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

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My guest today is Dr. Mike Gershon. Mike is a professor of pathology and Cell Biology at Columbia University, where his research focuses on the neural control of the gastrointestinal TR and the role of serotonin in the gut as a neurotransmitter. Mike earned his medical degree from Cornell University, followed by a postdoctoral fellowship at Oxford. Mike has received numerous awards and honors over the years, published hundreds of peer reviewed papers on the nervous system, and even authored a book on the role of the brain and the GI system. This episode's different from, I think, a lot of our episodes and truthfully I think it comes across more as a bit of a med school lecture, which is kind of how it felt to me. It was really interesting, but I think at the surface doesn't really come across as highly applicable. And I think the reality of it is you just sort of have to get through some of the embryology, anatomy and neurophysiology of the gut and the brain to kind of understand how these things coexist. So I just want to be honest and set expectations. If you're coming into this thinking that this is going to be a podcast that's about how to eat this and not that and affect your gut biome, it's really not about that. This is a much more basic discussion. And I mean basic not in simple, but I mean basic in more elemental explanation of how this system works. And truthfully, I learned a lot in this episode, much more than I normally do. A lot of times I go into podcasts kind of knowing the subject matter pretty well and maybe increasing my knowledge by 20% or something like that, but I think this was pretty different. So I think what I would just say is, rather than give you a blow by blow of everything we talked about here, which would probably take me 20 minutes I. I would say go into this assuming you're not going to know much of what we talk about, and you'll come out of this with a much greater appreciation for how your gut and your brain are connected. And unfortunately, I think we are only now beginning to think about how to translate that to clinical utility. So, in other words, I think that we don't yet have all of the insights. I don't come away from this episode saying, oh, all you need to do is eat this and your gut's going to be healthier. And if your gut's going to be healthier, then your brain's going to be better, or vice versa. So maybe you'll come out the other end of this podcast feeling like you've got it figured out. I certainly don't. But nevertheless, I feel like I have a much better foundational knowledge to evaluate half of the snake oil stuff that is out there, which, I mean, I got to be honest with you, most of what's out there on this topic is utter nonsense. Commercial tests that promise miracles that don't make any sense and supplements that just don't make any sense. And I think you'll come away from this kind of understanding how difficult it is to try to make the claims that are out there. So, without further delay, please enjoy my conversation with Dr. Mike Gershon. Hey, Mike, thanks so much for making time to speak with me today about a subject matter that I know very little about, but know enough to know that it probably matters. And I think that's why we're going to talk about it.

Okay, I'll do my best.

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

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

Or as the saying goes, the further you get from shore, the deeper the ocean gets. Right.

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

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

Absolutely, it would.

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

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

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

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

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

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

Without breaking down ourselves.

Correct. So we don't want to self digest. It's, it's a major problem. And the gut manages to solve all that. Now you asked where it comes from? Well, during development, the body forms a disc, a flat disc. And that disc undergoes a series of folds from head to toe and from side to side. And the lateral or side folding produces the tube from which the gut forms. And so the flat disc folds around to create an internal space and that tube becomes the gut.

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

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

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

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

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

That is correct.

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

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

Or closest to the head.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

That's correct, yes.

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

That's absolutely right.

And then, of course, inside the submucosa, you have the mucosa and then ultimately the lumen on the very inside with the enterocytes that form the endothelial lining of the gut. Give me a quick sense of the epithelial turnover. What is the, I don't know, median residence time of an epithelial cell in the gut?

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

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

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

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

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

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

Yes, but not quite. Because what the large intestine does is conserve sodium. So it absorbs sodium and secretes potassium, and water follows the sodium acids coming back into the body. So the colon acquired that function, and it enables organisms to live on land. When organisms lived in the water, conserving sodium and water was not such a problem. Living on land makes it so. The bulk of the water that the gut absorbs, however, is not in the large intestine. It's done in the small intestine, together with the bulk of most of what else you absorb. Still, the final hundred milliliters or so per day of what you absorb is polished off in the colon. And it is important in maintaining the body's fluid content. If you lose it as one does in cholera, where cholera toxin turns sodium absorption into chloride secretion, Water flows out and you can die of dehydration in about four hours. And people do with cholera. So it's a great plague. Perhaps 3 million people a year die of cholera even today.

3 million people a year die of cholera today?

