:06:40.740 problem for the GI tract to keep a barrier and a surface to defend the body and yet allow food to

00:06:52.280 be digested and absorbed and food stuff to come in. So it has to maintain the communication with the

00:06:59.840 lumen, which is what we call the inside of the GI tract, and yet at the same time, be protected.

00:07:07.840 That's a really good point, Mike, which is that we think about this all the time when we think about

00:07:12.520 our skin, which is the other part of us that is exposed to the outside world. And I think most

00:07:17.740 people would be familiar with how many bacteria we have colonizing our nasal passages, skin surface, 0.60

00:07:24.740 etc. I guess most people would probably understand that bacteremia is a bad thing. When bacteria enter

00:07:31.620 our body, and they can do so through many of these pathways, it's problematic. But you're right in that

00:07:38.700 the GI tract has a particularly unique challenge, which is it must still do a lot of transmission across

00:07:50.100 its surface, obviously all of nutrients. In that sense, for example, the respiratory system

00:07:55.360 only has to be serving for gas exchange. And not to minimize that, but you could make a case that

00:08:02.740 that's an easier problem to solve to allow gases to exchange, but not to allow organisms to go through.

00:08:09.420 So I think that's a very interesting way to begin this discussion.

00:08:12.200 Of course, I don't want to denigrate the importance of the respiratory tract in an age of COVID.

00:08:20.760 Let me tell you, it's important that gas exchange be easy and proper. Anyway, to get back to the GI 1.00

00:08:27.840 tract, the gut has a further problem in that the food we eat is not ready for absorption. It doesn't

00:08:34.780 come in. Food that you eat has to be digested. So that you eat complex products, and then you have

00:08:42.140 to digest it into small molecules that can be absorbed. So that not only does the gut have to

00:08:50.520 absorb a variety of things, it has to have a particularly awful witch's brew to turn the same

00:08:58.920 kind of thing that we're made of into juice, essentially break it down without dissolving

00:09:05.540 the body. The lining of the gut is absolutely remarkable. So it's complex molecules that are

00:09:12.480 not sterile as well, entering a non-sterile environment. And somehow we have to only allow

00:09:18.600 sterile nutritional building blocks to move across the border. Yes. And those nutritional building blocks

00:09:25.340 have to be made from the same kinds of things that we're made out of, which we have to break down

00:09:31.800 and digest. Without breaking down ourselves. Correct. So we don't want to self-digest. It's a major

00:09:37.940 problem. And the gut manages to solve all that. Now you asked where it comes from. Well, during development,

00:09:46.460 the body forms a disc, a flat disc. And that disc undergoes a series of folds

00:09:54.420 from head to toe and from side to side. And the lateral or side folding produces the tube

00:10:03.940 from which the gut forms. And so the flat disc folds around to create an internal space

00:10:11.960 and that tube becomes the gut. How many weeks, can you remind me, Mike, post-fertilization,

00:10:18.100 does that fold take place? The folding takes place during the first trimester and the gut is fully

00:10:26.900 developed during the second trimester and is between the second and the third trimester when

00:10:34.800 you're born. The gut is modeled and achieves its ability to do the kinds of things that we were just

00:10:43.360 talking about, digest and absorb. The first part of development is called embryogenesis.

00:10:52.160 That is, the fertilized egg forms the disc. The disc folds. The organs of the body form. And that's

00:11:02.200 the embryonic period. The fetal period follows that. And the fetal period models the organs into their final

00:11:11.980 or not necessarily final because some development continues to take place after birth, but appropriate

00:11:20.180 development so that it becomes functional enough to support a baby.

00:11:26.660 And my recollection, which is about 26 years old now, is that when that tube, that fold turns into

00:11:34.640 the tube, which will become the entire length of the GI system from, as you said, mouth to anus,

00:11:39.300 there are also these little outpouchings that come along later that become things like the pancreas

00:11:44.080 and the bile duct and things like that, which form other things that drain into the GI system that 0.83

00:11:49.440 obviously perform essential functions for digestion. Yes. That same fold gives rise to lots of things,

00:11:56.200 some of which drain into the gut, like the pancreas, the gallbladder, which you mentioned,

00:12:01.580 but it also forms the lungs, which do not drain into the GI system, and the liver, which has a component

00:12:11.140 that drains into the gut through the bile system. But those are all derivatives of the gut. So the

00:12:18.580 foregut forms the stomach, the first part of the small intestine, the lungs, the pharynx,

00:12:26.640 pancreas, gallbladder. The midgut is the business of small intestine, and the first part of the large

00:12:34.740 intestine, and the hindgut is the end of the large intestine. And my recollection, Mike, was that the

00:12:42.780 foregut, midgut, hindgut basically tracked with the three vessels coming off the aorta, the celiac,

00:12:50.380 the superior and inferior mesenteric. Is that correct? That is correct.

00:12:54.100 So maybe tell folks a little bit about that blood supply, what makes it unique, which is, of course,

00:12:59.840 we have a portal system, which is very important. We'll go from there into the nervous system, which is

00:13:04.660 perhaps the most complicated of the bunch.

00:13:07.500 As you said, the foregut is defined as the part of the gut from the celiac artery. The celiac artery

00:13:15.740 is the first of the, or the most rostral, or anterior, or...

00:13:21.240 Closest to the head.

00:13:22.060 Yes. I'm trying to put it into terminology that the entire world can understand. There is also the

00:13:29.220 terminology that the aficionados understand. So the celiac gives rise, or the foregut,

00:13:37.780 the celiac branch, supplies the pancreas, the stomach, the first part of the duodenum,

00:13:44.480 and the liver, and the gallbladder. The superior mesenteric artery supplies the midgut, and that's

00:13:54.320 the longest part of the gut, and that goes roughly to the mid-transverse colon. The colon has three

00:14:01.960 parts. It folds. It has an ascending colon, a transverse colon going sideways, and a descending

00:14:10.940 colon, which goes down to the rectum and anus, which is out. The inferior mesenteric supplies the end of

00:14:19.300 the gut. When the celiac gives rise to the stomach and first part of the small intestines arterial supply,

00:14:30.100 that then breaks into capillaries, absorbs materials from the gut. Those capillaries drain into veins

00:14:39.280 in the gut, and in a unique way, those veins then form large vessels, which then move into the liver.

00:14:50.620 They then break into capillaries, small vessels within the liver called sinusoids. So the venous

00:15:00.300 system that supplies the liver is actually acting like as if it were an artery, but it begins in the

00:15:08.840 gut. And so the liver depends for its oxygen on blood that the gut has had a first crack at. And to keep

00:15:19.300 the liver going, it gets a second arterial supply from the hepatic artery so that it gets a little

00:15:28.820 bit of arterial blood. And basically, the liver is perfused with blood coming from the gut. And when it's

00:15:36.240 about to asphyxiate, a sphincter shuts that down, opens up, and it gets a breath of fresh air or fresh

00:15:45.480 blood and gets some oxygen. And then it goes back to dealing with what it gets from the gut. And the

00:15:52.080 reason it does that is the liver is the first step in the body's ability to use the nutrients that the

00:16:01.200 gut absorbs. So when the gut absorbs fatty acids, the liver turns them into chylomicrons, which can go

00:16:11.380 out and supply energy to the body. So the liver is a major center of metabolism working on products

00:16:20.160 from the gut. So it gets the first crack at what the gut has absorbed. Now, how about the nervous

00:16:27.700 system of the gut? How is the gut innervated? Well, as you've said, and I'm glad you've given your

00:16:34.580 audience a warning, it's complex and different. The gut has its own intrinsic nervous system.

00:16:42.580 And I've called that the second brain. And that's the title of the book, by the way. And the reason I

00:16:50.220 called it the second brain is that like the brain in the head, the nervous system of the gut is able

00:16:58.460 to function and control reflexes and behavior independently of any influence from the brain

00:17:08.600 or spinal cord. So it is the only nervous system of the body that can work on its own. So if you

00:17:17.420 completely isolate the gut from the brain and the spinal cord, it will function. You're not dead.

00:17:26.360 Years and years ago, in the days when peptic ulcers were thought to be psychogenic,

00:17:34.720 surgeons used to cut the vagus nerves, which are the major conduits that connect the brain and the gut.

00:17:44.180 And after they cut the vagus nerves, the gut continued to soldier on as it would have to.

00:17:51.240 Unfortunately, it never did all that much to fix peptic ulcer disease. And that turned out to be

00:17:58.520 because peptic ulcer disease is mostly an infectious illness caused by helicobacter pylori.

00:18:07.220 So you're saying before the discovery of H. pylori, it was believed that stress was driving peptic

00:18:14.380 ulcer disease. And the idea was that the central nervous system would communicate the stress to

00:18:22.420 the gut via the vagus nerve. That's correct. Now, that wasn't all wrong. The central nervous system

00:18:30.380 can communicate stress to the gut via the vagus nerve. But that was not the cause of peptic ulcer

00:18:36.980 disease. And it did help to show that the gut could, in fact, be cut off from the brain and still

00:18:44.820 work. But that observation was made long ago. The nervous system of the gut has been known to be

00:18:52.420 present for a long time. It was discovered about the time of the American Civil War.

00:18:58.720 Auerbach, in Germany, noticed an extremely large nervous system in the human gut at that time.

00:19:08.060 He didn't know what it did. But later, around the turn of the last century, that is 19th to 20th,

00:19:17.660 in what I know to have been a very cold, chilly laboratory in England. The reason I know that is

00:19:24.840 I've worked in England, I did my postdoc training there. Laboratories were not heated, even when I

00:19:32.440 was there. We used to crack the ice off the organ bath to get started in the morning. And I'd wear

00:19:39.340 gloves with just the fingertips open so you could do experiments. Anyway, at that time, Bayless and

00:19:46.960 Starling cut all the nerves to the intestine of a dog.

00:19:51.980 This is the same Starling from whom we have Starling curves in cardiac physiology?

00:19:56.840 That's the Starling. And so when they cut all the nerves to the gut and then increase pressure

00:20:04.260 inside the gut in the lumen, the gut would respond with the stereotypic behavior of oral contraction,

00:20:13.560 anal relaxation that they called the law of the intestine, which was a name that I liked very much

00:20:21.220 and sounded very poetic in a sense. 17 years later, while armies were paralyzed during the First World

00:20:31.060 War, crossed trenches that cut Europe from the Swiss border all the way down to the English Channel

00:20:39.220 in France and Belgium. Behind the lines in Germany, another German scientist by the name of Trendelenburg

00:20:48.800 had tuberculosis. And that kept him out of the army, even the German army at that time. But he had to

00:20:57.720 keep busy. So he strung up a loop of guinea pig intestine in vitro that is in a test tube on a J-shaped

00:21:07.060 tube. And he blew into the J-shaped tube, which raised the pressure inside the intestine, very much

00:21:14.560 like Bayless and Starling had done. And he found that even in a test tube, when he did that, the gut

00:21:21.680 blew back at him. And it was a very profound observation because it showed that with nothing there but gut,

00:21:30.400 the gut could respond, sense the pressure, and show a coordinated wave of activity in response to it,

00:21:39.660 indicating that the intestinal nervous system is able to function independently of the CNS,

00:21:46.680 CNS of the central nervous system. No other nervous system outside the CNS can do that. And even the

00:21:53.980 spinal cord can't do that. It works in conjunction with the brain.

00:21:59.400 How preserved is that, Mike, across other species? Is that kind of a universal finding?

00:22:05.560 Yes. It begins with a little organism called amphioxus, which undergoes metamorphosis,

00:22:13.220 this turns into a vertebrate. So it's a vertebrate invention. And all vertebrates have it. You do not

00:22:20.500 find it in invertebrates. So it's a vertebrate invention. And it gets more complex as vertebrates

00:22:28.160 become more complex. So a fish has only one layer of enteric nervous system. Humans have two. Actually,

00:22:36.860 some people would say three.

00:22:38.200 And the two that we have are between which layers? I guess we didn't really finish our GI anatomy.

00:22:45.660 So when you go from the lumen at the very inside all the way out, you have a mucosal layer,

00:22:52.240 a submucosa, a muscular layer. Is that where these different bundles live?

