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Speaker A: Welcome to the Huberman Lab podcast, where.

Speaker B: We discuss science and science based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Doctor Diego Borquez. Doctor Diego Borquez is a professor of medicine and neurobiology at Duke University. He did his training in gastrointestinal physiology and nutrition, and later neuroscience. And by combining that unique training and expertise, he is considered a pioneer and leader in so called gut sensing, or the gut brain axis. Now, when most people hear the words gut brain axis, they immediately think of the so called microbiome, which is extremely important. But that is not the topic of doctor Borges expertise. Doctor Borquez focuses on the actual sensing that occurs within one's gut, just as one would sense light with their eyes or sound waves with their ears for hearing. Our gut contains receptors that respond to specific components of food, including amino acids, fats, sugars and other aspects of food, including temperature, acidity and other micronutrients that are contained in food. That give our gut the clear picture of what is happening at the level of the types and qualities of food that we ingest, and then communicate that below our conscious detection to our brain in order to drive specific patterns of thinking, emotion and behavior. And of course, everybody has heard of our so called gut sense, or our ability to believe or feel certain things based on perceptions that are of below or somehow different from conventional language. Today, doctor Borges teaches us about all aspects of gut sensing. How it occurs at the level of specific neurons and neural circuits, how the brain responds to that, how specific foods and components of food impact not just our feeling of digestion, or feeling good or bad about what we ate, but indeed how we feel overall. How safe we feel, how excited we feel, whether or not we feel depressed or sad, angry or happy. Today's discussion, I promise you, is unique among all discussions of neuroscience, at least that I've heard previously, in that it combines two seemingly disparate nutrition and neuroscience. Indeed, today's discussion gets into how different foods and food combinations impact how we feel and what we crave, and what we tend to avoid. We also get to hear the absolutely extraordinary story of Doctor Borque's upbringing in the Amazon jungle, and how his knowledge and intuition about plants has influenced his science, and how the incredible science that his laboratory is doing relates to all of us, and our ability to better tap into our gut sense. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Joov. Joov makes medical grade red light therapy devices. Now, if there's one thing that I've consistently emphasized on this podcast, it's the incredible impact that light, meaning photons, can have on our mental health and physical health. Red and near infrared light has been shown to have profound effects on improving cellular health, which can help with faster muscle recovery, boosting healthier skin, reducing pain and inflammation, enhancing sleep, and much more. What sets Juve apart is that it uses clinically effective wavelengths, emits a safe and effective dose of red and near infrared light, and most importantly, offers the only true medical grade red light panel available. I personally try to use the handheld Juve go unit, as it's called, every day, and especially when I'm on the road traveling.

Speaker A: If you'd like to try Joov, you.

Speaker B: Can go to joov.com huberman. That's joov.com huberman. Joov is offering an exclusive discount to Huberman Lab podcast listeners with up to $400 off Joov products. Again, that's joov.com Huberman. Today's episode is also brought to us by element. Element is an electrolyte drink that has everything you need. That means the electrolyte, sodium, magnesium, and potassium in the correct amounts and ratios, and nothing you don't, which means no sugar. Now, I and others on this podcast have talked about the critical importance of hydration for proper brain and body functioning. Even a slight degree of dehydration can diminish cognitive and physical performance. It's also important that you get adequate electrolytes. The electrolytes, sodium, magnesium, and potassium are critical for the functioning of all the cells in your body, especially your neurons, your nerve cells. Drinking element dissolved in water makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes. To make sure I'm getting proper amounts of hydration and electrolytes, I dissolve one packet of element in about 16 to 32oz of water when I wake up in the morning, and I drink that basically first thing in the morning. I'll also drink element dissolved in water during any kind of physical exercise I'm doing, especially on hot days when I'm sweating a lot, losing water and electrolytes, they have a bunch of different great tasting flavors of element. My favorite is the watermelon, although I confess I also like the raspberry and the citrus.

Speaker A: Basically, I like all the flavors.

Speaker B: And element has also just released a new line of canned sparkling element. So these aren't the packets you dissolve in water. These are cans of element that you crack open like any other canned drink, like a soda. But you're getting your hydration and your electrolytes with no sugar. If you'd like to try element, you can go to drink element spelled lmnt.com Huberman to claim a free element sample pack with the purchase of any element drink mix. Again, that's drinkelement.com hubermanda to claim a free sample pack. Today's episode is also brought to us by Helix Sleep. Helix Sleep makes mattresses and pillows that are of the absolute highest quality. I've spoken many times before on this and other podcasts about the fact that getting a great night's sleep is the foundation of mental health, physical health and performance. When we aren't doing that on a consistent basis, everything suffers. And when we are sleeping well and enough, our mental health, physical health and performance in all endeavors improves markedly. Helix mattresses are different in that they are customized to your unique sleep needs. So if you go to the Helix website, you take a brief two minute quiz and it asks you questions such as do you sleep on your back, your side, or your stomach? Do you tend to run hot or cold during the night? Things of that sort. Maybe you know the answers to those questions, maybe you don't. Either way, Helix will match you to the ideal mattress for you. For me, that turned out to be the dusk mattress. I started sleeping on a dusk mattress about three and a half years ago, and it's been far and away the best sleep that I've ever had because it's customized to my unique sleep needs. So if you go, go to helixsleep.com huberman and take that brief two minute quiz, you can figure out what mattress is ideal for your unique sleep needs. For the remainder of this month, May 2024, Helix is giving up to 30% off mattresses and two free pillows as part of their memorial day offer. Simply go to helixsleep.com huberman to get 30% off and two free pillows. And now for my discussion with Doctor Diego Borquez.