Correct.

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

At the moment it is, but there have been major league outbreaks in our hemisphere. One began off the coast of Peru with contaminated crab that led to cases that were as far north as new Jersey as people ate contaminated crab. Haiti, of course, is the most famous one. There was a great earthquake in Haiti, destroyed a lot of their infrastructure. They had a group of peacekeepers from the united nations, from Nepal, that was stationed there, and they brought cholera with them, put it into the water system of Haiti. It got into the rivers and streams and is now endemic in Haiti. So it reduced the population of haiti considerably. But it is mostly in Asia and africa.

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

Well, it's a very simple illness. All one has to do is keep track of the water. So you put a patient on what is known as a cholera cot, a gurney with a hole in the middle for the anus to be positioned over. You put a bucket under it. The nurse puts a ruler into that bucket periodically to see how much fluid is coming out. You replace it intravenously and orally. The great life saving discovery was that although cholera blocked the absorption of sodium, it does not block the absorption of glucose in the small intestine. And so adding a little bit of sugar to the fluid that you're using for oral rehydration has saved countless Millions of lives, Just that simple thing. So antibiotics have no use at all in cholera? 0.

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

Correct.

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

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

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

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

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

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

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

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

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

That's correct. And that all has to do with the enteric nervous system functioning. One theory, which I believe is that there are nerve cells in the gut called command neurons, and they receive the input from the cns. So it turns out that the number of fibers in the vagus nerve that are running to the gut are pretty small in humans. Three to five thousand, it's been estimated. And the number of nerve cells within the gut are in over 100 million.

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

So that raises the question, how do these nerve cells control it? As I've said as a CEO, they can get to command nerve cells and start reflexes going, keep things moving more rapidly. The gut has a number of different behaviors. It's not just propelling at all times. If the gut were propelling, as I described it, with oral contraction, anal relaxation, as it's capable of doing, then social discourse of the kind we're having right now would become impossible. The gut has to sometimes stop. And so one type of behavior is just essentially parasitism. The gut stops moving. A second type of behavior that the gut shows is mixing, in which it allows the enzymes that it puts out to do digestion. And anyone who's ever taken time in an organic chemistry laboratory will tell you nothing very much happens unless it's stirred. So the gut has a mixing process in which it just goes back and forth, back and forth, no propulsion. And then it's able to sense what goes on. And when digestion is occurred sufficiently, it propels it on. It can. Also, during night, while you're sleeping, a cleaning process goes through the gut, in which a wave begins at the stomach, goes down the small intestine, down the large intestine, and cleans the gut out, open sphincters. So the things that would ordinarily be much too big to pass can go through. So a little kid can swallow a paper clip, a dime, sometimes an open pin, and all those things are passed. And miraculously, I don't know how the gut manages it, but if an open safety pin goes in, somehow it manages to propel it, Always down with the small end down, and it almost never gets stuck.

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

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

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

That's correct. That summarizes it well.

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

Yes, to a lesser extent.

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

Correct.

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

Yes, it is.

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

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

Where does ghrelin fit into this?

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

So what amplifies ghrelin?

You mean what makes ghrelin be secreted?

Yes.

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

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

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

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

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

The point here you make about the particles needing to be sub 1 millimeter to get past the pylorus is kind of remarkable and gives you a sense of how much mechanical digestion the stomach is doing. I mean, the ph must be helping that, but really, there's just got to be a lot of mechanical shearing that goes on of foodstuff, correct?

Absolutely right.

The stomach doesn't get its recognition in this story when you think about how small a sub millimeter particle is and yet how big things of food that make it into your stomach are. And to think that it does this without fine instruments. It wouldn't be hard for me to make a bunch of 1 millimeter pieces if you gave me a knife. But it's doing this basically inside a soft reservoir using contraction and acid and some enzymes.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

And what's the frequency that this happens in?

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

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

Just during reinfection.

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

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

And if not there, at a minimum, you would probably get free dinner at Red Lobster every Tuesday for the rest of your life. That's the second prize after the Nobel prize. Yeah, it's interesting. I mean, we know it's a disease associated with aging or the reactivation is associated with aging, and we know that things like weakened immune system can see it. I think in the early days of HIV we would see patients.

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

And the current vaccine that we have, Mike, the Shingrix vaccine, the two shot separated by six months, this has Been kind of a step forward. Correct.

