The Science of Your Gut Sense & the Gut-Brain Axis | Dr. Diego Bohórquez

1. 0:00 – 2:37

   Dr. Diego Bohórquez

   1. AHAndrew Huberman0:00

      (Music) Welcome to the Huberman Lab Podcast, where 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 Dr. Diego Borquez. Dr. 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 Dr. Borquez's expertise. Dr. 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 below or somehow different from conventional language. Today, Dr. Borquez 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 fields: 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 Dr. Borquez' 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.

2. 2:37 – 6:49

   Sponsors: Joovv, LMNT & Helix Sleep; YouTube, Spotify & Apple Subscribe

   1. AHAndrew Huberman2:37

      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 Joovv. Joovv 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 cellar health, which can help with faster muscle recovery, boosting healthier skin, reducing pain and inflammation, enhancing sleep, and much more. What sets Joovv 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 Joovv Go unit, as it's called, every day, and especially when I'm on the road traveling. If you'd like to try Joovv, you can go to joovv.com/huberman. That's J-O-O-V-V.com/huberman. Joovv is offering an exclusive discount to Huberman Lab Podcast listeners with up to $400 off Joovv products. Again, that's joovv.com/huberman. Today's episode is also brought to us by LMNT. LMNT is an electrolyte drink that has everything you need. That means the electrolytes 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 LMNT 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 LMNT in about 16 to 32 ounces of water when I wake up in the morning, and I drink that basically first thing in the morning. I'll also drink LMNT 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 LMNT. My favorite is the watermelon, although I confess I also like the raspberry and the citrus. Basically, I like all the flavors. And LMNT has also just released a new line of canned sparkling LMNT. So these aren't the packets you dissolve in water. These are cans of LMNT 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 LMNT, you can go to drinklmnt, spelled L-M-N-T, .com/huberman to claim a free LMNT sample pack with the purchase of any LMNT drink mix. Again, that's drinklmnt.com/huberman 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 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 Dr. Diego Bortquez.

3. 6:49 – 11:35

   Gut-Brain Axis

   1. AHAndrew Huberman6:49

      Dr. Diego Bortquez.

   2. DBDiego Bohórquez6:52

      (laughs) .

   3. AHAndrew Huberman6:52

      Great to have you here.

   4. DBDiego Bohórquez6:54

      Thank you for, uh, having me, Andrew.

   5. AHAndrew Huberman6:56

      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-

   6. DBDiego Bohórquez7:36

      Mm-hmm.

   7. AHAndrew Huberman7:37

      ... and how it impacts everything from our cravings to our brain health and our cognition. So once again, welcome. And I'll just want to kick things off by asking you to educate us, explain, you know, what is this gut-brain axis that we hear about and what's going on in our gut besides digestion?

   8. DBDiego Bohórquez8:02

      Well, uh, Andrew, thank you so much for, uh, having me here. Uh, I'm thrilled to be here. Uh, I knew that, uh, since we met a few years ago, uh, that we will have this ongoing conversation and a great conversation. Um, the gut and the brain, you know, people call it an axis because traditionally thought to be an ima- imaginary line that was connected through, uh, hormones. So since 1902 when, uh, the first hormone secretin was, uh, uh, reported by Baileys and Starling, uh, uh, it was known that, uh, 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, you know. Uh, and for the next hundred or so years, the, the, the, the field focused on the, on the hormones and as a consequence, there was no direct line of communication between the gut and the brain. But as often I, I say, you don't, you don't say or we don't say the nose-brain axis, right? Like, or the eye-brain axis, right? Uh, and all of the organs are in sync, working in sync. So, uh, in the gut, there are also some sensory cells that are able to detect the outside world, uh, and then quickly communicate that information to the brain. And I say the out- 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, uh, if you, well, swallow a marble, it still has a chance to get out, um, just-

   9. AHAndrew Huberman9:51

      Please don't do that, anybody.

   10. DBDiego Bohórquez9:53

       (laughs) . But, uh, but it's still exposed to the surface.