Speaker A: Doctor Diego Borges, great to have you here.

Speaker C: Thank you for having me, Andrew.

Speaker A: I am super excited to learn from you today, as I know everyone else is. And if they don't realize why soon they will. Which is that you work on one of the more fascinating aspects of us, which is our gut. Our gut sensing the gut brain axis, which I think most people don't realize is nearby, but separate from the so called microbiome. So we're not talking about the microbiome. A very interesting and important topic, of course, but we are going to talk about this thing that we call our gut sense and how it impacts everything from our cravings to our brain health and our cognition. So, once again, welcome. And I just want to kick things off by asking you to educate us, explain what is this gut brain axis that we hear about and what's going on in our gut besides digestion.

Speaker C: Well, Andrew, thank you so much for having me here. Thrilled to be here. I knew that since we met a few years ago, that we will have this ongoing conversation and a great conversation. The gut and the brain. People call it an axis because traditionally thought to be an imaginary line that was connected through hormones. Since 1902, when the first hormone secreting was reported by Bayleys and Stirling, it was known that when we eat, then hormones, these molecules in the gut, are released, and then they will enter the bloodstream and then eventually will have a cause in distant organs. And for the next hundred or so years, the field focused on the hormones. And as a consequence, there was no direct line of communication between the gut and the brain. But as often I say, you don't say, or we don't say, the nose brain axis or the eye brain axis. And all of the organs are in sync, working in sync. In the gut, there are also some sensory cells that are able to detect the outside world and then quickly communicate that information to the brain. And I say the outside world, because the gut is the only organ that passes throughout our body, but it is still exposed to the outside. If you think about it, if you will swallow a marble, it still has the chance to get out.

Speaker A: Please don't do that, anybody.

Speaker C: But is it still exposed to the surface?

Speaker A: You're right. I never thought about the gut as the organ that is in contact with the outside world, unlike our heart, which is not in direct contact with the outside world, or our liver, or our pancreas. But the gut is.

Speaker C: The gut is. And if you think about it, it's just separated by some compartments that have all of these valves, the epiglottis, the gastroesophageal junction, the pylorus, the ileocecal junction, the rectum.

Speaker A: So these are the sequences of valves, of chambers with valves between them that food passes through air passes through. And within each, as I understand it, there are different functions related to digestion. But I think where you're taking us is that there are different modes of sensing what's coming through and signaling to the brain and other organs what's going on in the outside world by what's sensed coming through that passage. Is that correct?

Speaker C: That's correct. And if we think about it, when we swallow something, literally, we have to trust our gut. Perhaps that's why we use this phrase, trust your gut, because after that, there's not much that you can do, at least in regular humans, that you can do consciously, to expel something that perhaps is poisonous or toxic. It is the gut that has to make that distinction and then usually accommodate things for absorption or let them pass through digestion, and then ultimately they will be secreted. Right.

Speaker A: So if you could describe for us the architecture that is, the cells that respond to things in the gut and where they send that information and how they send that information. What is this thing that we call gut sensing made up of? What's the parts list?

Speaker C: So the parts list has been evolving recently. And while some of the elements we have known for a while, but in general, what we're talking about, because it's an external surface, it is lined by a single layer of cells that are called epithelial cells. And essentially, these cells are exposed to the outside world, but they also are attached in a little membrane, and they are the ones that interface with the inside of the body. So in the stomach, we have a stratified epithelium, for instance, that is thicker, so it can survive digestion, chemicals and other things, like a harsh environment. In the intestine, we have a little bit more of a more delicate epithelial layer. And within this epithelial layer, there are several different cell types. One of those is the so called enteroendocrine cell, to put it in more simple terms, is a gut endocrine cell, or a gut cell that releases hormones. The term was coined in 1938 by a german physician. His name was Frederick Fetter. And at that time, it was a major advancement in our understanding of physiology because he came up with the idea that the organs were not only communicating to organs, in fact, there were cells within the organs that were communicating to other organs through the release of some of these endocrine factors, these neuromorphic modulators or these neuropeptides that we know as hormones. And so he named the diffuse endocrine system of the gut. And then he came up with this word enteroendocrine cell. And these cells are dispersed at a ratio, roughly speaking, like one to 1000 epithelial cells throughout the digestive tract. And we thought for the longest time that these cells were not connecting directly to the nervous system, that they will release these neuromodulators, and the neuromodulators, through diffusion, will act on receptors into some of the nerve terminals. And that is true. That is a very well established system. But in 2015, we made an observation that some of these cells, anywhere from one third to two thirds of these cells, it depends on the type of systems that you use to identify. They were contacting directly the nervous system. That brought up a new dimension of how it is that the gut could be communicating to the brain, because, as you know, in the brain, the synapses are the ones that are most predominant. However, there is a lot of neuromodulation from endocrine functions in the brain, too. So in the gut, this was not well described. There had been, historically, a few examples that these cells may be making synaptic context, but they had not been studied. And perhaps one of the main reasons why they hadn't been studied is because the tools were not there. And if you recall, in the 1990s, with the advancement of green fluorescence protein as one of the main molecules to tag cells, now, all of a sudden, there was a revolution in biology, because you could identify the cells, you can take them out, you can do a transcriptomic analysis to see what genes they express. You could co culture them, you can modify their genome, and then you can start to interrogate what is their contribution to the entire body.