00:22:57.760 Yes. So the lining of the gut is called the mucosa. It has a superficial lining that is in contact

00:23:06.500 with the lumen called an epithelium. Underneath that is a loose nervous system called the lamina

00:23:14.800 propria. But together, that's the mucosa. Below that, there's a dense layer of connective tissue,

00:23:23.580 which allows gut to be used for stringing tennis rackets, allows gut to be used to suture material.

00:23:30.520 It's tough. You can't pull it out. The next layer is a circular layer of smooth muscle.

00:23:40.200 Another layer of smooth muscle, a second one called the longitudinal layer. And then if it's in the

00:23:47.420 peritoneal cavity, another layer of very thin epithelium. The major parts of the nervous system

00:23:54.780 of the gut are the submucosal plexus, which has the eponym Meissner, but it's submucosal plexus.

00:24:03.740 And that's in that dense layer of connective tissue. And that's the smaller of the two. The larger one,

00:24:12.340 by far, is the myenteric plexus. And that is in between the two layers of smooth muscle on the

00:24:20.020 outside of the gut. The two plexuses communicate with one another. And they both really do get

00:24:29.680 input from the central nervous system and speak back to the central nervous system. So although they

00:24:37.440 can function, as I've been emphasizing, independently of control by the brain, in practice,

00:24:45.300 they don't. They communicate. And there is constantly a bipolar or two-way communication

00:24:55.180 between the brain and the gut. The gut receives input from the brain and sends back information

00:25:01.800 to the brain. And in that function, bidirectional communication, the brain acts very much like a CEO.

00:25:12.160 That is, it gives general commands. The detail of what the gut actually does, that behavior

00:25:20.540 is controlled by the bowel itself.

00:25:24.040 Let me try to summarize that. You have these two muscular walls. One of them runs longitudinally,

00:25:30.100 so runs in the direction of the lumen. And one runs orthogonal to that. It runs circularly.

00:25:36.340 This is one of the things I remember from anatomy, was that you have these things where if the 0.79

00:25:42.240 circular inner layer contracts, that shrinks the lumen. And the longitudinal one, as it contracts,

00:25:49.600 shortens it along its long axis. And I think that's what permits this remarkable peristaltic,

00:25:55.780 rhythmic contraction of the gut.

00:25:57.260 Yes. I can talk to you about the behaviors of the gut. But the behavior of the gut is not so simple

00:26:05.260 as to have just one peristaltic movement. When you look at it, it seems to be moving rhythmically,

00:26:12.420 but it's much more complicated than that. It doesn't do that all the time.

00:26:17.060 Interesting. So that first part of the enteric nervous system, which is the myenteric plexus,

00:26:23.200 sits between those two layers, correct? That's correct. Yes.

00:26:28.000 And then beneath those muscular layers is when you get into that very tough submucosal layer.

00:26:36.380 And it's between that circular muscular wall and the submucosa that you have the submucosal plexus.

00:26:42.960 That's absolutely right.

00:26:44.520 And then of course, inside the submucosa, you have the mucosa, and then ultimately the lumen on the very

00:26:51.800 inside with the enterocytes that form the endothelial lining of the gut. Give me a quick

00:26:56.780 sense of the epithelial turnover. What is the, I don't know, median residence time of an epithelial

00:27:02.400 cell in the gut? They vary depending on the type of epithelial cell, but you turn the gut,

00:27:09.440 the epithelium over about once a week. Interesting. And when you say it varies, I assume you mean

00:27:15.400 from, say, the proximal jejunum to the ilium to the colon? Is that what you mean in terms of location?

00:27:22.380 No. What I was talking about is that you have certain cells in the lining of the gut,

00:27:28.360 such as a cell called the paneth cell, which is in the base of the crypt, which is getting into the

00:27:36.440 weeds here. But it's a part of the folding of the lining of the gut. But the paneth cell has two

00:27:44.300 major functions. One is that it's defensive and it puts out a number of antibacterial proteins

00:27:53.120 that keep the lining, particularly of the small intestine, sterile or close to sterile. Only a few

00:28:01.240 thousand microorganisms per cubic milliliter. But the large intestine doesn't have those, but it has

00:28:09.980 cells that put out the equivalent kind of antibacterial product that helps to fend off the bacteria from

00:28:17.540 getting too close to the lining of the gut. The other function of the paneth cell is to nurse

00:28:23.880 the stem cells that turn over all of the cells. So the paneth cell lasts perhaps three weeks.

00:28:32.920 You also have in the gut endocrine cells. These are enteroendocrine cells that produce hormones

00:28:40.960 that are in the lining of the gut and they're a little bit longer lasting. The enterocytes that

00:28:48.080 you talked about turn over very rapidly. Well, we're going to come back to those endocrine cells

00:28:54.080 pretty soon because that's a very big part of this gut-brain connection I want to explore.

00:28:58.700 I do have kind of a random question for you though, Mike, which is in some ways it's not

00:29:03.620 surprising that the colon is so susceptible to neoplasia, to the formation of cancer, because

00:29:12.300 it has at its surface a cell that turns over so frequently and therefore it's turning over

00:29:19.280 constantly. And as a result, you probably have more and more chances for genetic errors of

00:29:26.020 replication that produce mutations that are oncologic. I find it interesting that the small

00:29:32.000 intestine, which presumably turns over at roughly the same pace, is almost void of cancer. Do you

00:29:40.560 have a thought as to why that's the case? Well, people have speculated on that. One part of the

00:29:47.200 answer is that microbiome to which the large intestine is exposed as orders of magnitude larger,

00:29:56.020 than that of the small intestine. And the other part of it is that the products that sit in the

00:30:04.020 lumen of the large intestine sit there for much, much longer. The small intestine digests food and

00:30:11.040 it just goes by very fast. So in terms of being exposed to environmental toxins or toxins produced by

00:30:19.640 organisms that are split off from what you eat, the large intestine, which acts as a sewer,

00:30:28.920 really is exposed to very much more. My recollection is most of the nutrient absorption is taking place

00:30:35.980 in the small intestine and that the large intestine is mainly reabsorbing water. Is that right?

00:30:41.880 Yes, but not quite because what the large intestine does is conserve sodium. So it absorbs sodium and

00:30:51.480 secretes potassium and water follows the sodium as it's coming back into the body. So the colon acquired that

00:31:03.000 function and it enables organisms to live on land. When organisms lived in the water, conserving sodium

00:31:12.280 and water was not such a problem. Living on land makes it so. The bulk of the water that the gut absorbs,

00:31:21.720 however, is not in the large intestine. It's done in the small intestine together with the bulk of

00:31:28.920 most of most of what else you absorb. Still, the final 100 milliliters or so per day of what you absorb is

00:31:38.040 polished off in the colon and it is important in maintaining the body's fluid content. If you lose it,

00:31:47.400 as one does in cholera, where cholera toxin turns sodium absorption into chloride secretion, water flows out

00:31:57.000 and you can die of dehydration in about four hours. And people do with cholera. So it's a great plague.

00:32:06.200 Perhaps three million people a year die of cholera, even today.

00:32:09.720 Three million people a year die of cholera today?

00:32:13.000 Correct.

00:32:13.720 I had no idea. Where is this primarily happening? Is this in Africa and Asia?

00:32:17.880 At the moment it is, but there have been major league outbreaks in our hemisphere. One began off the

00:32:26.840 coast of Peru with contaminated crab. That led to cases that were as far north as New Jersey,

00:32:35.320 as people ate contaminated crab. Haiti, of course, is the most famous one. There was a great earthquake in

00:32:43.560 Haiti. Haiti destroyed a lot of their infrastructure. They had a group of peacekeepers from the United

00:32:51.160 Nations from Nepal that was stationed there and they brought cholera with them, put it into the water 1.00

00:32:58.680 system of Haiti. It got into the rivers and streams and is now endemic in Haiti. So it reduced the

00:33:05.480 population of Haiti considerably. But it is mostly in Asia and Africa.

00:33:11.400 Are there direct treatments for it or is the only treatment supportive care to prevent dehydration?

00:33:17.240 Well, it's a very simple illness. All one has to do is keep track of the water. So you put a

00:33:25.240 patient on what is known as a cholera cot, a gurney with a hole in the middle for the anus to be

00:33:31.720 positioned over. You put a bucket under it. The nurse puts a ruler into that bucket periodically to see 0.94

00:33:39.560 how much fluid is coming out. You replace it intravenously and orally. The great life-saving

00:33:49.080 discovery was that although cholera blocked the absorption of sodium, it does not block the

00:33:55.240 absorption of glucose in the small intestine. And so adding a little bit of sugar to the fluid that

00:34:03.320 you're using for oral rehydration has saved countless millions of lives. Just that simple

00:34:09.560 thing. So antibiotics have no use at all in cholera. Zero.

00:34:14.520 Does the immune system basically, if given enough time, fight it off and all you're doing is just

00:34:21.240 supporting the hydration status of the person until your immune system kicks in?

00:34:24.920 Correct.

00:34:25.720 I want to go back to something you said earlier. You made a point to talk about the intrinsic

00:34:30.760 innervation. And I realized that there are going to be people listening who might not know the difference

00:34:35.960 between intrinsic and extrinsic neurons. Can you explain what that means in the context of the gut,

00:34:41.400 please? So the intrinsic nervous system of the gut is a term representing the nerve cells that live

00:34:48.600 within the gut. We've described them, the two plexuses. The extrinsic innervation includes the brain,

00:34:57.880 which sends fibers to those neurons, and the sympathetic nervous system, which projects from outside the gut

00:35:08.600 into it. And it also includes the spinal cord and the ganglia associated with the spinal cord,

00:35:17.160 sensory ganglia, and dorsal root, which provide a sensory innervation of the gut. So those are all extrinsic

00:35:25.240 nerves. Intrinsic means that the cell body of the nerve cell resides within the gut. Extrinsic means that the

00:35:35.800 cell body is outside the gut wherever. Mike, one of the things I'm sure anybody listening to this can

00:35:42.440 appreciate is the incredible pain that one experiences with distention of the bowel. I used to be a general

00:35:50.680 surgeon, so when patients present with bowel obstructions, it can be as painful as a bowel

00:35:56.680 perforation. And it's so important to be able to put a nasal gastric tube in them and decompress them.

00:36:02.440 And again, even if you haven't had a bowel obstruction, just if you're bloated or something

00:36:06.040 like that, it can be incredibly uncomfortable. So explain to people how that pain of distention in

00:36:12.420 the gut is being communicated to their brain where they're obviously conscious of the discomfort.

00:36:17.080 Let me make two points. One is that essentially pressure of the kind that which you're speaking,

00:36:24.200 whether very severe, as you've mentioned, or much less so, the only way the gut feels pain is in

00:36:33.000 response to dilatation or pressure. You can cut the inside of the gut with impunity. So surgeons are

00:36:42.200 constantly doing that, taking biopsies from inside the gut, and that can be done without anesthesia.

00:36:48.920 Yeah. So it's differently innervated from the point of view of pain than the skin, for example.

00:36:56.200 The skin feels pressure, but it's much less of a painful stimulus than cutting. The gut is exactly

00:37:05.800 the reverse. Most of the fibers that get excited when you press increased pressure are located in the

00:37:15.200 dorsal root ganglia. Those are pain fibers that relay the signal to the brain by way of the spinal cord.

00:37:24.080 The vagus nerve has some pain, but not much. Mostly, the vagus nerve carries information back to the brain

00:37:33.920 that has to do with signaling what is called homeostasis, which means we don't know for

00:37:40.960 exactly what it all is, but you need it. Before we leave kind of the anatomy and

00:37:47.920 innervation of the gut, you mentioned the CNS functions kind of like the CEO providing broad

00:37:54.720 instruction, but not necessarily minutiae-driven operational instructions. Can you give an example of

00:38:04.000 what type of information is conveyed by the CNS and how that information is enacted locally?