   11. AHAndrew Huberman9:57

       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-

   12. DBDiego Bohórquez10:05

       That's right.

   13. AHAndrew Huberman10:05

       ... or our liver or our pancreas, but the gut is.

   14. DBDiego Bohórquez10:08

       The gut is. Uh, and if you think about it, it is just separated by, uh, uh, some compartments that have all of these valves, you know, the, the epiglo- epiglotis, the, uh, gastroesophageal, uh, junction, the pylorus, the, uh, ileocecal junction, the rectum.

   15. AHAndrew Huberman10:28

       So these are the, 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?

   16. DBDiego Bohórquez10:56

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

4. 11:35 – 15:26

   Gut Sensing, Hormones

   1. AHAndrew Huberman11:35

      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, what is this thing that we call gut sensing made up of? What, what's the parts list?

   2. DBDiego Bohórquez11:55

      So the parts, uh, list, uh, has been evolving, uh, recently. And, uh, while some of the elements we have known for, for a while, uh, but in, in general, what we are talking about, because it is 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 like attached in like a little membrane, and they are the ones that interface with the inside of the body. So in the stomach, uh, we have a stratified, uh, epithelium, for instance, that is, uh, thicker so it can survive digestion, chemicals, and other things like harsh environment. And in the intestine, we have a little bit more of a, um, a more del- delicate, uh, epithelial layer. And within this epithelial layer, there are several different cell types, and 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, uh, physician. Uh, his name was Frederick Vater. And, eh, 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 neuromodulators or these neuropeptides that we know as hormones. And, uh, so he named, uh, the diffuse endocrine system of the gut, and then he came up with this word enteroendocrine, uh, cell. And these cells are dispersed at a ratio of roughly speaking, like one to 1,000 epithelial, uh, 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, uh, system. Uh, 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 like the type of, uh, eh, systems that you use to identify, they were contacting directly the nervous system. And that brought up, uh, eh, a new dimension of how it is that the gut could be, could be communicating to the brain because as you know, in the brain, the synapses are the ones that are most predominant. However, there, there is a lot of neuromodulation from endocrine, uh, eh, functions in the brain too. So in the gut, uh, eh, this was not well-described. There had been historically, uh, a few examples that these cells may be making synaptic contacts, but they had not been studied. And perhaps one of the main reasons why they hadn't being studied is because the t- the tools were not there. And if you recall, in the, um, in 1990s, uh, with the advancement of, uh, green fluorescence protein as, uh, one of the main, uh, 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, a transcriptomic analysis to see what genes they express. Uh, 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.

5. 15:26 – 26:57

   Green Fluorescent Protein; Neuropod Cells & Environment Sensing

   1. DBDiego Bohórquez15:26

   2. AHAndrew Huberman15:26

      I'll just interrupt you for a second just to make sure that I and everyone else are- 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 these, of the food as it gets broken down and then release hormones-

   3. DBDiego Bohórquez15:50

      Correct.

   4. AHAndrew Huberman15:51

      ... into the bloodstream that could influence the brain. Those hormones could travel and influence things far away. In fact, um, for those that don't know, endocrine generally means signaling at a distance-

   5. DBDiego Bohórquez16:00

      Yeah.

   6. AHAndrew Huberman16:00

      ... between cells. So between gut and brain or gut and liver. It can also mean local effects. So, uh, 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. So these cells release hormones, the hormones influence the brain and other organs. And now I think you're gonna tell us that they also are able to make direct communication lines with other organs as well.

   7. DBDiego Bohórquez16:54

      Correct. Uh, so maybe here is fitting how it is that I, I got into, uh, eh, studying this system. And, uh, as you know, eh, between the '90s and the early 2000s, there was an explosion in tools to study, uh, the brain and neural circuitry and the connection of neurons and each one of the neurons, because up until the 1990s, um, the, the tools were, were limited. Electrophysiology, you know, behavior. Uh, but then not only we had, uh, green fluorescence, uh, protein, we, we had optogenetics, we had, uh, eh, rabies modified to be able to trace and how it is the, the neurons connect at one synapse.... which was, uh, it was a dream. I think that in fact that was the dream of, uh, Francis Crick. When he was at Salk, he, he talked about that, having the way to control-

   8. AHAndrew Huberman17:46

      For those who don't know Crick, one, uh, was a co-recipient of the Nobel Prize for the discovery of the structure of 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, uh, 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.