Speaker A: I'll just interrupt you for a second just to make sure that I and everyone else is on board. So, if I understand correctly, it's long been known that there are cells that are in these layers of the gut, in the intestine. And it's long been appreciated that as food passes through, these cells somehow can sense the chemical constituents of the food as it gets broken down and then release hormones into the bloodstream that could influence the brain. Those hormones could travel and influence things far away. In fact, for those that don't know, endocrine generally means signaling at a distance between cells. So between gut and brain, or gut and liver, it can also mean local effects. So hormones, endocrine effects, can also be local. But if I also understand you correctly, it was only about 15 years ago when you mentioned green fluorescent protein. We should probably just tell the tale in a few sentences. This is an amazing story in biology where, if you've ever seen fluorescing jellyfish. That's because they express a gene for so called green fluorescent protein. And biologists have hijacked that gene sequence and put it into mice and now actually other organisms as well, which allows you to see individual cells and cell types. These cells release hormones. The hormones influence the brain and other organs. And now I think you're going to tell us that they also are able to make direct communication lines with other organs as well.

Speaker C: Correct. So maybe here is fitting how it is that I got into studying this system. And as you know, between the nineties and the early two thousands, there was an explosion in tools to study the brain and neural circuitry and the connection of neurons and each one of the neurons, because up until the 1990s, the tools were limited electrophysiology, behavior. But then, not only we had a green fluorescence protein, we had optogenetics, we had rabies modified to be able to trace how it is that neurons connect at one synapse, which was a dream. I think that, in fact, that was the dream of Francis Crick when he was at the salk. He talked about having the way to control.

Speaker A: For those who don't know, Crick won was a co recipient of the Nobel Prize for the discovery of the structured DNA, but then, later in his career, developed an obsession for neuroscience. And, yeah, he daydreamed out loud about having tools to visualize individual connections in the nervous system. And as Diego is pointing out, scientists have hijacked the rabies virus, which hops between neurons labeled the rabies virus, with things that glow fluorescent. And in doing so, we now understand a lot about what Crick dreamed for, which was the ability to see different specific connections in the nervous system.

Speaker C: Yes. So then you could isolate the cells, and then you could do sequencing technology to see, like, what are the genes that the cells are expressing? And then you can start to understand the makeup of the cells. In 2009, Hans Cleavers, a scientist in the Netherlands, did a beautiful experiment. He discovered these factors that will trigger a receptor of the stem cells in the intestinal epithelium and will form, literally, a mini gut in a dish. These cells will be all lined up, and then they will have a lumen. And I remember seeing some of these papers coming out when I was a PhD student, and I was already studying the gut. So it was inspiring to see all of the things that all of a sudden you could do. When I began studying these cells, immediately by isolating the cells and simply observing the cells in the native tissue of these mice models, it quickly became evident that some of the cells had a very peculiar anatomy. Some of them had these very prominent arms at the base, literally in the sistine chapel, Adam reaching out to God with the hand, the cells will have that type of anatomical features and even ending with a little hand at the end of that arm. Obviously, I immediately thought, why would a cell, that it is supposed to react to food and release hormones into the bloodstream or just in the vicinity, will invest so much energy into developing an arm? Right. So then I started to look, well, perhaps it is because it's providing a bridge directly into the vasculature, into the vessels, to put the hormones into the bloodstream grown. I couldn't find that direct connection. So then I started to study perhaps they were associated with the nervous system. And that's how we made some of the first observations, that some of them, with the arm or without the arm, they will have a more intimate relationship with nerve fibers. And that, of course, opened up a bunch of new questions. But the first thing that we had to do it was to come up with a name for this food, and it kind of became organic. And I want to highlight this because I think that as we go through the discovery trajectory, we don't realize the need to also engineer language. How we go about language is we start to attach words that we already knew and we start to put them together to describe something that new that we're observing. Right. And I say this because at the very beginning with my mentor, we will start to call these little feet. First we call them axon, which is like the term for the long extending branches of the neurons, the main branches of the neurons. We will call them axon like, because they look like a baby axon. But then we call them also like pseudopod, because it was like a pot, but it was pseudo. And at some point, and it was coming from some cells in the. In the kidneys that they are called, or something like that. So it was axon, like, pseudopod, like, basal process to describe that it was on the base. So at some point, it became so long that we couldn't fit it in an abstract. Right.

Speaker A: That's a bit of a mouthful.

Speaker C: So we began thinking about it, and then eventually I came up with a term I thought like neuropod. And I remember pitching it to my mentor, and he said, like, let me think about the weekend. And then on a Monday, he came in and he said, like, you know, it has a ring to it. I think that we should use it. But essentially, the thought was that if these cells are contacting, then perhaps they are passing information directly onto the nervous system. That is very different than just spewing neuromodulators in the vicinity and hoping that some of those catch the nervous system. Like I said, while that still exists, I think that is just a matter of space and time. They modulate these terminals in a different space and time, the hormones. But the transmission, the neurotransmission, is directly and more precise in space and time.