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

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

Or even more important, the enteric neurons. It's about 97% effective. Remarkable vaccine.

Yeah, I got mine early, I'm not quite 50 yet, but I was like, ah, what the heck am I waiting for? And the other thing I'll tell you is what a kick in the chops that vaccine is that makes you sick.

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

I'm reaping the benefits of my young immune system as I get butchered by the Shingrix shot. What about diseases like autism? Children with autism seem to have, as the severity of their illness goes up, an increase in the prevalence of gastrointestinal illnesses. How well acknowledged is that? Is that kind of loosely accepted or is that now becoming more accepted?

It's so accepted. Right.

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

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

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

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

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

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

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

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

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

Oh, did you?

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

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

Yeah. Let's make sure people understand the difference there. Amino acids are the building blocks of peptides. A peptide is a string of amino acids, but the amino acid is the smallest functional unit that makes up a protein. So we have these 20amino acids and you can string them together in thousands and thousands to make complex proteins. But small peptide of 9 to 11amino acids, for example, would be what the immune system recognizes. And what you're saying, Mike, is from a GI standpoint, they have to be even smaller than an immunogenic peptide. If they're only sort of single amino acids or maybe two peptides, two amino acids joined.

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

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

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

You were threatened?

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

I'm not sure I understand.

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

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

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

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

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

I know it'll come to one of us as we continue this discussion. Let's talk about serotonin before we go further. Because serotonin levels are higher in at least a subset of kids with asd. And most people, when they think of serotonin, they associate it with a hormone in the brain that is responsible for mood. Can you say a little bit more about serotonin and in particular the role of serotonin in the gut?

Well, serotonin is a molecule that I've been working on since college. I did my senior thesis on serotonin when I graduated From Cornell in 1958, probably when dinosaurs roamed the Earth and I was young. In any case, serotonin was discovered actually in the gut. Enterochromophen cells, which are an endocrine cell of the gut, are responsible for making about 95% of the body's serotonin. The brain produces about 2 to 3% of the body's serotonin. So although the brain serotonin is probably what makes life worthwhile, that is living and is responsible for happiness, among other things, in terms of amounts, it's a little afterthought of evolution. So within the gut, serotonin is made in two places. The bulk of it is made as I've Just said in the enteroendocrine cells, which are the small endocrine cells that are part of the GI epithelium, it's a minor component of the epithelium, but a major component functionally of what the gut does. About 80% of the endocrine cells make serotonin. The other source is serotonin containing nerve cells within the enteric nervous system. So it is a neurotransmitter and an endocrine substance. In the gut, it's very important in feeling pain in the gut. It's very important in triggering nausea. So in sending signals from the gut to the brain, serotonin is an important transmitting substance. During development, serotonin is very important as a growth factor. The first nerve cells to form in the gut make serotonin. Subsequent nerve cells depend on serotonin, triggers them to develop. So if you knock serotonin out of the nervous system, the gut winds up with too few neurons, it doesn't have enough, and it doesn't work for very well. If you knock serotonin out of the epithelium, then there's problems signaling back to the brain. And the peristalsis reflex is impaired. It's not stopped, but it's impaired because the enteroendocrine cells in the gut can trigger peristaltic waves that are propulsive. But if you lose that, then in order to trigger it, you have to press harder and harder and dilate the gut and get the nervous system to do this directly. It's highly involved within the gut, and it also talks to the immune system. So it triggers inflammation, as you might imagine from the amount of it that's in the bowel. It does everything. It's a pan function, multifunctional molecule.

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

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

Are SSRIs contraindicated in pregnancy?

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

Is that understood by the physicians that prescribe them? And obviously there were going to be scenarios where those risks are worth it if the.

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

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

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

Less serotonin.

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

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

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

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

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

So, Mike, what would you say is the most common cause of leaky gut allergy? Okay, so meaning there is hypersensitivity, that.

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

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

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

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

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

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

If somebody has a substantially leaky gut, you would guess it from making a determination of the serum protein albumin. If the gut is leaking Albumin will be low. And so if you see a low albumin, you can look for it. If you think it's true, you can look for an enzyme called alpha1antrypsin. Trypsin is produced by the pancreas. Antitrypsin blocks it, its action and it gets into the lining, into the gut. It should not be absorbed. It's a measurement that will tell you whether the gut is leaking or not.