   9. DBDiego Bohórquez18:24

      Yes. Uh, eh, so then you could isolate the cells and then you could do sequencing technology to see, like, what are the genes that these cells are expressing, and then you can start to understand the makeup of the cells. Uh, in 2009, uh, Hans Clevers, a scientist, um, in the Netherlands, uh, did a beautiful experiment. Like, he- he discovered, uh, these factors that will trigger a receptor of the stem cells in the intestinal epithelium and will form literally a mini gut in a- in a dish. You know, these cells will be all lined up and then they will have a lumen. And I remember, like, seeing some of these papers coming out, uh, when I was a PhD student and- and I was already studying the gut, so it was inspiring to see, like, all of the things that all of a sudden you could do, right? So when I began studying these cells, um, immediately by isolating the cells and simply observing the cells in the native tissue of these, um, eh, mice models, it quickly became evident that some of the cells had a very peculiar anatomy. Uh, some of them had these very prominent arms at the base, like, uh, like literally like, um, in the Sistine Chapel, uh, Adam reaching out to- to God, right? Like with the hand. Uh, the cells will have that type of anatomical, eh, features and even ending with a little hand at the end of that arm. Uh, and obviously I- I immediately thought like, "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- the hormones into the bloodstream, right?" Uh, wrong. You know, like, uh, I couldn't find that, uh, that direct connection. Uh, so then I started to study perhaps they were associated with the nervous system, and that's how, uh, we made some of the first observations, that some of them, uh, with the arm, uh, or without the arm, they will have a more intimate relationship with nerve fibers. And that of course opened up, um, a bunch of new questions and... But the first thing is that, the first thing that we had to do, it was to come up with a name for this foot. And it kind of became organic, and I want to highlight this because I think that as we go through the discovery, uh, eh, trajectory, we don't realize the need to also engineer language. How we go about language is we start to attach, eh, 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, uh, with my mentor, we will start to call these little feet, first we call them axon, which is like, uh, the term for, like, eh, the long extending branches of the neurons, the main branches of the neurons. So we will call them axon-like because they look like a, a baby axon. Eh, but then we call them also, like, pseudopod because it was like a pod but it was pseudo. Uh, and at some point we... uh, and it was coming from, like, some cells in the- in the kidneys that they are called, uh, eh, pod, podia 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? So then I just- (laughs)

   10. AHAndrew Huberman22:02

       Yeah, it's a bit of a mouthful.

   11. DBDiego Bohórquez22:04

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

   12. AHAndrew Huberman23:00

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

   13. DBDiego Bohórquez23:24

       Correct.

   14. AHAndrew Huberman23:25

       So if I understand correctly, these, what you decide to call neuropod cells, and thank you for shortening the name, um, from the other description.

   15. DBDiego Bohórquez23:33

       (laughs) . Yeah.

   16. AHAndrew Huberman23:33

       Um, 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- where do they exist?

   17. DBDiego Bohórquez23:46

       So this is, uh, this is where the conversation becomes expansive because, uh, these neuropods or cousins of these neuropods... So these neuropods are simply a specialized-... neuroepithelial cells, meaning that are electrically excitable, that they can dis- discharge electricity. But they are, these type of cells are in every single epithelial cell or, uh, e- 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 code that they pass it on to the nervous system and then ultimately the brain integrates that and says like, "Ooh, my belly is feeling good, but I'm feeling cold in the skin," right? And that is thanks to all of these, uh, neuroepithelial cells that they are even in, um, tasting, so to speak, the, uh, the cerebrospinal fluid inside of the spinal cord and the ventricles. They are inside of the- the inner ears, the taste, uh, the taste buds. So it is... And in fact, there's a beautiful book from the '70s, uh, from, uh, some Japanese scientists, uh, Fujita, Kano, and Kobayashi, who, uh, called these cells para-neurons. And their whole concept is that there was not such a discrete distinction between an entire, uh, 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- the organism can bring the information from outside inside into the, uh, body to be able to process it, and then process it and then guide behavior.