00:38:11.760 Let me give you an illustration this way. One of the things we do as scientists is depend for our

00:38:19.120 funding on the NIH. And we send in grant applications in which we try to give our research its best look,

00:38:30.480 undergoes peer review, and then the government decides on the basis of the peer review on two levels,

00:38:38.800 whether to fund it or not. So when I wait to hear how my grant has done on peer review,

00:38:46.240 I become acutely aware of the kind of effect the CNS can have on my gut. And after three trips to the john,

00:38:54.640 I will go and open the computer and find out. So what I'm saying is most people can resonate with

00:39:04.640 that because they felt it. This feeling of butterflies, this feeling of tension-induced diarrhea,

00:39:11.760 that is all coming by way of the CNS. Similarly, some people, when they're frightened or traveling,

00:39:23.520 just completely lose the ability to defecate. They become constipated.

00:39:29.840 I always assumed that that was due to the dehydration of air travel, but it sounds like

00:39:34.080 you're saying there's more to it.

00:39:35.360 There may be, yes. I think there is. Well, what it seems to come to is, for example,

00:39:41.680 the sympathetic nerves can slow the gut and make it less likely to defecate. And that is in response

00:39:49.920 to, as opposed to anxiety, to true fright. So for example, if you're fleeing a foxhole

00:39:59.280 because the enemy is coming, it's best if you don't have to stop to defecate along the way.

00:40:07.200 You've alluded now to the sympathetic and parasympathetic overtone of the CNS. So it

00:40:12.080 communicates that via acetyl-CoA and acetyl-choline, things like that. But at the local level, how does

00:40:19.840 the gut receive that message? And then let's use the example of anxiety-induced diarrhea.

00:40:25.520 The actual action taken by the gut is presumably more rapid peristalsis and less absorption?

00:40:33.920 That's correct. And that's all has to do with the enteric nervous system functioning. One theory,

00:40:41.760 which I believe, is that there are nerve cells in the gut called command neurons,

00:40:48.720 and they receive the input from the CNS. So it turns out that the number of fibers in the vagus nerve

00:40:56.400 that are running to the gut are pretty small in humans, 3,000 to 5,000. It's been estimated.

00:41:04.960 And the number of nerve cells within the gut are in over 100 million.

00:41:10.320 So the intrinsics outnumber the extrinsics by three orders of magnitude, if not more.

00:41:16.480 So that raises the question, how do these nerve cells control it? As I've said, as a CEO,

00:41:24.080 they can get to command nerve cells and start reflexes going, keep things moving more rapidly.

00:41:32.400 The gut has a number of different behaviors. It's not just propelling at all times. If the gut were

00:41:38.000 propelling, as I described it with oral contraction, anal relaxation, as it's capable of doing,

00:41:45.840 then social discourse of the kind we're having right now would become impossible.

00:41:51.440 The gut has to sometimes stop. And so one type of behavior is just essentially parishes. The gut stops

00:42:02.240 moving. A second type of behavior that the gut shows is mixing in which it allows the enzymes

00:42:12.720 that it puts out to do digestion. And anybody who's ever taken time in an organic chemistry

00:42:19.600 laboratory will tell you nothing very much happens unless it's stirred. So the gut has a mixing process

00:42:26.240 process in which it's just goes back and forth, back and forth, no propulsion. And then it's able to

00:42:36.080 sense what goes on. And when digestion has occurred sufficiently, it propels it on. It can also during night

00:42:46.320 while you're sleeping, a cleaning process goes through the gut in which a wave begins at the stomach,

00:42:55.360 goes down the small intestine, down the large intestine, and cleans the gut out. Open sphincters,

00:43:02.880 so the things that would ordinarily be much too big to pass can go through. So a little kid can swallow

00:43:10.000 a paper clip, a dime, sometimes an open pin, and all those things are passed. And miraculously,

00:43:19.520 I don't know how the gut manages it. But if an open safety pin goes in, somehow it manages to propel it

00:43:26.640 all the way down with the small end down. And it almost never gets stuck.

00:43:32.080 So let's pivot a bit to appetite. Obviously, the gut plays a very important role in the regulation

00:43:39.440 of our appetite. And this, I suspect, is an area where the gut and the brain

00:43:45.040 are in a high level of communication. Can you walk us through what that looks like?

00:43:51.040 And let's assume we're talking about this in a non-pathologic state, because obviously,

00:43:54.640 there's going to be things that I assume can hijack this process.

00:43:58.320 A number of factors play into it. Distension of the stomach being one, so that as the stomach is

00:44:08.000 pushed out, it tends to cause satiety and decrease your urge to eat. Another factor is not the level

00:44:18.160 of blood glucose, but the rise of blood glucose, the ascent of it. And these factors are sensed,

00:44:26.800 one by receptors within the gut, which send signals to the brain. And the other are cells within the brain

00:44:35.920 that are chemosensitive and detect nutrients within the gut. Another factor, which you alluded to before,

00:44:45.120 are the endocrine cells within the gut, which make hormones such as cholecystokinin,

00:44:52.800 which can signal to the brain by going through the blood-brain barrier to be received by neurons,

00:45:03.200 leptin within the gut. So there are a large number of hormones, hormone receptors in the brain

00:45:10.400 that can trigger your urge to eat, as well as nutrients that you absorb, as well as distension

00:45:20.000 of the bowel itself. So that the gut has receptors in it, and the brain has signals within it that

00:45:29.200 trigger the urge to eat. So basically mechanical and chemical are the two big means through which

00:45:35.600 this is communicated? That's correct. That summarizes it well.

00:45:39.120 So the mechanical are both in the actual stomach, but also in the small bowel?

00:45:45.840 Yes, to a lesser extent. And those are transmitted back from the gut via the vagus nerve?

00:45:52.960 Correct. The glucose rate of change, as opposed to absolute level,

00:45:58.880 is that directly sensed in the CNS? Yes, it is.

00:46:02.640 And that's fine because, of course, glucose easily traverses the blood-brain barrier,

00:46:07.200 so the gut doesn't need to be involved in that decision.

00:46:09.600 The blood vessels that provide blood to the brain have transporters that allow certain

00:46:18.880 chemicals from the gut, such as leptin and cholecystokinin, to be transported

00:46:25.040 so that they can affect the CNS directly. Where does ghrelin fit into this?

00:46:31.280 Ghrelin is another hormone from the gut that works in the opposite way

00:46:36.320 what we've been talking about. I've been talking about things that decrease food absorption. Ghrelin

00:46:43.280 is a gut hormone that promotes it.

00:46:46.160 So what amplifies ghrelin?

00:46:48.480 You mean what makes ghrelin be secreted?

00:46:51.120 Yes.

00:46:51.760 Well, there are certain chemicals in food that you eat that can do that. Mostly it's nutrients

00:46:58.960 that come into the body that suppress, like amino acids and fatty acids can suppress ghrelin

00:47:05.680 secretion.

00:47:06.320 Does that mean that ghrelin's natural state is to be secreted and it's the presence of nutrients

00:47:12.480 that simply turn that down?

00:47:14.480 Yes. It's secreted at a constant rate and it can be upped or downed.

00:47:20.480 So that inhibiting it is important to prevent the development of ghrelin effect.

00:47:27.280 And what about the type of meal? So if you took, you know, and this is the kind of stuff that's

00:47:32.080 done of course all the time in research models. I think Rudy Leibel and Mike Rosenbaum have done

00:47:36.560 a number of these experiments where you'll take mixed meal shakes versus solids. What are some of

00:47:41.840 the differences in the way that those things would affect satiety? And is it all done purely through

00:47:48.000 change in the speed of absorption or are there other factors between liquids and solids that might

00:47:52.640 factor into that?

00:47:54.240 Well, there are a number of factors. I just want to mention while we're on it that Rudy Leibel is

00:48:00.240 just across the street. He's a colleague over here of mine at Columbia.

00:48:04.240 Columbia. The rate at which the stomach empties varies tremendously depending on what you put into

00:48:12.640 it. So for example, if you just eat a saline meal, the stomach will empty much more rapidly than if

00:48:21.680 there's protein in it. And even protein will empty much more rapidly than if there's fat in it. So the

00:48:30.480 stomach senses the nutrients and the speed at which it empties regulates the dilatation of the stomach

00:48:40.320 and the signal that the stomach is sending back to urge satiety on the brain, which means that if

00:48:47.760 you're eating protein and fat, you will reach satiety much sooner than if you're eating just salt and sugar.

00:48:58.560 In terms of solids, solids do the same. Particles can't get through the pyloric sphincter unless

00:49:08.800 they're ground down to be millimeter or less in diameter. So only tiny things can get into the

00:49:18.880 small intestine. So solids will delay gastric emptying. The stomach has a particular form of behavior

00:49:28.880 which is amazing when you watch it. But one part of the stomach contracts massively and suddenly

00:49:36.560 and forces the bolus that's in the stomach up against the pyloric sphincter, which is the exit 0.54

00:49:44.160 of the stomach, which is shut tight. And this ramming action breaks up solids into the small particles

00:49:52.560 that can get through. At the end of it, if you still have some solids that are too big to reach that

00:49:59.840 level, they can get through, but during sleep when cleaning process operates and then the sphincter is

00:50:07.680 open. So solids will slow the emptying of the stomach. And anything that slows the emptying of the

00:50:16.160 stomach will tend to induce satiety and reduce the length of time during which you feel hungry and want

00:50:23.760 to eat.

00:50:25.200 The point here you make about the particles needing to be sub one millimeter to get past the pylorus is

00:50:32.400 kind of remarkable and gives you a sense of how much mechanical digestion the stomach is doing.

00:50:37.440 I mean, the pH must be helping that, but really there's just got to be a lot of mechanical shearing

00:50:42.000 that goes on of food stuff, correct?

00:50:44.160 Absolutely right.

00:50:44.980 The stomach doesn't get its recognition in this story. When you think about how small a

00:50:49.300 sub-millimeter particle is and yet how big things of food that make it into your stomach are,

00:50:55.140 and to think that it does this without fine instruments, it wouldn't be hard for me to make

00:50:59.380 a bunch of one millimeter pieces if you gave me a knife, but it's doing this basically inside a

00:51:04.100 soft reservoir using contraction and acid.

00:51:07.140 And some enzymes. It is a remarkable structure, but you can live without the stomach.

00:51:13.860 Given everything we've just learned about the stomach, let's talk about an operation where

00:51:17.780 we bypass it, right? One of the most successful operations for the treatment of both obesity and

00:51:23.780 type 2 diabetes is a gastric bypass. What happens in a patient, and this is kind of a remarkable

00:51:29.380 operation in the sense that in an instant, their upper GI tract is rerouted. It's not like they had

00:51:37.540 months and months to adapt to something new. I mean, there obviously is an adaptation post-op,

00:51:42.820 but it's an immediate change. Explain to folks what's actually happening in that procedure and how

00:51:48.900 it might explain some of the benefits we see almost universally in post-obesity and post-type 2 diabetes.

00:51:56.580 Well, for one thing, why does the stomach just put all those little tiny particles through?

00:52:03.700 That's because if they were to get into the small intestine, it would set up a lot of emergency,

00:52:13.540 don't do this kind of apparatus. In other words, satiety, stop eating signals,

00:52:19.540 signals go into high year. And what the gastric bypass is doing is it's triggering that emergency

00:52:29.700 procedure so that you're getting that satiety signal a lot. In other words, the kind of thing that the

00:52:38.340 stomach has evolved to keep in reserve is now coming to the foreground. It's no longer there as an

00:52:47.300 emergency to stop eating because I'm getting overwhelmed with signals. Usually, you get this

00:52:54.580 because people, as in the Roman Empire, when they would overeat, would force the system. The stomach 0.97

00:53:02.260 would dilate so much. They just overwhelmed the body and they ignored the signals. And so the small

00:53:11.300 intestine is there to back that up and get them to stop by making eating just so objectionable that it 1.00

00:53:18.980 stops. What the gastric bypass is doing is to make eating so objectionable that it stops sooner.

00:53:26.980 And you eat much, much less. That's the goal of it. Another way to do this is to put a band on the

00:53:34.740 stomach and interfere with that process of grinding the food down. So large particles do come through

00:53:42.900 the banded stomach and the same thing happens. And that would explain, Mike, why both of these procedures

00:53:51.220 can fail if a patient continues to consume very high-calorie liquids.

00:53:57.700 That's right. High-calorie liquids are the way around it.