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

Yes.

What do those patients present with?

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

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

Correct.

Do you have to see low albumin to make the diagnosis of leaky gut? Because that's a very significant leaky gut. I mean, if a person is exuding protein to the level where it shows up in their serum albumin, that would strike me as a lot of leak. Correct. Are there milder leaks that don't allow something as massive as albumin to escape, but do allow toxins and microorganisms in?

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

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

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

Let's go back and explain again. Now that we've talked more about serotonin, what do we think is the relationship between. Do we see more leaky gut in asd?

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

And remind me again the phenotype of the former. When you have in utero exposure to.

An ssri, you have too many nerve cells in the gut. And so gut motility becomes defective.

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

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

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

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

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

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

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

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

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

Oh, it goes well beyond that. We don't know the nutrient broths and things through which they can live. It's easy enough to make an atmosphere that has no oxygen in it, but it's not so easy to figure out what they need to live. Colon produces a great environment and how to match it is not so easy to figure.

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

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

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

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

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

Let's go one year.

Okay. That tells me something really changes.

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

So their immune system must be horrible.

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

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

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

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

Not far.

Under a controlled setting. Why do you think that type of research, while admittedly complicated, is technically feasible.

And has a potential for enormous fecal transplantation in humans? It's not without danger, for sure.

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

Yeah. Let me just say Clostridium difficile is a normal component of the GI tract. Many, many people have it, and it sits there. And with your organisms, one of the major ways that you control the various bacteria is to have other bacteria. And so the bacteria control themselves. There's a competition for how much nutrient is there, and they make toxins that affect one another. But people then take antibiotics, and the major effect on the human microbiome is an antibiotic. For the most part, we like to think antibiotics are used effectively and appropriately when you have an infection and they're given to you to fix that. Unfortunately, that happens not to be the case. A lot of people are exposed to antibiotics because they're used in Agriculture. And they're used in agriculture because it was found probably 60 years ago that giving antibiotics will cause animals to grow faster and get bigger faster. And so you can give antibiotics for that reason. You can also keep pigs more safely in small quarters by giving them antibiotics because infections are not wiping them out so badly. This profligate, if I might use the term use of antibiotics in agriculture, exposes the human population to antibiotics and changes our bacteria in ways that we would never have appreciated. Just to give you an illustration, my son, who is now just turned 60, but was young once, when he was a child, he got pneumonia. Kids do. And so culture was taken. It was found that it was pneumococcal pneumonia. He was 2, so he was given penicillin to treat pneumococcal pneumonia. He got an exudative enteropathy for it. His skin peeled off, his teeth came in mottled, his hair changed, his fingernails changed. He. He was taking baths in oatmeal. We nearly lost him. So he is deathly allergic to penicillin. How the hell did he get to be allergic to penicillin at age 2 when he'd never had it? Well, part of the answer was that my wife had a very bad infection and so he had to be bottle fed after the first month of life. And so he had cow's milk for a long time. Nothing wrong with that. Kids always drink cow's milk. But cow's milk is coming now with penicillin in it, because the agricultural industry treats penicillin. So he developed an allergy to penicillin, he then got treated with it. So now he doesn't take penicillin anymore, anymore. As it turns out, I discovered many years later, I too am allergic to penicillin. That's where he got it from. I apologize to him, but it's a gene.

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

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

But let's go back and explain how a stool transplant works for C. Diff. You were also explaining how it's not a zero risk procedure, even though in the case of C. Diff, it's life saving.

What happens in C. Diff is that patients get antibiotics. It knocks out the bulk of the bacteria. C. Diff is resistant and it emerges as dominant. It produces a toxin. The toxin causes massive diarrhea and that can wipe you out. Very similar to the way cholera toxin does. Works in a different way. It works on the nervous system, but it's a bad toxin. So to QXI Diff one takes oral vancomycin is the first step. Vancomycin is an antibiotic to which C. Diff is usually sensitive. It hasn't become all that resistant because vancomycin isn't used that much and it's not absorbed. So it just goes down the gut. But if 25% of patients don't respond to oral vancomycin or C. Diff recurs after they take it and they can't get rid of it in that case, the only thing that can be done is a fecal transplant. That can be done as an enema or it can be done as an enteric coated capsule. Now, so that the capsule goes down, bacteria recolonize. The antibiotic wiped out gut. It then suppresses the C. Diff. That's life saving use and it's approved. Now what's the difficulty? So you get stool for C. Diff treatment. That has been very carefully looked at. And one knows that there are no organisms in it that are potentially dangerous. You have perhaps 500 species of organism in your gut that are potentially lethal. So one has to be careful. There used to be people were giving it husband to wife, people doing this kind of home bruise. We've lost a few patients that way. Not a good thing to do. One has to be very careful when you do doing fecal transplantation.