   18. AHAndrew Huberman25:40

       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, the, that is how relatively basic or acidic something is-

   19. DBDiego Bohórquez26:09

       Correct.

   20. AHAndrew Huberman26:09

       ... 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, right? I mean, until you describe it, I think most of us are, have not been aware that this is happening.

   21. DBDiego Bohórquez26:34

       And we probably shouldn't be aware, you know, like as I often say, like, um, 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 it got inside of the lettuce that we swallowed in, uh, at lunch, right? Like, it's just do your thing so we can keep co- communicating, right? (laughs)

   22. AHAndrew Huberman26:52

       Except maybe don't eat more of that lettuce, right? Which is the, um...

   23. DBDiego Bohórquez26:56

       (laughs) That's right.

6. 26:57 – 35:28

   Brain & Gut Connection, Experimental Tools & Rabies Virus

   1. DBDiego Bohórquez26:57

   2. AHAndrew Huberman26:57

      Okay, so you discovered these neuropod cells.

   3. DBDiego Bohórquez27:01

      That's right.

   4. AHAndrew Huberman27:01

      And you...

   5. DBDiego Bohórquez27:02

      Or I described them.

   6. AHAndrew Huberman27:03

      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 is I always say, you know, brain and spinal cord and all the connections to the body and back again is the nervous system. But what- what did you discover in terms of the connections with the brain proper?

   7. DBDiego Bohórquez27:27

      Here is where the tools started to make a- a big difference. You know, all of a sudden you could see, uh, the resolution of a receptor inside of a cell using certain type of microscopes, right? So I remember that one of the first questions that I will always get drill on, you know, how these, uh, uh, laugh meetings can get intense, right? Like, when they all bring data and showing just very simple, um, immunohistochemistry, meaning labeling to see how these cells were interacting with, uh, the nervous system. Um, as I now will show some of the images, then, uh, the other scientists will say, "Well, you know, yeah, those are nice images, but remember that contact does not mean connection." And then I went thinking about that. Like, at the very beginning I thought that it was silly semantics, you know? Um, but I- 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, uh, contacting or connecting. But much to our surprise, we actually saw that in real time, they... 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, right? Like, it's the gut and the brain in a dish.

   8. AHAndrew Huberman29:12

      Amazing.

   9. DBDiego Bohórquez29:12

      Uh, yeah, and that- that was an eye-opener, you know? (laughs) I still remember, it was somewhere, I think it was, like, June 27, uh, 2012 when I saw that experiment because, um, it opened my abs- 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, uh, we had lost the notion that this thing is constantly moving, right?

   10. AHAndrew Huberman29:40

       The cells are actually moving.

   11. DBDiego Bohórquez29:41

       The cells are actually moving.

   12. AHAndrew Huberman29:43

       So these cells line the gut, meaning they're along the walls of the gut-

   13. DBDiego Bohórquez29:47

       Yeah.

   14. AHAndrew Huberman29:47

       ... and intestine.

   15. DBDiego Bohórquez29:48

       Yeah, the intestine.

   16. AHAndrew Huberman29:48

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

   17. DBDiego Bohórquez29:53

       Yeah.

   18. AHAndrew Huberman29:54

       And then...

   19. DBDiego Bohórquez29:54

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

   20. AHAndrew Huberman30:00

       Mm-hmm.

   21. DBDiego Bohórquez30:01

       You know?