00:54:00.980 One of the things I always say to people that are trying to lose weight is a pretty obvious

00:54:06.340 insight, but this provides a better mechanistic explanation for why, is try not to drink any

00:54:11.940 calories. Drink water, drink tea, drink coffee, etc., but minimize the number of calories that are

00:54:16.740 coming in via liquid, which includes alcohol, by the way. Yes. Last I saw, alcohol is a liquid.

00:54:23.620 Let's talk now a little bit about the role of neurodegenerative diseases and the gut.

00:54:29.940 How long have you personally been interested in this connection between diseases of the CNS

00:54:34.980 and the gut? Oh, probably about 30 years or so. I've recently become, if I might digress for just

00:54:43.860 a second, even more interested in the sense that I've discovered with my wife that the gut is a source

00:54:52.260 of infection by varicella zoster virus, which is the virus of chicken pox and shingles.

00:54:58.900 And so shingles of the gut can occur. That can be very, very serious.

00:55:04.660 So I've never heard of that. Let's give people a bit of background on how varicella zoster remains

00:55:10.580 dormant after you have chicken pox and comes back as shingles. I think people are probably

00:55:15.060 somewhat familiar with that, but maybe worth re-explaining and then, of course, bringing in

00:55:20.020 this new idea that you've just brought up. The word that is generally used is latent rather than

00:55:26.660 dormant, but people get the picture. It's because it's essentially there, but not sleeping. It's just

00:55:34.660 quiet. Anyway, so when you get chicken pox, you clear the virus and it forms what is known as an

00:55:43.060 episome in neurons and just sits there latent without causing infection for years and years and years.

00:55:50.820 And essentially, all of us die with the virus that gave us chicken pox. It just stays with you for

00:55:57.540 life. For reasons that are unknown and only be speculated upon, they reactivate. And reactivation

00:56:08.440 gives rise to the re-emergence of active virus. And it always starts in a nerve cell because it's been

00:56:16.680 latent in a nerve cell. That's the site of latency. We know the virus becomes latent when

00:56:23.400 it's in dorsal root ganglia because then it goes down the axon or the process from the dorsal root

00:56:31.720 ganglion to the skin and causes a rash. And because you have immunity, it stays just in the nerve and in

00:56:41.960 the skin and doesn't give you a systemic disease like chicken pox was because when you had chicken

00:56:49.640 pox, you had no immunity. So it stays localized. And because the nerve cells die and become extremely

00:56:57.240 active in their pain nerve cells, it can be an extremely painful rash. In 15% of people in which

00:57:05.000 that happens, there's a condition called post-herpetic neuralgia or PHN in which pain

00:57:11.720 persists for years that is very difficult to treat. And some people are driven to suicide

00:57:18.440 because of this uncontrollable pain. Mike, is that not something that's amenable to

00:57:24.120 nerve killing? You know, for example, they can sclerose the dorsal root ganglion from which the pain is

00:57:30.020 emanating? No, there's no good at all. It's pathological pain and the virus isn't there.

00:57:36.340 The nerve cells are no longer causing the pain. It's coming from within the CNS. It's sort of like

00:57:43.140 a phantom limb in which people cut off a limb and people have the feeling the limb is still there,

00:57:49.700 but it's not. So it's very difficult, as I've said, to treat. There are some drugs that do some

00:57:56.340 good, like gabapentin, but nothing is wonderful. What is it about the varicella zoster virus

00:58:03.380 that produces this very peculiar inability to die even after the immune system gets ahead of it?

00:58:10.740 Back when I was a kid and you were a kid, we all got chicken pox. I think today they even vaccinate

00:58:15.460 kids, don't they? Yes, my wife developed that vaccine. She's famous for that. Oh, wow. So despite

00:58:22.340 either natural immunity or vaccine-induced immunity, when this virus comes into you,

00:58:27.140 it stays, as you said, and remains latent in the dorsal root ganglion. Why is that the case? Why

00:58:32.660 doesn't the immune system completely eradicate it like it does in virtually every other virus we

00:58:37.540 encounter? Because when the virus is in a nerve cell, the immune system can't see it. I see. So this

00:58:43.780 is more of an artifact of where this virus likes to spend its time, or where it retreats to,

00:58:49.220 maybe is a better way to describe it. Let's call it a sequestered virus, and it sits as a piece of

00:58:56.500 DNA inside of your body, and your immune system can't see it because it's not expressed on the

00:59:02.660 surface of the nerve cells that have it. The immune system has a very good look at it when it reemerges,

00:59:09.940 and you attack it, kill the cells in which it reemerges, but pain can continue in a small number

00:59:17.540 of people even so. What we've discovered, much to our chagrin, is that the enteric nervous system

00:59:26.180 can be infected by this virus when you have chickenpox, or when you get the live virus vaccine.

00:59:33.540 It can establish latency within the intrinsic nervous system of the gut, in the enteric nervous

00:59:39.620 system. And when it re-arises, even if it gets killed by the immune system, it's killing nerve

00:59:46.580 cells. And so you get diseases such as pseudo-obstruction in which the gut loses the ability

00:59:54.580 to work and just becomes totally paralyzed. Or if the virus emerges and gets into the mucosa,

01:00:03.380 the gut can perforate. And what's the frequency that this happens in?

01:00:07.460 We don't know. It's just been discovered. The most shocking thing that we've just published on

01:00:13.860 with this is that it gets into the nerve cells and reemerges in the esophagus and causes a disease

01:00:21.700 called achalasia. And the ability of the esophagus to deliver food to the stomach is lost. The esophagus

01:00:30.500 can't open, so you can't swallow it all. And just to be clear, this can occur during primary

01:00:37.140 infection or reinfection, or is this just during reinfection? Just during reinfection.

01:00:42.660 What triggers the reinfection? I mean, I think most people understand that...

01:00:46.260 If I could answer that question, I believe I could get an all-expenses-paid trip to Stockholm in December.

01:00:54.340 And if not there, at a minimum, you would probably get free dinner at Red Lobster every Tuesday for the

01:01:02.340 rest of your life. That's the second prize after the Nobel Prize. Yeah, it's interesting. I mean,

01:01:07.700 we know it's a disease associated with aging, or the reactivation is associated with aging,

01:01:11.700 and we know that things like weakened immune system can see it. I think in the early days of HIV,

01:01:16.500 we would see patients.

01:01:17.620 A weakened immune system is part of it, and that's how you get to aging. That sets the state. It seems

01:01:24.100 likely that the virus keeps reactivating periodically throughout your life, and that when you have

01:01:33.060 shingles, just exceed a threshold because the immune system has receded just enough to let it out,

01:01:42.820 reach the clinical threshold. That's the idea.

01:01:46.100 And the current vaccine that we have, Mike, the Shingrix vaccine, the two-shot separated by six

01:01:51.860 months, this has been kind of a step forward, correct? That has been a giant leap forward. That's

01:01:57.700 been amazing. And the purpose of that vaccine is just to prime our immune system to the virus once

01:02:06.100 again to either catch it more quickly if it escapes DRG, or... Even more important,

01:02:15.060 the enteric neurons. It's about 97% effective. Remarkable vaccine.

01:02:22.500 Yeah, I got mine early. I'm not quite 50 yet, but I was like, ah, what the heck am I waiting for?

01:02:27.860 And the other thing I'll tell you is, what a kick in the chops that vaccine is. That makes you sick. 0.93

01:02:33.540 Actually, interestingly, the older you are when you get it, the less likely you are to be bothered by the

01:02:40.100 injection. I'm reaping the benefits of my young immune system as I get butchered by the Shingrix shot.

01:02:47.860 What about diseases like autism? You know, children with autism seem to have, as the severity of their

01:02:55.860 illness goes up, an increase in the prevalence of gastrointestinal illnesses. How well acknowledged

01:03:02.660 is that? Is that kind of loosely accepted or is that now becoming more accepted?

01:03:07.620 It's so accepted it's right. What can we take from that? What does that suggest potentially?

01:03:13.860 Well, autism is a disease involving probably synaptic transmission. It occurs in the CNS,

01:03:23.540 the well-known behavioral effects. It occurs also in the enteric nervous system with small effects on

01:03:32.100 the GI tract, some of which are constipation, but more frequently diarrhea.

01:03:39.940 There also seems to be a higher degree of food sensitivities and allergies, doesn't there?

01:03:44.260 Yes. That's not so well understood, but it does seem to be related to activation of mast cells.

01:03:53.300 Spoken with many parents of kids with autistic children and a lot of them are pretty convinced

01:03:59.620 that if they pay more attention to what their kids eat, they can reduce the severity of their

01:04:05.540 symptoms. This would not seem like an entirely unreasonable idea given the simple observation

01:04:13.860 of this association, correct?

01:04:15.540 It wouldn't seem to be unreasonable, but having said that, I would like to point out to you that

01:04:23.780 there's no regularity to the symptoms that you can point to. It's hard to back it up,

01:04:30.100 and people have been unable to produce any sort of rigorous background for that so that when you

01:04:37.780 put controls and constant observation, you just can't document it.

01:04:42.660 There must be so much variability that it almost seems like you have to be kind of empirical in

01:04:49.620 approach and probably no, I hate the term, but no one size fits all here, which is stating the obvious,

01:04:54.820 I suppose.

01:04:55.220 I should also point out that the area is a bit fraught because in 1991, a British gastroenterologist

01:05:05.780 by the name of Andrew Wakefield published a study of a large number of children, not a large number.

01:05:14.260 Yeah, it was actually a very small number. We actually did a podcast on this entire subject

01:05:19.140 matter, Mike.

01:05:19.780 Oh, did you?

01:05:20.660 Yeah, yeah. But by all means, go ahead and tell the story because not everyone will have heard that

01:05:25.140 podcast with Brian Deer.

01:05:26.740 Oh, well, he knows much more about it than I do. But in any case, Wakefield associated it with GI

01:05:35.700 inflammation, and his idea was that if you ate gluten-containing material, you could produce

01:05:45.540 from what you were eating what he called endorphins. That is, you'd eat an opiate-like material.

01:05:53.460 Magically, the enzymes, the digestive tract would liberate opiate-like products. You'd absorb these

01:06:02.260 opiate-like substances, and they would go to the immature developing nervous system and cause autism.

01:06:10.020 That is not the case. And his idea was that if you got measles, mumps, and rubella vaccine,

01:06:18.260 it would cause the defect in the gut, which could lead to the absorption of these products,

01:06:27.060 that was also incorrect. You can't train an enzyme to cut something differently than the way the genes

01:06:37.380 have programmed it to. So that trypsin looks for particular amino acids and cuts proteins there.

01:06:44.580 It doesn't care. It doesn't care what kind of endorphin is sitting somewhere else. Nothing can

01:06:50.420 ever make it cut that out. And then when it gets peptides out, peptides are essentially not absorbed.

01:06:59.700 The only thing that's absorbed are amino acids or maybe dipeptides, tripeptides. So tiny little

01:07:07.220 molecules are absorbed.

01:07:08.500 Yeah, let's make sure people understand the difference there. Amino acids are the building

01:07:13.860 blocks of peptides. A peptide is a string of amino acids, but the amino acid is the smallest

01:07:19.940 functional unit that makes up a protein. So we have these 20 amino acids, and you can string them

01:07:25.220 together in thousands and thousands to make complex proteins. But a small peptide of 9 to 11 amino

01:07:32.100 acids, for example, would be what the immune system recognizes. And what you're saying, Mike,

01:07:36.900 is from a GI standpoint, they have to be even smaller than an immunogenic peptide if they're only

01:07:43.060 sort of single amino acids or maybe two peptides or two amino acids joined.

01:07:47.940 That's correct. That gets absorbed. But even if there was some miracle happened and they got absorbed,

01:07:53.620 they couldn't get to the blood-brain barrier. They wouldn't, in fact, go past the liver.

01:07:57.460 So I testified, actually, to Congress on that subject.

01:08:04.180 Yeah, it's funny. Now that I think about it, Mike, I think you were actually mentioned

01:08:07.300 in Brian Deer's book.

01:08:09.680 I might have been. There was an exhibit at Science Museum in London called The Autism Files,

01:08:16.580 and I had a section called Mike's Miracles. And Mike's Miracles had to do with the way I was

01:08:24.240 phrasing in it when I testified to Congress. And I was threatened then by Congress.