Speaker A: Could I just interrupt for a moment, please? So, hormone signaling, endocrine signaling, generally is slower than the forms of communication directly between neurons. Could be on the order of seconds, sure, but typically on the orders of minutes or hours. Whereas neural communication on the order of milliseconds.

Speaker C: Correct.

Speaker A: So if I understand correctly, these what you decide to call neuropod cells. And thank you for shortening the name from the other description line, the gut. Are we talking about everything from esophagus down to the stomach to the intestine? Or is it just at the level of the stomach and intestine? Where do they.

Speaker C: This is where the conversation becomes expansive, because these neuropods, or causings of these neuropods. So these neuropods are simply specialized neuroepithelial cells, meaning that are electrically excitable, that they can discharge electricity. But they are, these type of cells are in every single epithelial cell, or epithelial layer of the body, because that's how the body creates a representation of the world through sensor cells that are equipped to detect the outside world, meaning that they can be exposed to fluctuations in temperature, fluctuations in ph, fluctuations in concentrations, and then they quickly can generate a chemo electrical coat that they pass it on to the nervous system. And then ultimately the brain integrates that and says, like, oh, my belly is feeling good, but I'm feeling cold in the skin. That is thanks to all of these neuroepithelial cells that they are even in tasting, so to speak, the cerebrospinal fluid inside of the spinal cord and the ventricles, they are inside of the inner ears. The taste, the taste buds. In fact, there's a beautiful book from the seventies from some japanese scientists, Fujita Kanon, Kobayashik, who call these cells paraneurons. And their whole concept is that there was not such a discrete distinction between an entire neuron that lives inside of the brain or the central nervous system and a neuroepithelial, or a neuroendocrine cell that lives exposed to the outside. Simply that there is a continuum of adaptation. So the organism can bring the information from outside into the body to be able to process it, and then process it and then guide behavior.

Speaker A: So, based on the way you describe it, we have these neuropod cells that line our gut, and we also have these similar cell types in the other organs of the body. And these cells are responding to the chemical constituents of what we eat as the food is broken down, also to the temperature of the environment, to the ph. That is how relatively basic or acidic something is that we ate, and presumably to other features in our environment as well. And all of that information is activating these cells to some degree or another, and then we're releasing hormones into our body as a consequence. But also, there's a direct line to the brain, and we're not necessarily aware of all of this happening.

Speaker C: Right?

Speaker A: I mean, until you describe it, I think most of us are, have not been aware that this is happening, and.

Speaker C: We probably shouldn't be aware. You know, like, as I often say, like, if you and I are having a conversation, we probably shouldn't be aware of the macrophage in the spleen that is chasing this bacterium that got inside of the lettuce that we swallow it in a lunch. Right? Like, you just do your thing so we can keep communicating. Right.

Speaker A: Except maybe don't eat more of that lettuce. Right, which is the. That's right. Okay, so you discovered these neuropod cells.

Speaker C: That's right. Or I described them.

Speaker A: You described them, yeah. And you had in hand some tools to selectively label them. What did that reveal about their connectivity with. You're referring to it as the nervous system, which I love, because a resounding theme on this podcast, as I always say, brain and spinal cord and all the connections to the body and back again is the nervous system. But what did you discover in terms of the connections with the brain proper?

Speaker C: Here is where the tools started to make a big difference. All of a sudden, you could see the resolution of a receptor inside of a cell using certain type of microscopes. I remember that one of the first questions that I will always drill on, you know how these laugh meetings can get intense, right? Like, when I will bring data and showing just very simple immunohistochemistry, meaning labeling, to see how these cells were interacting with the nervous system. I will show some of the images. Then the other scientists will say, well, yeah, those are nice images, but remember that contact does not mean connection. And I went thinking about that at the very beginning. I thought that it was silly semantics, but I specifically remember that there was one time I was running, and I was thinking, like, how do you demonstrate connection between two cells? And then I thought that since we had the ability to identify these cells by fluorescence, we could isolate them based on their fluorescence. And what will happen if we put them in front of a sensory neuron and then just record them inside of a microscope? Right. Over time. And I thought, maybe they will get close to each other, and then we can go and do some more labeling and show that they are contacting or connecting. But much to our surprise, we actually saw that in real time. When you isolate them from the mouse and you put them in a dish, they both look like these round circles. But after a few hours, not only they get close to each other, but they recapitulate the circuitry in the dish. Literally, they form, like, two brains in a dish. The gut and the brain in a dish. Yeah. And that was an eye opener. I still remember it was somewhere. I think it was, like, June 27, 2012, when I saw that experiment, because it opened my eyes to so many different things. One was that these cells are not static, because since we have been seeing them for decades just in slices or fixed tissue, we had lost the notion that this thing is constantly moving. Right.

Speaker A: The cells are actually moving.

Speaker C: The cells are actually moving.

Speaker A: So these cells line the gut, meaning they're along the walls of the gut. And intestine.

Speaker C: Yeah, the intestine.

Speaker A: They reach a hand into the gut to sense whatever chemicals are there.

Speaker C: They have little cilia, little hair, or microvilli that is literally like little hair that is exposed to the lumen.

Speaker A: So the lumen, folks, is the cavity, the empty cavity of the gut. Not empty, but the internal part. And so they're sensing the chemicals there, and you're saying they can move. Okay. And they're sending a process. By the way, folks, anytime you don't know whether or not something is a dendrite or an axon, just call it a process, you'll get it. Right. A process up to the brain underneath.