   22. AHAndrew Huberman30:01

       So the lumen, folks, is the- the cavity, the empty cavity of the gut. Not empty, but, you know, the- the wo- the internal pro- 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-

   23. DBDiego Bohórquez30:21

       Yeah. (laughs)

   24. AHAndrew Huberman30:21

       ... you'll get it right. Uh, a process up to the brain.

   25. DBDiego Bohórquez30:25

       Underneath, that will connect to the nervous system.

   26. AHAndrew Huberman30:28

       I see, so through a series of-

   27. DBDiego Bohórquez30:29

       Yeah.

   28. AHAndrew Huberman30:29

       ... of stations.

   29. DBDiego Bohórquez30:31

       Yeah.

   30. AHAndrew Huberman30:31

       Okay. Um, amazing. So, what we're talking about here is Diego's discovery of a pathway from the gut to the brain that essentially allows sensing of what's happening in the gut to inform feelings? Decisions?
7. 35:28 – 37:00

   Sponsor: AG1

   1. AHAndrew Huberman35:28

      system. I'd like to take a brief break and acknowledge our sponsor, AG1. By now, most of you have heard me tell my story about how I've been taking AG1 once or twice a day every day since 2012, and indeed that's true. I started taking AG1, and I still take AG1 once or twice a day because it gives me vitamins and minerals that I might not be getting enough of from whole foods that I eat, as well as adaptogens and micronutrients. Those adaptogens and micronutrients are really critical because even though I strive to eat most of my foods from unprocessed or minimally processed whole foods, it's often hard to do so, especially when I'm traveling and especially when I'm busy. So by drinking a packet of AG1 in the morning, and oftentimes also again in the afternoon or evening, I'm ensuring that I'm getting everything I need. I'm covering all of my foundational nutritional needs.And I, like so many other people that take AG1 regularly, just report feeling better. And that shouldn't be surprising because it supports gut health and, of course, gut health supports immune system health and brain health, and it's supporting a ton of different cellular and organ processes that all interact with one another. So while certain supplements are really directed towards one specific outcome, like sleeping better or being more alert, AG1 really is foundational nutritional support. It's really designed to support all of the systems of your brain and body that relate to mental health and physical health. If you'd like to try AG1, you can go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs with your order, plus a year supply of vitamin D3 K2. Again, that's drinkag1.com/huberman. Okay,

8. 37:00 – 43:55

   Neuropod Cells & Nutrient Sensing

   1. AHAndrew Huberman37:00

      so you, uh, identified these, you said described, but you, I'll say discovered 'cause, um, that's what happened, you discovered these, 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?

   2. DBDiego Bohórquez37:29

      Uh, so here comes, uh, the key experiment, and this was building obviously on the work of other scientists that had already described that the gut had some, uh, receptors for, uh, sugars, for, specifically for glucose, for other nutrients. Around this area in the early 2000s when we were starting to be able to identify some of these cells, then, uh, it quickly became, uh, obvious that, uh, these cells, these enteroendocrine cells throughout the lining of the stomach, intestine, colon, they had multiple receptors for multiple nutrients. You know, like we have the macronutrients, for instance, uh, sugars, fats, proteins, but, uh, within them we have, you can a repertoire of molecules, you know, multiple, uh, lipids, multiple types of sugars and so on and so forth. And these cells, depending on their location, they will express, uh, different type of receptors or a combination of those receptors. And I say that depending on the location, because when we're eating, let's say, an apple, you know, the apple is gonna be partially undigested by the time that it enters intestine, but by the time that it gets to the, the colon, most of those nutrients have being absorbed and perhaps only fibers are surviving to feed off most of the microbes that live in the colon, right? So, uh, the gut has evolved to mirror and to become a Velcro to the molecules that will be in that, uh, in that specific space, so it will detect. So, um, it will detect sugars more in the proximal intestine, but fibers or, uh, fermented byproducts more in the distal intestine or in the colon, like short-chain fatty acids, butyrate, pro- uh, propionate, um, and so on and so forth, you know?

   3. AHAndrew Huberman39:14

      What other kinds of nutrients do these neuropod cells detect from food? So you mentioned sugars, you mentioned ferment- fermentation, so, um, presumably short and long-chain fatty acids?