01:08:31.280 You were threatened?

01:08:32.560 Yes. I was told that if I didn't recant my testimony, I would be charged with perjury.

01:08:39.680 I'm not sure I understand.

01:08:41.120 So I testified at the Congressional Committee on Government Oversight. And the chair of the

01:08:50.080 committee did not like my testimony in a major way. In fact, he had to be restrained

01:08:57.120 from throwing a gavel at me. And after that, when I went cringing into the cloakroom afterward,

01:09:05.920 Congressman Waxman from California came over to me and gave me a high five.

01:09:11.200 Remind me the name. I've forgotten now. What was the name of the congressman who was

01:09:15.360 adamant that Wakefield was right?

01:09:18.960 You got me. I can't believe it. I'm trying to think of the name. I was afraid you were

01:09:23.920 going to ask me that question.

01:09:25.360 Yes. Now this is all kind of coming back to me like a horrible, bad dream.

01:09:30.160 His grandson had autism and he was sure he got it from his vaccine. He said he could see this

01:09:37.200 wonderful child develop autism before they even got the needle out of his arm.

01:09:42.320 I know it'll come to one of us as we continue this discussion. Let's talk about serotonin before we

01:09:48.800 go further. Because serotonin levels are higher in at least a subset of kids with ASD.

01:09:58.000 And most people, when they think of serotonin, they associate it with a hormone in the brain

01:10:04.000 that is responsible for mood. Can you say a little bit more about serotonin and in particular,

01:10:09.760 the role of serotonin in the gut?

01:10:12.960 Well, serotonin is a molecule that I've been working on since college. I did my senior thesis

01:10:20.160 on serotonin when I graduated from Cornell in 1958, probably when dinosaurs roamed the earth when I was

01:10:28.560 young. In any case, serotonin was discovered actually in the gut. Enterochromaffin cells,

01:10:38.000 which are an endocrine cell of the gut, are responsible for making about 95% of the body's

01:10:44.560 serotonin. The brain produces about two to three percent of the body's serotonin. So although the

01:10:52.880 brain serotonin is probably what makes life worthwhile, that is living, and is responsible

01:11:01.040 for happiness, among other things. In terms of amounts, it's a little afterthought of evolution.

01:11:09.200 So within the gut, serotonin is made in two places. The bulk of it is made, as I've just said,

01:11:17.600 in the enteroendocrine cells, which are the small endocrine cells that are part of the GI epithelium.

01:11:25.760 It's a minor component of the epithelium, but a major component functionally of what the gut does.

01:11:32.720 About 80% of the endocrine cells make serotonin. The other source is serotonin-containing nerve cells

01:11:41.360 within the enteric nervous system. So it is a neurotransmitter and an endocrine substance in the

01:11:48.640 gut. It's very important in feeling pain in the gut. It's very important in triggering nausea. So in

01:11:59.200 sending signals from the gut to the brain, serotonin is an important transmitting substance.

01:12:06.720 During development, serotonin is very important as a growth factor. The first nerve cells to form

01:12:17.680 in the gut make serotonin. Subsequent nerve cells depend on serotonin, triggers them to develop.

01:12:28.560 So if you knock serotonin out of the nervous system, the gut winds up with too few neurons. It doesn't have

01:12:35.440 enough and it doesn't work very well. If you knock serotonin out of the epithelium, then there's

01:12:43.600 problems signaling back to the brain. And the peristaltic reflex is impaired. It's not stopped,

01:12:54.080 but it's impaired because the endocrine cells in the gut can trigger peristaltic waves that are

01:13:01.760 propulsive. But if you lose that, then in order to trigger it, you have to press harder and harder

01:13:09.360 and dilate the gut and get the nervous system to do this directly. It's highly involved within the gut,

01:13:18.800 and it also talks to the immune system. So it triggers inflammation. As you might imagine,

01:13:24.720 from the amount of it that's in the bowel, it does everything. It's a multifunctional molecule.

01:13:34.000 Now there's a class of medication, of course, that are used to treat the symptoms of depression,

01:13:39.200 and in some cases anxiety. And these medications, SSRIs, prevent the reuptake of serotonin,

01:13:46.400 this neurotransmitter in the brain, presumably leaving more of it around to exert positive effects.

01:13:53.120 What are the effects of SSRIs outside of the CNS? Do they impact the gut specifically?

01:13:59.680 Yes. They tend to cause nausea by enhancing the ability of serotonin to talk back to the brain

01:14:08.000 to trigger nausea. Drugs that are used in cancer chemotherapy also trigger the release of serotonin

01:14:16.160 within the gut and trigger that reflex. Same one. The SSRIs also first make the gut go a little bit

01:14:26.160 faster. But then when the gut keeps doing that, the receptors, that is the molecules upon which

01:14:33.760 serotonin acts, desensitize. One way they do that is to internalize. And so they can actually block the

01:14:44.000 effect of serotonin in transit. So in terms of motility, they can make the gut go faster,

01:14:51.440 and ultimately they stop the gut and give rise to long-term constipation and have to be stopped.

01:14:59.760 So they're nauseating, they change motility. And during development, if you give them to a mouse,

01:15:08.320 during fetal development, that is given to the mother during fetal development, you get an abnormal

01:15:13.920 nervous system in the mouse's nervous system because of the effect during fetal life.

01:15:20.880 Are SSRIs contraindicated in pregnancy?

01:15:24.640 They are used frequently and in large numbers, large amounts, in pregnancy because pregnancy is very

01:15:32.960 often associated with depression. Fortunately, most commonly postpartum. But even then it's a problem

01:15:39.760 because SSRIs can be communicated to the child in breast milk. But there is evidence that a number of

01:15:48.560 conditions are increased, such as irritable bowel syndrome, in the offspring of mothers who are treated

01:15:56.320 with SSRIs during pregnancy. Is that understood by the physicians that prescribe them? And obviously,

01:16:03.680 there were going to be scenarios where those risks are worth it if the...

01:16:08.160 Yeah, people worry about it. But let me tell you, depression is a potentially lethal illness.

01:16:16.400 And if you've got something in which to treat it, sometimes you just have to use it.

01:16:22.320 Yeah, I just wonder if, because there are alternatives, right? I mean, SNRIs can also be

01:16:28.400 very efficacious. Presumably, they don't have the same effect.

01:16:30.880 They do have some of the same effects because the SNRIs, serotonin and norepinephrine reuptake

01:16:39.840 inhibitors, they're just less... Less serotonin.

01:16:42.560 Not less serotonin, less selective for serotonin. They include norepinephrine as well. So that doesn't

01:16:49.360 get you anywhere. Let's talk a little bit about leaky gut. This is a term I think a lot of people

01:16:54.960 have heard of, and I think they sort of maybe get the gestalt of. But in the context of everything

01:17:00.320 we've been discussing, where we now have a pretty clear sense of what these enterocytes are up against,

01:17:08.000 on their one side. On the luminal side, they've got just a never-ending barrage of toxins, microorganisms,

01:17:16.960 bacteria, viruses, food stuff that have to be absorbed. At the same time, they can't be digested

01:17:23.680 by these things. We didn't talk about tight junctions specifically. Do you want to maybe

01:17:27.840 tell people what the tight junctions are that sit between these things?

01:17:30.800 Dr. Epithelia are the cells that line cavities. Epithelia have three types of junctions that

01:17:39.360 hold the cells together. One type is called the desmosome or a spot weld, just very tenacious,

01:17:48.720 hard to pull out connection between the cells. Another one is called the tight junction. Tight

01:17:56.880 junction has protein in the membrane on one cell, forms an attraction to the membrane across the cell,

01:18:05.280 transmembrane, and it obliterates the space between two cells. So the function of tight junctions

01:18:13.520 is to prevent material going through the channel between two epithelial cells. It's a plug in the

01:18:20.800 bathtub. There's another junction called an adhesion junction, which is essentially like

01:18:26.720 the spot weld, but it also is contractile. But let's concentrate on the tight junction because

01:18:34.160 that's what we're now talking about. And the more of these tight junctions you have between two epithelial

01:18:41.440 cells, the less leaky or permeable that connection is between them. So anything that interferes with tight

01:18:52.640 junctions can make the channel open and allow material from the lumen to get into the body but at the same

01:19:04.000 time allow material within the body to get into the lumen. And material going into the lumen is very

01:19:13.840 dangerous because, as I've told you, anything going into the lumen is lost from the body.

01:19:21.760 And so if you open tight junctions in the lining of the gut, you can essentially flow out into your

01:19:28.800 bowel. And Mike, besides the obvious, which would be water or electrolytes, is there ever a scenario where

01:19:37.600 nutrients that were actually absorbed now go back into the lumen?

01:19:43.120 Absolutely. And worse than that, protein from the body. It turns out that underneath the lining of the

01:19:50.000 gut, capillaries are very permeable and there's a lot of protein in the lymph, the fluid underneath the

01:19:59.040 lining. And so if you open the lining of the gut, that protein gets into the GI tract. And that's a

01:20:06.480 disease called exudative enteropathy. You lose protein and people with that disease can blow up and

01:20:14.320 look like balloons because edema goes all over the body. It's a terrible thing.

01:20:21.040 So Mike, what would you say is the most common cause of leaky gut?

01:20:25.440 Allergy.

01:20:26.000 Okay. So meaning there is...

01:20:28.800 Hypersensitivity. That is, the immune system is reacting and causing tight junctions to open.

01:20:36.480 Is this an allergy in the food specifically because the allergen is in the lumen?

01:20:42.640 Not always. For example, bee sting can cause this or can be injected or some other way that

01:20:50.560 you can get a toxin that can do this. I want to ask a question going back to something you said

01:20:55.880 earlier that I never really have thought about until now, but I've never thought this deeply

01:20:59.580 about the gut. You know when they say a shark, like great white sharks have multiple rows of teeth

01:21:04.600 so that they're kind of constantly just pushing forward. So when teeth fall off,

01:21:08.360 you kind of have new ones that have already grown into place. How does this epithelial layer

01:21:13.160 replace itself while preserving the tight junction? We're talking about every week or so these epithelial

01:21:21.560 cells slough off and new ones are present. Does that mean we have several rows of them ready to sort of

01:21:27.880 spring into action already tightly bound to their neighbors or how does that happen to preserve the

01:21:33.480 integrity? The gut is a range lining of the small intestine and to a lesser extent large intestine

01:21:42.040 so that the gut lining is highly folded. And there are projections that come up from the surface of the

01:21:51.480 gut that look like fingers. And these are called villi. So most absorption occurs on the surfaces of these villi.

01:22:03.160 Now between the villi, there are clefts called crypts. And at the base of crypts, there are stem cells.

01:22:12.360 And the stem cells, which live next to this other cell that I mentioned earlier called the panath cell,

01:22:20.440 can give rise to each of the cells that form the villi or line the gut. And there's an escalation

01:22:30.040 of those cells. The progeny of the stem cells keep rising. So as new ones form, other ones move up.

01:22:39.240 In part, the proliferation in the crypt produces a pressure that causes cells to rise as they

01:22:46.520 differentiate. But they're also mobile. So they crawl a little bit as well. And if you wound the

01:22:53.880 lining of the gut, then adjacent cells can crawl over the space and cut it off. At the tips of the villi, 0.93

01:23:02.040 there's a zone called the extrusion zone. And so the cells are born at the base of a crypt, climb up the

01:23:11.800 crypt, up the villus, reach the tip of the villus, die, and are puffed off at that point. So they stay

01:23:22.040 in contact with one another, and the tight junctions finally lose it when the cells die,

01:23:29.320 or the desmosomes, and they pop off. So the mechanism of death is called apoptosis. So they're

01:23:38.200 programmed to die. We talked about the importance of toxins, allergies, things like that playing a role

01:23:46.120 in leaky and inflamed gut cells. Are there any reputable assays that can identify what these are

01:23:54.920 in an individual that has otherwise vague symptoms?

01:23:58.120 If somebody has a substantially leaky gut, you would guess it from making a determination of

01:24:06.920 the serum protein, albumin. If the gut is leaking, albumin will be low. And so if you see a low albumin,

01:24:16.680 you can look for it. If you think it's true, you can look for an enzyme called alpha-1 antitrypsin.