Speaker C: That will connect to the nervous system.

Speaker A: I see. So through a series of stations. Okay, amazing. So what we're talking about here is Diego's discovery of pathway from the gut to the brain that essentially allows sensing of what's happening in the gut to inform feelings.

Speaker C: That's right. Yeah. So that was the first experiment, like, showing, in addition. Right. The next experiment was, well, does it happen in the mouse? And then through a series of. I have a friend, neuroscientist, that she calls these rabies gymnastics, because you have to put in some genes and make things work. Then we demonstrated that these cells, that the virus will be capable of infecting these cells. Specifically, instead of infecting the other epithelial cells, it will infect these neuro epithelial cells because rabies likes neurons, and then it will jump from that cell into a nerve fiber, and these rabies can only jump one connection. And what was surprising is that the fluorescence from that rabies will show up in the brain stem and in the bodies of the cells that are in the notos gang ganglia, which is this cluster where the cell bodies of the neurons of the vagus nerve are located right underneath the neck, meaning that there was just one stop between the surface of the intestine and the brain stem. The two cells were connecting that space. So, obviously, the information that was the anatomical basis for the information to travel very rapidly up into the brain and rapidly in the subconscious, we're not necessarily aware of it, although I've read that there are some instances in which people become more aware of it, either in atypical fashion or with meditation and other things. Like people can become aware.

Speaker A: Yes, people definitely can become more aware of their so called interoception, what's going on at the level of their heartbeat frequency or their gut sensing, if they spend time on it. Some people, as you mentioned, develop an almost pathologic sense of interoception, such that they have trouble navigating normal life because they're so aware of what's going on inside their body. This is actually an interesting issue in the field of psychiatry. My colleagues in psychiatry at Stanford tell me that some people with a lot of anxiety, for instance, are so aware of their heartbeat that it becomes disruptive and distracting to them. So it's not always the case that it's better to become more aware of your internal processing. Sometimes it can be deleterious. Other times it can be good for us. Some people are very unaware of what's happening in their body, and they need to develop more awareness of that. I feel like as long as we're talking about rabies, we should have a little bit of fun and explain to people something about rabies, viruses. Because what we've been talking about is the use of viruses as experimental tools in order to take a virus, basically attach or put something in so that whatever cell is infected by it glows a certain color, so you can see the cells and visualize the circuitry. But as long as we're talking about rabies, I feel like it's such a word that has such salience. The rabies virus, which exists in nature, is amazing because I don't know if it has a consciousness, but it essentially propagates between animals by way of the animals that have it bite. They become more aggressive. They bite a target animal. The virus gets in, it's picked up by the nerve terminals and is carried back from one cell to the next across synaptic connections. Synapses get little gaps between neurons. What doctor Diego Borquez has been telling us is that scientists have engineered the rabies virus so that it only jumps one station and then stops. You can do this by modifying the coat protein. There's a bunch of fun virology that can be done to do that. But what I find amazing about rabies virus, and there's a great book, by the way, called rabid, which is essentially a history of the study of rabies, is that that once it travels from the site of the bite up to the brain, what does it do? It changes the brain to make the now infected animal or person more aggressive so that then they go bite somebody else. So, I mean, in some ways that the viruses have a kind of unconscious genius to them. Right. What's the best way to get from one animal to the next? Well, there are a number of different ways, but one way is to just make that animal more aggressive. So it goes and bites things.

Speaker C: Yeah. Make wild.

Speaker A: Right.

Speaker C: Make the animal work for you.

Speaker A: Make the animal work for you. Right. It's almost exploitive. It exploits certain circuitry in the nervous system. I'd like to take a brief break.

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Speaker A: Huberman okay, so you identified these, you said described, but I'll say discovered, because that's what happened. You discovered these cells. You label their connections. You see that there's just two stations between these cells or one station, really, between these cells and the brain. And so now these cells can sense chemicals in the gut that are the consequence of the breakdown of food and send that information directly to the brain. What does the brain do with that information?

Speaker C: So here comes the key experiment. And this was building, obviously, on the work of other scientists that had already described that the gut had some receptors for sugars, specifically for glucose, for other nutrients around this area. In the early two thousands, when we were starting to be able to identify some of these cells, then it quickly became obvious that these cells, these enteroendocrine cells, throughout the lining of the stomach, intestine, colon, they had multiple receptors for multiple nutrients. We have the macronutrients, for instance, sugars, fats, proteins. But within them, we have a repertoire of molecules, multiple lipids, multiple types of sugars, and so on and so forth. These cells, depending on their location, they will express different types of receptors, or a combination of those receptors. And I said it, depending on the location, because when we're eating, let's say an apple, the apple is going to be partially undigested by the time that it enters intestine. But by the time that it gets to the colon, most of those nutrients are being absorbed, and perhaps only fibers are surviving to feed off most of the microbes that live in the colon. So the gut has evolved to mirror and to become a velcro to the molecules that will be in that specific space. So it will detect, so it will detect sugars more in the proximal intestine, but fibers or fermented by products more in the distal intestine or in the colon, like short chain fatty acid, butyrate, propionate, and so on and so forth.

Speaker A: What other kinds of nutrients do these neuropod cells detect from food? So, you mentioned sugars, you mentioned fermentation, presumably short and long chain fatty acids.