   4. DBDiego Bohórquez39:27

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

   5. AHAndrew Huberman40:39

      Amazing.

   6. DBDiego Bohórquez40:39

      ... in the esophagus, right?

   7. AHAndrew Huberman40:40

      So if I understand correctly, these neuropod cells have a variety of different receptors-

   8. DBDiego Bohórquez40:45

      Correct.

   9. AHAndrew Huberman40:45

      ... depending on where they are located along the trajectory from the mouth to the rectum.

   10. DBDiego Bohórquez40:50

       That's correct.

   11. AHAndrew Huberman40:51

       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, 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 a- amino acids for all sorts of important biological processes. Um, and these cells are essentially evaluating how much sugar, how much leucine, how much, um, uh, short-chain fatty acid, how much, uh, you know, essential fatty acids of different kinds and then making changes to the gut itself, but then presumably signaling that information elsewhere in, in the body.

   12. DBDiego Bohórquez41:42

       So, um, here I'm gonna give you a, something that will get your gut churning, uh, so to speak (laughs) . So these cells have to make sense not only of the molecule that had been ingested, meaning the chemistry of the molecule. Let's say if it's 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, uh, compound. ATP is for energy, for instance. That has also have to be taken into account. For instance, in the, in the, in glucose, glucose activates the TAS1R3, which is a sweet taste receptor. Then the glucose is absorbed by some of the sodium glucose transporters, which are active transporters, and these transporters, uh, 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 farther activates another, uh, voltage-gated, uh, channel, farther depolarizing the cell, and then the cell releases in turn, uh, a transmitter, for instance, glutamate that very rapidly tells the vagus nerve within milliseconds, "You know, I got sugar." Uh, and it tells it in two phases because that glutamate will activate two different type of receptors, ionotropic, which are very fast, and metabotropic, which are a little bit more, uh, you know, more delayed. Uh, but then the metabolism of that glucose that produces the ATP and farther depolarizes the cell, uh, we believe that, um, it will cause the release of the hormone of the neuropeptide. So then the neuropeptide comes on top of that and gives you the full experience of what it means to, uh, consume sugar, right? Um, 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.

9. 43:55 – 51:14

   Gastric Bypass Surgery, Cravings & Food Choice

   1. DBDiego Bohórquez43:55

   2. AHAndrew Huberman43:55

      So if I stand back from this picture, um, what I get is there are, 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, you know, simple versus complex sugars, et cetera. 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, um, 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?

   3. DBDiego Bohórquez44:50

      Yes. Uh, thank you for, uh, bringing that story, Andrew. That story is very personal to me. I often say when I get on stage that we are, uh, constantly influenced by two things in life, the food that we eat and the people that we meet, you know, like, uh, now I, uh, 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 a- a starting my PhD in nutrition at North Carolina State University, I was, uh, so I didn't grow up in the United States. I, uh, grew up in Ecuador, and, uh, eh, I was invited to my, uh, first, eh, Thanksgiving celebration. So I sat at dinner and, you know, as we began chatting with, uh, the people that were next to each other, uh, all of a sudden I was, uh, eh, enthralled in this conversation of a woman telling me this story about, uh, her experience with gastric bypass surgery for treating obesity. So gastric bypass surgery, uh, was began to be, um, developed by surgeons, uh, in the '60s and by the '90s it had become a mainstream, uh, type of surgery for the treatment of, uh, chronic obesity. So she told me that there were primarily three things that happened. She said, "Well, within, uh, 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-

   4. AHAndrew Huberman46:16

      Significant amount.

   5. DBDiego Bohórquez46:17

      ... yeah, 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, uh, that you're having. I was like that, you know, I don't know much about diabetes, but I know that is, is a major health, uh, 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 sunny side up eggs?" She said, uh, "Just looking at the yolk will make me queasy, you know, 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, uh, we go on Saturday to a, a restaurant for breakfast, I will take the toast and I will actually clean the plate, uh, of the yolk. So how is it that rewiring the, the gut, uh, alter my perception of, uh, of flavor, alter my, my cravings and my mind to, to get the, the yolk?" She said.