01:24:26.520 Antitrypsin. Trypsin is produced by the pancreas. Antitrypsin blocks it, its action,

01:24:34.840 and it gets into the lining, into the gut. It should not be absorbed. It's a measurement

01:24:41.480 that will tell you whether the gut is leaking or not. By the way, there's an alpha-1 antitrypsin

01:24:47.240 deficiency disease, isn't there? It's a hereditary condition? Yes. What do those patients present with?

01:24:52.760 It's usually vascular and lung disease because there's too much digestive action damaging in

01:25:00.280 those organs. I think I said it wrong. Alpha-1 antitrypsin is on the luminal side,

01:25:07.560 sorry, on the vascular side. And if it gets into the stool, that's the problem.

01:25:13.640 I see. So we shouldn't be seeing it in the stool. Correct.

01:25:17.320 Do you have to see low albumin to make the diagnosis of leaky gut? Because that's a very

01:25:23.680 significant leaky gut. I mean, if a person is exuding protein to the level where it shows up

01:25:29.620 in their serum albumin, that would strike me as a lot of leak, correct? Correct.

01:25:34.280 Are there milder leaks that don't allow something as massive as albumin to escape,

01:25:39.320 but do allow toxins and microorganisms in? That is now getting onto the level of controversy,

01:25:49.240 but it has probably not toxins in, at least not to a great extent. Maybe a little bit, yes,

01:25:57.160 and take it back a little bit. And you can look for those by giving various peptides or fluorescein

01:26:07.240 or dyes that measure it by oral that should be excluded from the blood and seeing if the fluorescence

01:26:17.080 gets into the blood. Or you can measure it with certain sugars that should not be absorbed. And if

01:26:24.600 the non-absorvable sugar gets into the body, then you'd assume there's a slight leak of the kind

01:26:31.480 you're talking about. And do we think that there is a causal relationship between leaky gut and autism

01:26:39.320 spectrum disorder? Or do we think that these are things that move together for a similar underlying

01:26:44.840 pathology? The problem in the gut in autism spectrum disorder is a disorder of the nervous system. It has

01:26:53.800 nothing to do with leaky gut. That's part of the Wakefield hypothesis, leaky gut. No evidence that

01:27:00.680 that's correct. Let's go back and explain again, now that we've talked more about serotonin,

01:27:06.280 what do we think is the relationship between, do we see more leaky gut in ASD? Not really. Let me give

01:27:14.280 you an illustration. My collaborators and I have produced a mouse called G56A. This mouse has a

01:27:25.880 mutation in the serotonin transporter. The serotonin transporter is the protein that you spoke of before

01:27:37.320 that is the target of SSRIs. It is what the SSRIs inhibit and which removes serotonin from the

01:27:46.520 circulation or from the synaptic cleft when it's a neurotransmitter. What this mutation does though

01:27:56.040 does not inhibit SIRT is not inhibit SIRT but make it more active. So SIRT becomes what I like to call

01:28:03.880 the super-SIRT mouse. This animal has essentially a deficiency of serotonin. It is so effective

01:28:12.680 at inactivating serotonin after its release that it doesn't have a chance to act. So that animal has

01:28:22.040 a smaller nervous system in the gut, too few neurons, and it has slow transit and it has

01:28:32.200 a problem in the gut. In the brain, it doesn't socially interact with other mice. If you put them

01:28:41.000 in a tube, two mice convene. One with the mutation backs out and lets the other mouse through all the time.

01:28:49.480 And it has repetitive behaviors. It keeps tapping its foot, hitting its head against the side of the

01:28:56.760 cage. So it has central features that look like autism, and it has a GI tract which is abnormal.

01:29:07.320 Abnormality is seen in about two percent of patients with ASD. So it was the human abnormality put into

01:29:17.160 a 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

01:29:28.440 can give rise to autism, put into a mouse, shows autism, and also defect in the gut. The defect in

01:29:38.200 the gut has to do with serotonin and the ability of serotonin to act as a growth factor. So there's

01:29:45.880 a deficiency in terms of numbers of neurocells in the bowel. In a patient with autism spectrum disorder,

01:29:55.080 similar kinds of things happen. This, by the way, is exactly the opposite effect of giving a mouse

01:30:03.480 during development an SSRI. So if you give a mother SSRI, they get too many nerve cells 0.97

01:30:12.760 growing in the gut. If you knock out the transporter, you have too many nerve cells in the gut.

01:30:19.160 And if you make the transporter more active, you have too few.

01:30:23.320 And remind me again, the phenotype of the former, when you have in utero exposure to an SSRI.

01:30:30.520 You have too many nerve cells in the gut. And so gut motility becomes defective.

01:30:38.360 Let's talk about bacteria now. We very briefly touched on it earlier, and I knew if I started,

01:30:43.400 I wouldn't stop. And the first time it came up was when we talked about the difference between the colon

01:30:48.040 and the small intestine. And one of the many differences between them, of course, is the flora.

01:30:53.560 Can you give people a sense of how many bacteria exist in the small intestine? And let's start,

01:31:00.280 maybe even divide them into three. Let's talk about the proximal small intestine. So the jejunum,

01:31:05.800 the late small intestine, you know, the ileum before it gets to the cecum, and then the colon.

01:31:11.320 What's the relative difference in bacterial colony? 0.72

01:31:14.200 The numbers of organisms descend, that is, or ascend as you go down the gut, so that you have more of

01:31:24.120 them close to the colon. And it's thought in large way that stomach acid sterilizes to a large extent

01:31:34.840 the food that you eat. Although there are bacteria that can be found even in the stomach in the

01:31:41.640 presence of one normal hydrochloric acid, helicobacter pylori being the prime example of an organism that

01:31:49.640 can survive. But the small intestine then neutralizes stomach acid, but benefits from that acid because

01:31:59.320 very few organisms are dumped into it. The motility of the small intestine and the fact that the smaller

01:32:08.600 numbers of organs of organs come in contribute to keeping the number down as the gut pumps its way on 0.96

01:32:15.480 down. In addition, there are cells like PAN-S cells, which make antibacterial proteins, which are called

01:32:24.600 defensins, which help to keep the lumen of the gut not sterile, but close to it. As you get closer and

01:32:33.640 closer to the colon, the mechanisms, the numbers of PAN-S cells decline, the gut slows down, and you're getting

01:32:43.560 close to a large number of organisms which live in the colon. And they're separated by the ileocecal

01:32:50.840 sphincter from the colon. When the bolus of food gets into the colon, well, not just food, it's by then

01:32:59.800 chyme. It's been digested. When that material is delivered to the colon, it goes into a region where

01:33:07.560 it will spend some time. And in the colon, there are huge numbers of organisms. Now, the numbers of

01:33:15.080 organisms are about equal in number to the number of cells of the body. We're talking trillions.

01:33:21.320 And you have perhaps tenfold more bacterial genes than you do your own genes in your body.

01:33:30.360 And what are the classes of bacteria? Are these all gram-negative?

01:33:34.440 No. A lot of them are gram-negative. What they do have in common is that they are almost all

01:33:42.280 anaerobes. That is, they live in the absence of oxygen. And most of them are very hard to culture.

01:33:50.200 And so until relatively recently, we had no idea what a teeming mass of organisms were in there.

01:33:59.160 I mean, people all knew for a long time that the colon stool wasn't sterile. And people culture

01:34:06.360 stool. But most of the organisms are highly resistant to culture and have been detected through molecular

01:34:14.600 biology. You look for the genes.

01:34:17.880 So now that that's been done, I assume we've done the equivalent of the human genome project

01:34:22.840 for the human colon. There tend to be a few classes of these things, right? I mean,

01:34:26.840 Bacteroides is pretty common, Actinobacteria, Proteobacteria. I mean, what are the broad categories

01:34:33.000 of these facultive anaerobes and such?

01:34:35.400 Well, there are about 16 different classes, and I can't remember them all. One of the largest of

01:34:42.760 them is the Firmicutes. But Bifidobacteria and Lactobacteria, those tend to be bacteria that we

01:34:51.320 think of as good. Clostridia tend to be organisms that mostly are bad, but not entirely. Some of those

01:35:02.040 bacteria are related to causing cancer. Some of those bacteria are highly protective.

01:35:10.200 And they do stuff for us. For example, one of the things we eat a lot of is fiber. Celery,

01:35:18.600 for example, celery or lettuce. We don't digest that. We have no enzymes that can digest that.

01:35:26.600 But we have bacteria in our gut that live on that. And they digest that. And they make

01:35:34.840 short-chain fatty acids from that. And those short-chain fatty acids are absorbed by the lining

01:35:41.560 of the colon. And our colonic epithelia are dependent on the bacteria to keep going. And they get the bulk

01:35:50.840 of their energy from the bacteria in the gut. The bacteria also make certain vitamins that we can't

01:35:58.360 live without. Vitamin K being the most famous of them. So clotting of blood depends on the bacteria.

01:36:07.080 And as you probably know, they also seem to regulate things like mood and obesity.

01:36:17.400 It just strikes me as one of the most poorly understood connections for something that has

01:36:25.080 such a high impact on human health at this point still. Obviously, we know more today than we did

01:36:31.720 20 years ago. But in many ways, it still feels like this is a bit of a black box. Is that just my ignorance?

01:36:37.320 No, it's our ignorance. So why are we ignorant, you might ask? And the answer is, I've just told you, 0.93

01:36:45.640 we can't culture most of those organisms. They are extremely difficult to study.

01:36:51.720 And Mike, is that, pardon my ignorance, I'm not a cell biologist, how much of that difficulty is

01:36:57.960 because they're anaerobic and just logistically it's more complicated to culture organisms in the

01:37:04.520 absence of oxygen? Or is there something that even goes beyond that?

01:37:07.400 Oh, it goes well beyond that. We don't know the nutrient nor broths and things through which they

01:37:12.840 can live. It's easy enough to make an atmosphere that has no oxygen in it, but it's not so easy to

01:37:19.960 figure out what they need to live. Colon produces a great environment and how to match it is not so easy

01:37:27.160 to figure. This is a very remarkable evolutionary tale and also perhaps the most interesting symbiosis

01:37:34.760 we experience. This strikes me as a more interesting symbiosis than the one we share with bacteria on

01:37:42.760 our skin. Is that a fair statement? I think so, because the bacteria are able to get involved with

01:37:51.320 the nervous system in a way that bacteria in the skin pretty much do not. So for example, the bacteria

01:38:00.520 that are in the gut can activate lining epithelial cells for enteroendocrine cells to release serotonin

01:38:10.520 or other factors, other chemicals from them. And that can signal by way of the vagus nerves

01:38:17.320 to the brain. Or chemical products that the bacteria make can also trigger nerve signals that send signals

01:38:27.640 back to the brain or even go through the blood-brain barrier to affect the brain. So that experiments

01:38:34.760 can be done, for example, with mice in which one can breed germ-free mice. Germ-free,

01:38:42.520 notobiotic is the term for that. Germ-free animals grow up without any contact or organisms in them.

01:38:49.640 I'm not trying to understand how that's possible, Mike. I mean, I've heard about it,

01:38:52.360 but I've never really understood it. How do you have a germ-free animal? How do you feed it?

01:38:57.800 You're feeding it sterile food into a, and they had to have been born because this would have begun 0.96

01:39:03.400 gestationally. That's right. So they're all born by cesarean section. They're fed sterile food,

01:39:10.760 and they live in incubators, and people handle them with gloves. What's the phenotype of that

01:39:17.480 animal after two years relative to an otherwise identical animal that's born normally and fed

01:39:23.480 normally? Let's go one year. Okay. That tells me something really changes. Yes. So for one thing,

01:39:32.200 the numbers of nerve cells in their gut, their motility, the lining of the gut, they're all different.