Mike, is there any potential for using synthetic biology to create the microorganisms so that you could control exactly what you're giving people, so you could effectively capsulize the exact organisms that people are deficient in and replace those without the risk of providing anything. You don't want to be part of the recolonization.

I've already told you why that cannot be done. Because for the most part, we can't grow these organisms. If you can't grow them, you can't produce them in such a way as.

To synthesize them, knowing their genetic sequence. You can't synthesize them if you don't have the media in which to keep them alive. Once you've synthesized them.

That's correct. You have to be able to not only make their DNA but make their food. Yeah. Keep them going.

How many people are working on this, Mike? This seems like a really enormous opportunity. If the code could be cracked, Right. If you could figure out how to support these bacteria in vitro, it does open the door to synthetic biology. It does open the door to basically medicines that are bacteria, right?

Well, medicines that either are bacteria or are derived from them. So knowing what the bacteria produce and knowing how they produce it are just as good. So there is a huge amount of modern GI biology going into study of the GI microbiome. Over the past 10 years, it's been the growth industry of the field.

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

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

Say more.

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

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

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

So, like cologuard and things like that.

Yes, those are excellent. But even those kits, let's remind people.

Exactly what cologuard is looking for.

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

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

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

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

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

Yeah. And a lot of them basically are paired with supplements or probiotics or prebiotics that are supposed to, quote, unquote, fix the defects that are found in the test. Right. Isn't that the RXDX model?

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

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

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

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

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

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

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

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

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

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

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

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

Less so. But the answer is yes, they are absorbed and so to some extent they can get into the body directly through.

Chylomicrons, as regular fatty acids would, or.

No, no, no, they're very short and they're soluble and they tend like acetic acid is a short chain fatty acid that would be a 1 carbon.

So fiber sounds like it's going to be the most important nutrient in terms of fueling the bacteria of the gut, which in turn pay service back to providing energy for the epithelial cells. Correct.

Not just fiber. Polysaccharides do as well. They can digest those. Everything that gets down there, they can live on. It's just that very little of the protein that you eat will get down to the colon.

Then tell me about things like artificial sweeteners or non nutritive additives to food. There's been a lot of discussion that, for example, aspartame or other sweeteners that aren't caloric may still provide some impact on the microbacteria of the colon. How well is that understood?

There are bacteria that can metabolize them, and so there are effects on the bacteria. The net effect of that is I really can't speak to because that's a literature that I find to be self contradictory. Some people think they do things, some people think the effect is negligible.

I haven't spent much time in that literature, but the little time I've spent in it, I've come away without much of an understanding of how these things are potentially creating an impact. You mentioned protein already. What do we know about the role of fatty acids in the colon? How many of them are making their way there?

Well, most of the fatty acids that get to the colon are derived from fiber.

In other words, they're not exogenous.

That's true normally, but not always. So for example, under abnormal conditions in which bile salts or pancreatic enzymes are deficient, then those fat can get into the colon. One gets fatty stool, bacteria can metabolize that. And so in celiac disease, for example, there's a lot of fat in the stool, or in biliary tract disease, there's often a lot of fat in the stool. The stool is described as greasy and foul smelling because the bacteria do metabolize it.

What about the scenario where a person has taken antibiotics, potentially for a protracted course? What can they do to appropriately repopulate their gut?

What a good question. Probably taking appropriate probiotics at the same time they're taking those antibiotics or afterward is helpful.

And what constitutes appropriate probiotics? This is a world I know very little about.

It varies. Some people think that yeast derived saccharomyces is good. Some people swear by lactobacilli or bifidobacteria. There is evidence that when you're taking antibiotics and saccharomyces at the same time, I'm trying to think of the name of the pill that they sell. It's over the counter.