   6. AHAndrew Huberman47:18

      And even inverted her sense of what was aversive versus appetitive. And, and I guess for those of us that don't know, meaning me, um, I understand that gastric bypass surgery involves the removal of a portion of the, of the gut. Um, how much gut tissue do they actually take? Is it centimeters, inches?

   7. DBDiego Bohórquez47:39

      Yeah, so, uh, yeah.

   8. AHAndrew Huberman47:39

      Is it... I mean the guts a, a long distance. So what, what, what do they do for gastric bypass?

   9. DBDiego Bohórquez47:42

      So in, in, in simple terms, the most, um, eh, the, the classic surgery is called, uh, Roux-en-Y gastric bypass surgery, which involves a reduction of the stomach and short-cutting the connection of the stomach to the intestine. So you'll cut, uh, you know, uh, one third, which will be the duodenum, uh, one third of that will be, uh, cut, and then that portion will be reconnected to the stomach, meaning that you're short-circuiting the, 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, uh, body weight by the simply, um-... reduction of surface that is exposed to the food that is absorbed, right? And, uh, what it became very clear is that well before the body weight, uh, changes got taken place, uh, there was already, like, some dramatic changes in, uh, physiology like gut, and like, the hormones and neuropeptides that were released from, uh, the intestine in response to nutrients. You know, uh, it will change very rapidly. Then as I mentioned, the food choices will change, diabetes will be resolved. Um, so then it became obvious that it was not necessarily just the, uh, the, uh, reduction in the surface of, of the gut. So that's one of the main, uh, surgeries. The other one, um, as I understand is vertical sleeve gastrectomy. And this vertical sleeve gastrectomy is simply, uh, a reduction in the size of, uh, the stomach. So it's now the stomach is very tiny and the idea is that will accumulate, uh, less. It, it could hold less food and then the food will go very rapidly into the intestine. And what is very, uh, is becoming very obvious is that there is a rapid change in the sensory function of the gastrointestinal tract. So the gut seems to, uh, rapidly shift, perhaps become more, um, so to speak in general terms, more sensitive to the presence of nutrients, right?

   10. AHAndrew Huberman49:45

       Interesting. So this woman that you met at Thanksgiving had gas- 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.

   11. DBDiego Bohórquez50:00

       Yeah.

   12. AHAndrew Huberman50:00

       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, uh, r- you know, sunny side egg yolks was somehow related to a shift in appetite or something else? Or is it merely a, a, a, um, a qualitative, albeit a dramatic qualitative shift in, in what she craved?

   13. DBDiego Bohórquez50:29

       So two, uh, contextual pieces of information. Uh, 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. Um, and I realized that it was very little was known. Even the g- uh, gastroenterologists knew very little about this. The first clinical report that, um, the alteration in food choices was common in these patients, uh, came out, I believe in 2011. Uh, and, uh, then later on, uh, scientists have replicated that even in rats or in mice. Uh, we have it only in the laboratory. And consistently, they, they change their food preferences, their, their, um, uh, food choices. So,

10. 51:14 – 1:00:29

    Optogenetics; Sugar Preference & Neuropod Cells

    1. DBDiego Bohórquez51:14

       uh, in, in recent years, we have been, we have been, uh, studying that, that system. Um, and I will tell you that in 2022, this is another important contextual piece that we have gotten, have now gotten to it. So after we, uh, uh, uh, 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 it's affecting, right? Like, how is it that it's affecting the, the responses of the organism? And that took a little bit of a technical hurdle. And here is where optogenetics, uh, comes in.

    2. AHAndrew Huberman51:56

       Yeah, please, um, explain for people what optogenetics is, in, at least in a top contour level.