01:39:39.720 They're very much more primitive. They have almost no spleen. They have none of the pyre's patches

01:39:47.560 that we, you know, talking of the immune cells. So their immune system must be horrible. Yes. They

01:39:53.320 have no immune system, but they have a thymus. And so they can develop an immune system in a big hurry

01:40:01.320 if they survive. You take them out and expose them to bacteria. But what you can do with the organisms,

01:40:07.960 with the gut, is use them as vessels and recolonize the gut with organisms. So for example, if you take

01:40:17.320 those animals and colonize them with bacteria derived from a strain of mice that tend to be lean,

01:40:24.760 you get lean, you get lean mice derived from those animals. If you colonize them from a strain of mouse that tends to be fat,

01:40:35.640 those animals grow up to be fat. And you can cross strains. So that seems to indicate that bacteria can determine

01:40:47.320 obesity or lack thereof.

01:40:50.040 Yeah. How do we think this plays out in humans where it's not as extreme? We don't have sterile humans,

01:40:56.440 but your point is, and I believe there have been some experiments done. You'll have to correct me

01:41:01.080 because I don't follow this literature, but haven't they done some fecal transplants from lean to obese that

01:41:08.040 have at least partially addressed the phenotype?

01:41:12.200 Correct. And also anxiety seems to work in its very similar fashion. But what you have to take with

01:41:21.640 the human is always everything with a grain of salt because the experiments are very difficult to do

01:41:29.320 and they're all flawed because you can't deal with pure organisms, pure humans, what they're retaining.

01:41:37.080 Do you have any idea how many such transplants have been done where they've done a fecal transplant

01:41:42.840 from a lean to an obese individual? How many times has that been done under a controlled setting?

01:41:48.120 Why do you think that type of research, while admittedly complicated, is technically feasible

01:41:54.040 and has a potential for enormous... Fecal transplantation in humans, it's not without danger.

01:42:01.400 For sure. Tell people how the procedure works and obviously what the risks are because I believe the

01:42:06.440 only approved use of the therapy is for C. difficile. So you've already alluded to clostridia before.

01:42:13.720 Yeah. Let me just say clostridium difficile is a normal component of the GI tract. Many,

01:42:21.320 many people have it. And it sits there. And with your organisms, one of the major ways that you control

01:42:29.480 the various bacteria is to have other bacteria. And so the bacteria control themselves. There's a

01:42:36.760 competition for how much nutrient is there and they make toxins that affect one another. But people then

01:42:46.440 take antibiotics. And the major effect on the human microbiome is an antibiotic. For the most part,

01:42:56.200 we like to think antibiotics are used effectively and appropriately when you have an infection. And they're

01:43:03.960 given to you to fix that. Unfortunately, that happens not to be the case. A lot of people are exposed to

01:43:12.600 antibiotics because they're used in agriculture. And they're used in agriculture because it was found

01:43:20.280 probably 60 years ago that giving antibiotics will cause animals to grow faster and get bigger faster.

01:43:31.800 And so you can give antibiotics for that reason. You can also keep pigs more safely in small quarters

01:43:42.200 by giving them antibiotics because the infections are not wiping them out so badly.

01:43:49.080 This profligate, if I might use the term, use of antibiotics in agriculture, exposes the human population

01:43:57.880 to antibiotics and changes our bacteria in ways that we would never have appreciated. Just to give you an

01:44:07.160 illustration. My son, who is now just turned 60, but was young once, when he was a child, he got pneumonia.

01:44:18.680 Kids do. And so culture was taken. It was found that it was pneumococcal pneumonia. He was two.

01:44:27.400 So he was given penicillin to treat pneumococcal pneumonia. He got an exudative enteropathy for it.

01:44:36.280 His skin peeled off. His teeth came in, mottled. His hair changed. His fingernails changed.

01:44:43.240 He was taking baths in oatmeal. We nearly lost him. So he is deathly allergic to penicillin.

01:44:52.600 How the hell did he get to be allergic to penicillin at age two when he'd never had it?

01:44:59.880 Well, part of the answer was that my wife had a very bad infection. 0.99

01:45:05.800 And so he had to be bottle fed after the first month of life. And so he had cow's milk for a long

01:45:14.840 time. Nothing wrong with that. Kids always drink cow's milk. But cow's milk is coming now with

01:45:23.000 penicillin in it because the agricultural industry treats penicillin. So he developed an allergy to

01:45:29.400 penicillin. He then got treated with it. So now he doesn't take penicillin anymore. As it turns out,

01:45:37.800 I discovered many years later, I too am allergic to penicillin. That's where he got it from. I

01:45:43.960 apologize to him, but it's a gene. But do you think he would have been less allergic to it,

01:45:50.040 despite his susceptibility genetically, if he had been breastfed normally?

01:45:54.280 Well, if he'd been breastfed normally, the first time he got penicillin, he would have been

01:45:59.960 sensitized, but he wouldn't already have had the allergy. He behaved as if he was exposed to

01:46:06.280 penicillin because he had been, but in a way we never knew. And lots of kids are getting it. But

01:46:14.360 the major effect of it is that it's affecting a microbiome.

01:46:18.600 But let's go back and explain how a stool transplant works for C. diff.

01:46:22.840 You were also explaining how it's not a zero-risk procedure, even though in the case of C. diff,

01:46:28.360 it's life-saving.

01:46:29.480 What happens in C. diff is that patients get antibiotics. It knocks out the bulk of the

01:46:37.400 bacteria. C. diff is resistant and it emerges as dominant. It produces a toxin. The toxin causes

01:46:47.080 massive diarrhea and that can wipe you out, very similar to the way cholera toxin does. It works

01:46:54.760 in a different way. It works on the nervous system, but it's a bad toxin. So to cure C. diff,

01:47:02.120 one takes oral vancomycin is the first step. Vancomycin is an antibiotic to which C. diff is

01:47:09.080 usually sensitive. It hasn't become all that resistant because vancomycin isn't used that much

01:47:16.520 and it's not absorbed. So it just goes down the gut. But if 25% of patients don't respond to oral

01:47:26.760 vancomycin or C. diff recurs after you, they take it and they can't get rid of it. In that case, the only

01:47:34.280 thing that can be done is a fecal transplant. That can be done as an enema or it can be done

01:47:40.920 as an enterocoded capsule now. So that capsule goes down, bacteria recolonize the antibiotic,

01:47:50.120 wiped out gut. It then suppresses the C. diff. That's life-saving use and it's approved. Now,

01:47:59.320 what's the difficulty? So you get stool for C. diff treatment that has been very carefully looked at,

01:48:07.800 and one knows that there are no organisms in it that are potentially dangerous. You have perhaps

01:48:17.000 500 species of organism in your gut that are potentially lethal. So one has to be careful.

01:48:25.160 There used to be people were giving it husband to wife and people doing this kind of home bruise. 1.00

01:48:33.960 We've lost a few patients that way. Not a good thing to do. One has to be very careful when you're

01:48:39.960 doing fecal transplantation. Mike, is there any potential for using synthetic biology to create

01:48:48.120 the microorganisms so that you could control exactly what you're giving people? So you could effectively

01:48:55.240 capsulize the exact organisms that people are deficient in and replace those without the risk of

01:49:03.720 providing anything you don't want to be part of the recolonization?

01:49:07.080 I've already told you why that cannot be done. Because for the most part, we can't grow these organisms.

01:49:15.240 If you can't grow them, you can't produce them in such a way as to synthesize them.

01:49:21.160 Knowing their genetic sequence, you can't synthesize them if you don't have

01:49:25.640 the media in which to keep them alive once you've synthesized them.

01:49:29.720 That's correct. You have to be able to not only make their DNA, but-

01:49:33.800 Make their food.

01:49:34.680 Yeah. Keep them going.

01:49:36.840 How many people are working on this, Mike? This seems like a really enormous opportunity. If the code

01:49:43.160 could be cracked, right? If you could figure out how to support these bacteria in vitro,

01:49:49.080 it does open the door to synthetic biology. It does open the door to basically medicines that are

01:49:55.080 bacteria, right?

01:49:55.880 Well, medicines that either are bacteria or are derived from them. So knowing what the bacteria

01:50:04.840 produce and knowing how they produce it are just as good. So there is a huge amount of

01:50:11.800 modern GI biology going into study of the GI microbiome. Over the past 10 years, it's been the

01:50:20.920 growth industry of the field. One of the things that's very common today is commercial home kits

01:50:28.680 that they're going to tell you what your sequence looks like. This seems to be a field that's really

01:50:35.000 full of a lot of nonsense. So there's been outright frauds, right? There was that company out of UCSF

01:50:41.000 called Ubiome that turned out to be kind of like the Theranos of this space. There seem to be a lot of

01:50:46.680 companies that if you give them a small stool sample, they're going to send you a lengthy

01:50:51.160 report of what your gut biome is. And let's assume that they're even able to do that accurately. Is that

01:50:56.200 a fair assumption? Are they able to provide this information? Are they able to do the sequence and

01:51:00.200 tell you what makes up your gut bacteria? What they give you is the classes of organisms and the

01:51:07.880 percentage of the total bacteria each of the classes represent. And that turns out to be

01:51:13.480 remarkably unuseful. Say more. Well, you need to know species by species at a very, very fine level

01:51:25.720 before you get to be able to really do something with it. To get this class of bacteria and proportion

01:51:33.480 of it's too high in the genome, too high in the... So far too little resolution is being provided by these

01:51:41.080 tests. Correct. You can say you can change anxiety. You can change body form with the microbiome.

01:51:51.560 But to say that you can go look at the microbiome and then determine what that is,

01:51:57.320 is not yet there. You can't just go look at somebody's stool and say what that consists of.

01:52:04.120 The best of the kits that I know of that do this are the ones that look for cancer.

01:52:09.800 So like Cologuard and things like that? Yes. Those are excellent. But even those kits...

01:52:17.320 Let's remind people exactly what Cologuard is looking for.

01:52:20.760 As the cells age and undergo apoptosis, they're sloughed off into the lumen. And so human DNA

01:52:29.640 is in the lumen of the gut as well as bacterial DNA. And what Cologuard does is looks at the stool

01:52:38.040 and you can look at the DNA in the stool and look for the genetic signatures of a number of

01:52:45.560 GI cancers. And so about 90% of GI cancer can be picked up effectively by Cologuard,

01:52:54.920 which means it's wonderful and it's a great advance, but it doesn't mean you don't have to go

01:53:02.520 also do colonoscopy. Yeah, the goal of colonoscopy is to find it before it's cancer. It's to find the

01:53:09.000 polyp that's going to become cancer, not wait until you have cancer. That's a major point. But if you do

01:53:15.080 have cancer and you find it early in a colonoscopy, that's great. And the problem with Cologuard is if

01:53:23.000 you're missing 10% of cancer, you don't want that to happen. It seems to me that Cologuard is really

01:53:29.800 a great tool in areas where access is limited, where there might be hesitancy for colonoscopy

01:53:36.680 and things like that. But I agree with you, it's not a substitute for a colonoscopy. So this is an

01:53:41.000 interesting point, Mike, which is basically all of these commercial tests out there that are giving you

01:53:46.840 information about your gut microbiome, are not doing it yet at a resolution that's actionable.

01:53:53.160 Is that kind of a fair synthesis of what you've said? Right. And my particular quarrel with them

01:54:00.280 is that because they're not doing it at a level that is sufficiently documented and sufficiently

01:54:07.480 informative for you to be actionable on that information, they cost money abnormally and they

01:54:15.880 change what you do for reasons that are not well documented and you shouldn't be following them

01:54:22.520 yet. Yeah. And a lot of them basically are paired with supplements or probiotics or prebiotics that are

01:54:33.160 supposed to, quote unquote, fix the defects that are found in the test, right? Isn't that the RXDX model?

01:54:39.720 That's what they're doing. But what they're really doing is making money.

01:54:43.560 I think they're a con. I don't know enough to draw a strong enough conclusion. I can just say,

01:54:50.840 based on a decade of looking at them in many, many patients who have been adamant about having these

01:54:57.560 tests done, I'm still looking for a great example of where it mattered. I worry also that there is a lot

01:55:05.080 of noise created without a signal. What are the most important things nutritionally that people can do

01:55:10.920 to make sure that they have the optimal flora for their gut? I want to break this into two categories,

01:55:20.680 Mike. The first is just as general health maintenance. And the second is after taking antibiotics. So like

01:55:29.000 it or not, we're going to take antibiotics and they're going to save our lives from time to time.