Speaker C: Yes. The short answer is that I think that in due time, we are going to realize that they detect just about every single thing that we put on our mouths every day. You know, that they have some. Either a specific receptor that is dedicated to it, or a combination of receptors to be able to detect some of these compounds. And not only the chemical compounds, but also an area that I think that is going to be fascinating in the future is the mechanical distinction, plus the adjustment in temperature as the chyme starts to flow from the mouth into the colon. Like, for instance, I heard this from a bioengineer not long ago that was engineering artificial gut and a stomach. And he shared with me a piece of information that I was not aware of, that the esophagus has to adjust the temperature of the food very rapidly, within seconds, into physiological temperature of the inside of the body. So we are having hot coffee within a couple of seconds. It has to be at the physiological temperature of the body by the time that it gets into the stomach. And all of that happens very rapidly. Amazing in the sufferers. Right?

Speaker A: So if I understand correctly, these neuropod cells have a variety of different receptors, depending on where they are located along the trajectory from the mouth to the rectum.

Speaker C: That's correct.

Speaker A: And some are sensing sugar, some are sensing temperature, some are sensing ph. So relative acidity, some are sensing amino acids, presumably. I mean, I've heard it said, and I believe there's a researcher down in Australia who's been very bullish on the theory that we are not exclusively, but we are predominantly amino acid foraging machines, because we need amino acids for all sorts of. Of important biological processes. And these cells are essentially evaluating how much sugar, how much leucine, how much short chain fatty acid, how much essential fatty acids of different kinds, and then making changes to the gut itself, but then presumably signaling that information elsewhere in the body.

Speaker C: So here I'm going to give you something that will get your gut churning, so to speak. So these cells have to make sense, not only of the molecule that had been adjusted, meaning the chemistry of the molecule, let's say it is glucose, it has to make sense a little bit. Of the taste. Is it sweet? Right? Is it bitter? Then it has to take into account how much of the molecule is absorbed inside of the cell, right? So that's the second layer of integration. Then once the cell has eaten that molecule, so to speak, then that molecule will be digested inside of the cell to release ATP or some other compound ATP for energy, for instance, that has also had to be taken into account. For instance, in glucose, glucose activates the task one r three, which is a sweet taste receptor. Then the glucose is absorbed by some of these sodium glucose transporters, which are active transporters. And these transporters depolarize the cell. And then once glucose gets inside of the cell, glucose enters the TCA cycle, is catabolized, and then produces ATP. And the ATP further activates another voltage gated channel, farther depolarizing the cell. And then the cell releases, in turn, a transmitter, for instance, glutamate, that very rapidly tells the vagus nerve within milliseconds, you know, I got sugar, and it tells it in two phases because that glutamate will activate two different types of receptors, ionotropic, which are very fast, and metabotropic, which are a little bit more delayed. But then the metabolism of that glucose that produces the ATP and farther depolarizes the cell. We believe that it will cause the release of the hormone of the neuropeptide. Then the neuropeptide comes on top of that and gives you that full experience of what it means to consume sugar. So that happens at the level of one cell and at the level of one molecule. So imagine, like all of the computation that the gut has to be making for each one of the molecules throughout the digestive tract.

Speaker A: If I stand back from this picture, what I get is there are very interesting cell types that line our gut that are evaluating all of the not just macronutrients, proteins, fats and carbohydrates, but micronutrients within the food we eat, as well as some of the other qualitative features, temperature, for instance, maybe even quality of the amino acids or the sugars, simple versus complex sugars, etcetera. If we could just further zoom out for a moment and take a human perspective on this at the level of experience. I once heard you tell a story about someone you knew who changed their gut radically and that changed their entire perceptual experience of food, including certain cravings. Would you mind sharing that story?

Speaker C: Yes. Thank you for bringing that story, Andrew. That story is very personal to me. I often say when I get on stage that we are constantly influenced by two things in life. The food that we eat and the people that we meet. Now, we have known each other, but now we meet in person and we are knowing other people. Right? And I remember that when I was starting my PhD in nutrition at North Carolina State University. So I didn't grow up in the United States. I grew up in Ecuador, and I was invited to my first Thanksgiving celebration. So I sat at dinner, and, you know, as we began chatting with the people that were next to each other, all of a sudden I was enthralled in this conversation of a woman telling me this story about her experience with gastric bypass surgery for treating obesity. So gastric bypass surgery was begun to be developed by surgeons in the sixties, and by the nineties, it had become a mainstream type of surgery for the treatment of chronic obesity. So she told me that there were primarily three things that happened. She said, well, within six months of the surgery, I had lost about 40% of body weight. You know, she said, like, I was about 300 pounds. You do the math, you know? So it was a. It was a significant amount. Significant amount. She said, within one week of the surgery, my diabetes was gone. She said, I did not need more insulin shots. So I had the same reaction that you're having. I was like, I don't know much about diabetes, but I know that is a major health burden. Right. But the thing that really caught my eye was when she said, but since you're studying nutrition, I want you to answer this to me. She said, why is it that before the surgery, I could not even look at Sony side up x? She said, just looking at the yolk will make me queasy. But after the surgery, not only I can eat sunny side up eggs, I actually have a craving for the yolk. She said, every time we go on Saturday to a restaurant for breakfast, I will take the toast and I will actually clean the plate of the yolk. So how is it that rewiring the gut alter my perception of flavor, alter my cravings and my mind to get the yolk?