And sorry, just for semantics, what's the difference between a pro and a prebiotic?

Probiotic is defined as an organism that has beneficial effects. And prebiotic is defined as a material that will enable the body to grow organisms that have beneficial effect. So the difference between them is that prebiotic enables you to make your own healthy organisms probiotic as you eat them. So, for example, I eat activia every day now that I've aged. It fights the problems of aging.

So fermented foods are obviously valuable probiotics.

An important point to bear in mind. It's not just that it's fermented. I mean, all yogurt is fermented. But that something like Activia has Bifidobacter animalis in it, which actually gets through, survives the stomach acid, goes down the GI tract and comes out in the stool.

And just to be clear, that's an anaerobic bacteria or aerobic.

It's an anaerobe, but it can get down the gut and survive in the stool.

It's so interesting that we can be eating something anaerobic that it can be in our food. Right.

It's added, I guess it's aerobic. Has to be aerobic.

Kind of gets to the challenge of this whole anaerobic problem, right?

Yes, but the organism that's put in has actually goes through the GI tract and survives. So the importance of a probiotic is not only that it be there, but that it survive and do something in the GI tract.

How can people navigate this world, Mike? Because this is another one of those places where there's a lot of opportunity for charlatans to sell you things that a don't even have the colonies that they claim they do, or if they're there, they're dead on arrival. And if they're not, they don't survive the transit from mouth to colon. I mean, how does one kick the tires on these things?

Well, for one thing is you can trust the FTC and the fda. So claims cannot be made for foodstuff like a probiotic that are medical unless it has been subjected to actual tests and pass FDA muster to show efficacy and safety. Most of what they call probiotic or prebiotic has not done that. Foodstuff then is regulated through the advertising by the ftc. So I was interestingly called upon to testify at a hearing for a game I consult for Danon. And so when I mentioned Activia that I take that doesn't mean that I want to tell everybody out there that this is better than any other. It's just one I know about. So in any case, the FTC looked very carefully at the claims made for that product and wanted to see and carefully evaluated all of the evidence. And in order to make the claims that Dannon makes for that product, they actually have to demonstrate to the FTC that they have the evidence that it does what they say it does. So they say that if you eat as much as two cups a day of activity, it will cause the GI tract to speed up. And the answer is it will.

And how many colony forming units are provided in that?

I Honestly don't know. I can't answer that question. But there are, I think, something on the order of 10 to the 11th going in. And I'm trying to think of what comes out the other end, but it's much less. But they do have evidence, at least for that product that it survives and goes through.

When it comes to getting your GI system back in track after a course of antibiotics, what are the most important elements to look for in the probiotic? Is it Lactobacilli then?

Not a specific Lactobacillus, just the ability to colonize the GI tract. So Saccharomyces works very well in that case. That's the one I'm trying to think of the trade name for.

We'll figure that out and link to it in our show notes.

It's well known and it's a yeast derived product.

And it's over the counter, not.

Yes, it's over the counter.

Now, by definition, does a probiotic need to be refrigerated?

It just needs to be able to survive. You can take it as a pill.

But even pills don't need to be stored in the refrigerator.

No, they don't. Not necessarily. It depends on which one. I mean, so for example, Bifidobacteria animalis, which is in Activia, has to be refrigerated, but so does the activia because it's yogurt based.

Again, it just seems to me that the big opportunity here is going to come with kind of the bioengineering that's necessary to grow these bacteria in culture. That seems to be just an enormous blind spot we still have in this space, both from a diagnostic standpoint, but also from a therapeutic standpoint.

Absolutely right. And from a point of view of really having what is sort of a fringe popular economy to a really effective major product. So that if you could make an organism and know exactly what it does, and you could make it in scale and give it to people to take it safely, big time bucks.

Well, Mike, thank you very much for this tour of one of the most probably underappreciated systems in the human body. We've talked a lot about its unique embryology, very unique innervation, and of course, perhaps most importantly, its cohabitation with bacteria that basically outnumber us. As we said, I think at the outset, I can't remember if we talked about this before we were recording or not, but this really feels like a bit of a black box. And I guess that speaks to why 60 years later you're still working just as hard.

That's right. Or as you said, as you get further away from shore, the water gets deeper.

Yeah, well, the water feels awfully deep right now. Mike, thank you very much for your time and your expertise today.

Thank you.

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