01:55:34.360 I have found myself to be more and more reluctant to take them. And I generally tend to resist as

01:55:40.280 long as possible until I have no choice. But I'm going to hold out a long time before I take a Z-Pak.

01:55:46.520 If I'm sick, I'm going to really try to make it go. But, you know, I think the last time I took

01:55:50.440 antibiotics was for a dental issue where it just required something more significant. So

01:55:55.560 let's start with kind of the general maintenance principle. You're not someone who's taking a lot of

01:55:59.800 antibiotics, but you want to do what's best for your gut. And I assume that nutrition is one of

01:56:05.560 the most important levers we have. To my way of thinking, the best kind of diet is a balanced diet,

01:56:12.840 not one that tries to be like the South Beach or one of those diets to lose weight. Having a balanced diet

01:56:21.160 with appropriate nutrients, including vitamin C, but not in excess, although it won't hurt you to have

01:56:29.000 an excessive vitamin C, but there's no reason to do it. And particularly fiber included is good for

01:56:35.960 your body. So I would be opposed to having particular diets. For example, a cleanse. I like to point out to

01:56:46.360 people that they should consider that the microbiome is something they live with and has evolved with

01:56:53.400 human beings as long as they've been human beings. And cleansing the inside of the gut is not a good

01:56:59.880 thing to be doing. I'm not even sure I really understand what a cleanse is. I've heard so many

01:57:03.960 different variants of it, but certainly one method in which we do some form of a cleanse is a prep for

01:57:08.920 a colonoscopy. How much does that alter the flora of the gut, even though its purpose is really to just

01:57:15.800 mechanically get rid of all stool matter so that the endoscopy can be performed with better visibility?

01:57:21.720 Does that alter the gut flora in a way that doesn't return to normal quickly?

01:57:26.360 No, remarkably little. That doesn't kill organisms or change the balance between them. What it does is

01:57:33.720 just moves the mechanical stool out. And so the gastroenterologist doing a colonoscopy can have a

01:57:40.680 clear view of what's in you. When people do these dietary cleanses, they're usually drinking a lot of

01:57:46.440 water with pepper and presumably some nutrients, but they're kind of doing a bowel prep, aren't they?

01:57:54.120 Some of them are also supplementing it with enemas. And I worry about those people getting into

01:58:01.080 electrolyte imbalance.

01:58:02.600 I see. But they shouldn't be killing the bacteria.

01:58:05.800 No, they're not killing the bacteria. But on the other hand, they're not doing their body a favor

01:58:12.760 by eating strange foods and that kind of thing.

01:58:16.520 You alluded to insoluble fiber earlier, the things that we can't digest at all in lettuce and celery

01:58:23.720 and things of that nature. Tell me the importance again of that in the human diet, because there

01:58:28.360 presumably are people who don't eat much or any insoluble fiber. And that's going to clearly change

01:58:33.560 their gut bacteria. Is there evidence that that is impacting their health negatively?

01:58:39.000 Not that much has been done on low fiber for negative impact as so much as to show that there

01:58:45.640 are health benefits of fiber. One of the benefits is that fiber can absorb toxins

01:58:52.040 so that it can decrease its thought carcinogen effects long term. It also provides the colon

01:59:01.720 something to chew down on and is good for motility, keeping the bowel going and in shape. And it also

01:59:11.080 provides a substrate for the bacteria of the colon for them to chow down on and produce short chain 0.85

01:59:20.360 fatty acids, which are good for the lining of the gut and provide it with its energy metabolism.

01:59:28.600 By the way, do any of those short chain fatty acids, Mike, make their way into the person to provide

01:59:35.240 ATP or energy there beyond just the epithelial cells?

01:59:39.960 Less so, but the answer is yes. They are absorbed. And so to some extent they can get into the body.

01:59:47.320 Directly through chylomicrons as regular fatty acids would?

01:59:50.520 No, no, no. They're very short and they're soluble and they tend, like acetic acid is a

01:59:57.720 short chain fatty acid. That would be a one carbon.

02:00:00.920 So fiber sounds like it's going to be the most important nutrient in terms of fueling the bacteria

02:00:08.360 of the gut, which in turn pay service back to providing energy for the epithelial cells, correct?

02:00:14.760 Not just fiber. Polysaccharides do as well. They can digest those. Everything that gets down there,

02:00:23.560 they can live on. It's just that very little of the protein that you eat will get down to the colon.

02:00:31.320 Then tell me about things like artificial sweeteners or non-nutritive additives to food. There's been a lot

02:00:39.000 of discussion that, for example, aspartame or other sweeteners that aren't caloric may still provide

02:00:47.880 some impact on the microbacteria of the colon. How well is that understood?

02:00:54.440 There are bacteria that can metabolize them. And so there are effects on the bacteria.

02:01:01.560 The net effect of that is I really can't speak to because that's a literature that I find to be

02:01:08.600 self-contradictory. Some people think they do things. Some people think the effect is negligible.

02:01:14.520 I haven't spent much time in that literature, but the little time I've spent in it, I've come away

02:01:20.760 without much of an understanding of how these things are potentially creating an impact. You

02:01:26.680 mentioned protein already. What do we know about the role of fatty acids in the colon? How many of them

02:01:31.800 are making their way there?

02:01:33.000 Well, most of the fatty acids that get to the colon are derived from fiber.

02:01:39.320 In other words, they're not exogenous.

02:01:41.800 That's true normally, but not always. So for example, under abnormal conditions

02:01:48.920 in which bile salts or pancreatic enzymes are deficient, then those fat can get into the colon

02:01:58.280 and one gets fatty stool. Bacteria can metabolize that. And so in celiac disease, for example,

02:02:07.720 there's a lot of fat in the stool or in biliary tract disease, there's often a lot of fat in the stool.

02:02:15.880 The stool is described as greasy and foul smelling because the bacteria do metabolize it.

02:02:23.000 What about the scenario where a person has taken antibiotics, potentially for a protected course?

02:02:30.040 What can they do to appropriately repopulate their gut?

02:02:34.040 What a good question. Probably taking appropriate probiotics at the same time

02:02:40.360 they're taking those antibiotics or afterward is helpful.

02:02:44.120 And what constitutes appropriate probiotics? This is a world I know very little about.

02:02:49.080 It varies. Some people think that yeast-derived saccharomyces is good. Some people swear by

02:02:58.680 lactobacilli or bifidobacteria. There is evidence that when you're taking antibiotics and saccharomyces

02:03:07.640 at the same time, I'm trying to think of the name of the pill that they sell. It's over the counter.

02:03:13.480 And sorry, just for semantics, what's the difference between a pro and a prebiotic?

02:03:19.480 Probiotic is defined as an organism that has beneficial effects. And prebiotic is defined

02:03:27.800 as a material that will enable the body to grow organisms that have beneficial effect. So the

02:03:36.600 difference between them is that prebiotic enables you to make your own healthy organisms. Probiotic

02:03:43.400 because you eat them. So for example, I eat Activia every day. Now that I've aged, it fights

02:03:52.680 the problems of aging.

02:03:54.680 So fermented foods are obviously valuable probiotics.

02:04:00.200 An important point to bear in mind is not just that it's fermented. I mean, all yogurt is fermented,

02:04:06.920 but that something like Activia has bifidobacter animalis in it, which actually gets through,

02:04:15.800 survives the stomach acid, goes down the GI tract and comes out in the stool.

02:04:20.760 And just to be clear, that's an anaerobic bacteria or aerobic?

02:04:24.440 It's an anaerobic, but it can get down the gut and survive in the stool. 0.82

02:04:30.360 It's so interesting that we can be eating something anaerobic that it can be in our food, right?

02:04:34.920 It's added. And I guess it's aerobic. It has to be aerobic.

02:04:38.520 It kind of gets to the challenge of this whole anaerobic problem, right?

02:04:42.120 Yes. But the organism that's put in has actually goes through the GI tract and survives. So the

02:04:49.800 importance of the probiotic is not only that it be there, but that it survive and do something in the GI tract.

02:04:59.000 How can people navigate this world, Mike? Because this is another one of those places where

02:05:02.920 there's a lot of opportunity for charlatans to sell you things that, A, don't even have the colonies

02:05:10.120 that they claim they do, or if they're there, they're dead on arrival. And if they're not,

02:05:15.400 they don't survive the transit from mouth to colon. I mean, how does one kick the tires on these things?

02:05:23.080 Well, for one thing is you can trust the FTC and the FDA. So claims cannot be made

02:05:32.280 for a foodstuff like a probiotic that are medical unless it has been subjected to actual tests and

02:05:43.480 pass FDA muster to show efficacy and safety. Most of what they call probiotic or prebiotic has not done

02:05:53.160 that. Foodstuff then is regulated through the advertising by the FTC. So I was

02:06:02.040 interestingly called upon to testify at a hearing for a game. I consult for Danid. And so when I

02:06:11.560 mentioned Activia that I take, that doesn't mean that I want to tell everybody out there that this

02:06:18.280 is better than any other. It's just one I know about. So in any case, the FTC looked very carefully at

02:06:27.240 the claims made for that product and wanted to see and carefully evaluated all of the evidence.

02:06:36.360 And in order to make the claims that Danid makes for that product, they actually have to demonstrate

02:06:43.480 to the FTC that they have the evidence that it does what they say it does. So they say that if you eat

02:06:51.480 as much as two cups a day of Activia, it will cause the GI tract to speed up. And the answer is it will.

02:07:01.160 And how many colony forming units are provided in that?

02:07:04.200 I honestly don't know. I can't answer that question. But there are, I think 10, something

02:07:11.080 in the order of 10 to the 11th going in. And I'm trying to think of what comes out the other end,

02:07:17.080 but it's much less, but they do have evidence at least for that product that it survives and goes

02:07:23.320 through. When it comes to getting your GI system back in tract after a course of antibiotics, what are

02:07:29.160 the most important elements to look for in the probiotic? Is it lactobacilli then?

02:07:35.080 Not in specific lactobacillus, just the ability to colonize the GI tract. So Saccharomyces works

02:07:43.160 very well in that case. That's the one I'm trying to think of the trade name for.

02:07:48.120 We'll figure that out and link to it in our show notes.

02:07:50.840 It's well known and it's a yeast derived product.

02:07:53.560 And it's over the counter?

02:07:55.000 Yes, it's over the counter.

02:07:56.920 Now, by definition, does a probiotic need to be refrigerated?

02:08:02.040 It just needs to be able to survive. You can take it as a pill.

02:08:06.760 But even pills don't need to be stored in the refrigerator?

02:08:09.720 No, they don't. Not necessarily. It depends on which one. I mean, so for example,

02:08:15.720 Bifidobacteria animalis, which is in Activia, has to be refrigerated. But so does the Activia,

02:08:23.160 because it's yogurt-based. Again, it just seems to me that the big opportunity here is going to come

02:08:29.560 with kind of the bioengineering that's necessary to grow these bacteria in culture. That seems to be

02:08:36.440 just an enormous blind spot we still have in this space, both from a diagnostic standpoint, but also

02:08:41.560 from a therapeutic standpoint. Absolutely right. And from a point of view of really having what is

02:08:50.200 sort of a fringe, popular economy to a really effective major product, so that if you could

02:08:59.160 make an organism and know exactly what it does and you can make it in scale and give it to people to

02:09:08.760 take it safely, big time, bucks.

02:09:11.960 Well, Mike, thank you very much for this tour of one of the most probably underappreciated systems

02:09:20.200 in the human body. We've talked a lot about its unique embryology, very unique innervation,

02:09:26.600 and of course, perhaps most importantly, its cohabitation with bacteria that basically outnumber us.

02:09:35.640 As we said, I think at the outset, I can't remember if we talked about this before we were recording or

02:09:39.320 not, but this really feels like a bit of a black box. And I guess that speaks to why 60 years later,

02:09:46.120 you're still working just as hard. That's right. Or as you said, as you get further away from shore,

02:09:51.880 the water gets deeper. Yeah. Well, the water feels awfully deep right now, Mike. Thank you very much

02:09:57.320 for your time and your expertise today. Thank you.

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The Peter Attia Drive - July 25, 2022

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

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