Speaker A: She said, and even inverted her sense of what was aversive versus as appetitive? I guess for those of us that don't know, meaning me, I understand that gastric bypass surgery involves the removal of a portion of the gut. How much gut tissue do they actually take? Is it centimeters? Inches? I mean, the gut's a long distance. What do they do for gastric spinal?

Speaker C: In simple terms, the most. The classic surgery is called rou en yden. Gastric bypass surgery, which involves a reduction of the stomach and short cutting, the connection of the stomach to the intestine. So you will cut one third, which will be the duodenum. One third of that will be cut, and then that portion will be reconnected to the stomach, meaning that you're short circuiting the gut. And the whole idea was, at the very beginning was like, well, if we reduce the surface that is exposed to food, then we can reduce body weight by the simply reduction of surface that is exposed to the food that is absorbed. What it became very clear is that well before the body weight changes got taken place, there was already some dramatic changes in physiology. The hormones, the neuropeptides that were released from the intestine in response to nutrients, will change very rapidly. Then, as I mentioned, the food choices will change. Diabetes will be resolved. So then it became obvious that it was not necessarily just the reduction in the surface of the gut. So that's one of the main surgeries. The other one, as I understand, is vertical, is leaf gastrectomy. And this vertical gastrectomy is simply a reduction in the size of the stomach. So now the stomach is very tiny, and the idea is that will accumulate less, it could hold less food, and then the food will go very rapidly into the intestine. And what is becoming very obvious is that there is a rapid change in the sensory function of the gastrointestinal tract. So the gut seems to rapidly shift, perhaps become more, so to speak, in general terms, more sensitive to the presence of nutrients. Right.

Speaker A: Interesting. So this woman that you met at thanksgiving had gastric bypass surgery. And presumably, I think it's fair to assume, a good number of these neuropod cells that sense different nutrients were removed, and as a consequence, she completely shifted her craving of a particular food. And is there any sense whether or not, no pun intended, the lack of sensing of what was in sunnyside egg yolks was somehow related to a shift in appetite or something else? Or is it merely a qualitative, albeit a dramatic qualitative shift in what she craved?

Speaker C: So, two contextual pieces of information. So I remember leaving that dinner, and I was like, whoa, this is major, you know, like, I'm sure that people have written about this or done research, and I realized that it was very little was known. Even gastroenterologists knew very little about this. The first clinical report that the alteration in food choices was common in these patients came out, I believe, in 2011. And then later on, scientists replicated that even in Radhe or in mice, we have done it in the laboratory, and consistently, they change their food preferences, their food choices. So in recent years, we have been studying that system, and I will tell you that in 2022, this is another important contextual piece that we have not gotten to. So after we found and we described that these cells were connecting to the nervous system and that they were sending information up to the brain very rapidly, the challenge was, well, if this is a sense, what behavior is affecting, how is it that is affecting the responses of the organism? And that took a little bit of a technical hurdle. And here is where optogenetics comes in to.

Speaker A: Yeah, please explain for people what optogenetics is, at least at a top contour level.

Speaker C: Yeah. So, optogenetics. In 2005, Professor Carl Diceroth, Ed Boyden, and other scientists had been able to make this dream of an experiment which was isolate the genes that encode for these opsins that are sensitive to specific wavelengths of light and put them into neurons. And now by turning that light, they could make the neuron activate. And then ultimately, then later on, they went on to describe that that could be used to control specific cells that are regulating behavior, and then by that, define what cells are orchestrating certain type of behaviors, like movement, food intake, thirst, anxiety, so on and so forth. So in 2014, we began trying to adapt that technology to the gut. Very quickly, we realized that the way that light was brought into the brain was through a fiber optic cable that was rigid. And in the brain, it helps that it's actually rigid, but in the gut, it doesn't help, because the gut is constantly moving and so on and so forth. So it's not compatible for running those experiments. And here's where I usually say, like, you know, we really don't know what is going on because some forces, like, move around us. And in 2017, Professor Paulina Nikeva from MIT came to give a talk at Duke. And she reached out to me, and literally she came, and as we were chatting, she said, like, diego, I see that you're working between in this interface of the gut and the brain, and I have this fiber optic that is flexible. Would you have any use for it? So with that fiber optic, that made a big difference to study, interrogate the function of these cells to behavior. So when we were able to put those opsins, the light sensitive proteins, inside of these neuropods, and now when we turn the light on to shut off these cells very rapidly, we found something very interesting. So, normally, animals, when you give them the choice between a sweetener, which is devoid of caloric value.

Speaker A: So, like aspartame or sporadia or stevia.

Speaker C: Or something, and you give them sugar, table sugar. The animal invariably will go to sugar.

Speaker A: They prefer sugar?

Speaker C: They prefer sugar. If they have never seen sugar, it will take them a little bit more time. But regularly, by the second day, is within 90 seconds, that they detect what is sugar.

Speaker A: So they're drinking out of one tube, they get some water with stevia, they drink out of another tube, water with sugar, and they invariably prefer the water with sugar.

Speaker C: That's correct. And people have described this phenomenon for a while. And, in fact, in 2007, there was an elegant experiment done by Professor Ivan de Raujo at Duke University, in which the sweet taste receptors were. All the taste receptors were genetically erased, and the animals were not capable of distinguishing the sweetener from the water, but they could still distinguish sugar from water, meaning that there was something else that was detecting that sugar.

Speaker A: So just to make sure people are on board, an experiment where sensing of sweet taste at the level of the mouth is eliminated does not disrupt the preference for sugar water.

Speaker C: Correct.

Speaker A: Which means that there's something going on below the depth of consciousness that causes mammals, presumably us included, to prefer things that have sugar.

Speaker C: Yes. And then Professor Tony Esclafani, he had been studying these behaviors, and he went in so far to suggest that perhaps these sodium glucose transporters are some of the ones that are detecting the sugar as it enters the intestine, and that's what is causing the behavior. So we began working on this system, and we wonder, could these cells be the ones that are guiding that behavior? And around the time that we published this work, Professor Charles Zucker at Columbia also further advanced that area by building on the. On the previous work and demonstrated that there were a population of neurons in the brainstem that were integrating this information from the gut. And by that, the gut and the brain were guiding these behaviors.

Speaker A: And it is true that from the earliest of ages, we crave sugar, or at least if we are exposed to the taste of sugar, it tends to drive, seeking of more sugar. You can see that in babies, even.

Speaker C: Correct? And as I usually say, I call it instinctively because our mother doesn't have to teach us, hey, Diego, that is glucose. You know, it may present us in some ways, but at the end of the day, I have to go and get my glucose, get my amino acids right, because eating is very simple. We're just trying to solve this issue of getting our carbons, getting our nitrogen, getting our phosphorus, our potassium, our sodium, and our chloride in so many different ways, shape or forms. Right. So I went back to the experiment, the key experiment. So when we were able to put these opsins and bring the light and shut off these cells very rapidly, when we had presented the animal with a choice of sweetener over sugar, then all of a sudden, the animal became blind to the solutions. It couldn't discern between the stevia, so to speak, or the sweetener from the.

Speaker A: Actual sugar and the entire manipulation. The experimental manipulation that is, is occurring at the level of the gut.

Speaker C: The intestine. That's right. Right after the stomach is like just a small portion of the intestine.

Speaker A: So if we make an attempt to transfer this to the human real world experience. If I have some ice cream, it tastes sweet. I like it. And now I'm thinking about it, and I'm craving it just a little bit. I don't have a huge craving for sweets, but I do like some of them. So eating ice cream, it tastes sweet, the tendency is to crave more.

Speaker C: That's correct.

Speaker A: You have to eat a lot of ice cream before you're truly full.

Speaker C: Yeah.

Speaker A: And most people self regulate, or their parents regulate for them by limiting the number of scoops or something. And that sweet taste is part of the motivator. But what you're saying is that as the ice cream enters the gut, there are neuropod cells there that are also sensing the sugar and signaling to the brain. And the brain is responding to pursue more of that sweet containing substance.

Speaker C: That's correct.

Speaker A: And it's happening below our awareness. It is independent from the sweet taste of the ice cream.

Speaker C: Correct.

Speaker A: The conscious sweet taste.

Speaker C: The conscious sweet taste. Which of you, think about it, it's not fully conscious. Right. You know, as a. What we detect of the world is just a very tiny little portion. Right. Even sight, you know, like, we think we are looking for light, but I don't know what is happening behind my. My back. I trust that everything is going okay. Right. So when we shut off these cells, the animal, and as I usually say, like, became blind to the sugars because it's kind of like akin to having turn off the cells that are able to detect light, the wavelength of light, for us to be able to discern color. And it's not that the animal is losing its memory, because then if you remove the light and now the cells are functional again, then the animal again is able to distinguish one solution over the other. And then we did a couple more experiments in there. And what happens if we do the reverse? If we turn on the cells now. And the fascinating thing is that when we turn on the cells now, they, the mouse will eat the sweetener as if it will be sugar.

Speaker A: Interesting. So the activation of these cells makes them crave non caloric sweetener or low calorie sweetener, as if it were sugar. But is it blinding them to the difference between sugar and low calorie sweetener?

Speaker C: So here's another piece of information. We will offer them water and we will turn on the cell. The animal will drink the water as if it will be sugar, like it will be appetizing, even though it's just plain water. Yes. And what is becoming very obvious is that the gut has this sense at the most basic level. What the senses are doing is calculating a couple of things. One is the salience of the stimulus is like, how intense is the stimulus? And the other one is the valence of the stimulus is a pleasurable or painful, so to speak, in like, broad terms. And I say this because on the pain side, Professor David Julius, Professor Holly Ingram, Jim Baira at UCSF, they have done some beautiful work demonstrating that there are these serotonin releasing cells, specifically in the colon. They have focus in the colon, that they couple two nerve fibers of the spinal cord. And when they are activated now, all of a sudden they drive what we call in the clinical realm, visceral hypersensitivity. So they are responsible for triggering the hypersensitivity of the nerve fibers, the colonic nerve fibers, because they detect noxious stimuli. And then ultimately they gate that noxious stimuli and pass it on to the nerve fiber, in broad terms, as a painful stimulus.

Speaker A: So is this irritable bowel syndrome?

Speaker C: It is, we could call it as the biological basis of what could degenerate into irritable bowel syndrome and so on and so forth, or these chronical GI, they call them disorders of gut brain interactions.