    3. DBDiego Bohórquez52:02

       Yeah, so optogenetics, uh, 2005, uh, uh, Professor Karl Deisseroth, uh, Ed Boyden, and, uh, other, uh, scientists, uh, have been able to make this, this dream of, uh, an experiment which was, uh, isolate the, 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, they find what cells are orchestrating certain type of behaviors like movement, food intake, thirst, anxiety, so on and so forth. So in 2014, we, we began, uh, trying to adapt that technology to the gut. And very quickly, we realized that the way that was, that light was brought into the brain was through a fiber optic cable that was rigid. And, uh, and in the brain, you know, it, 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, some forces, like, move around us. And in 2017, uh, Professor Polina Nikieva from MIT came to give a talk at, at Duke, and, uh, she reached out to me. And literally she came and as we were chatting, she said like, "Diego, I see that you're, you're working between, uh, in this interface of the gut and the brain, and I have this fiber optic that is flexible. You know, would you have any use for it?" So with that, uh, 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, uh, proteins inside of these neuropods, now when we turn the light on to shut off these cells very rapidly, uh, we found something very interesting. So normally animals, when you give them the choice between a sweetener, which is devoid of caloric value-

    4. AHAndrew Huberman54:19

       So like a, like a-

    5. DBDiego Bohórquez54:20

       Like, like, yeah.

    6. AHAndrew Huberman54:20

       Aspartame or, or-

    7. DBDiego Bohórquez54:21

       Like Splenda or-

    8. AHAndrew Huberman54:22

       ... Stevia or something.

    9. DBDiego Bohórquez54:23

       Stevia.

    10. AHAndrew Huberman54:23

        Yep.

    11. DBDiego Bohórquez54:24

        Uh, and you give them sugar, uh-... table sugar, the animal, uh, invariably will go to sugar.

    12. AHAndrew Huberman54:33

        They prefer sugar.

    13. DBDiego Bohórquez54:34

        They prefer sugar. You know, uh, if they have never seen sugar, it will take them a little bit more time, but regularly, um, by the second day, is within 90 seconds that they detect what is sugar.

    14. AHAndrew Huberman54:48

        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.

    15. DBDiego Bohórquez54:57

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

    16. AHAndrew Huberman55:33

        Got it.

    17. DBDiego Bohórquez55:33

        ... that was detecting the, the sugar.

    18. AHAndrew Huberman55:35

        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.

    19. DBDiego Bohórquez55:48

        Correct.

    20. AHAndrew Huberman55:49

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

    21. DBDiego Bohórquez56:02

        Yes. And, uh, then, uh, Professor Antonio Sclafani, uh, he had been studying these, uh, these behaviors and he went in so far to suggest that perhaps the sodium glucose transporters are some of the ones that are detecting the, the sugar as it enters intestine and that's what is causing the behavior. Um, eh, so we began working on this system and we, we wonder, could these cells be the ones that are guiding that behavior? Uh, and around the time that, uh, we published this work, uh, uh, Professor, uh, Charles Zuker at, uh, Columbia also farther, uh, advanced that, that area by, uh, building on the, on the previous work and demonstrating that, um, there were, uh, population of neurons in the brain stem that were integrating this information from the gut. Uh, and by that, eh, the gut and the brain were guiding this, this behavior, so.

    22. AHAndrew Huberman56:55

        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. I mean, you can see that in babies even.

    23. DBDiego Bohórquez57:10

        Correct. And as I usually say, um, I, I call it instinctively because our mother doesn't have to teach us, "Hey, uh, Diego, that is glucose." You know? Uh, it may present as in, uh, some ways, but, uh, at the end of the day, I have to go and get my glucose to get my amino acids, right? Because eating is very simple. We are 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 s- the, the stevia, so to speak, or the sweetener from the actual sugar.

    24. AHAndrew Huberman58:08

        And the entire manipulation, the experimental manipulation that is, is occurring at the level of the gut?

    25. DBDiego Bohórquez58:14

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

    26. AHAndrew Huberman58:19

        So if we make an attempt to transfer this to the human real world experience, um, 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, um, I do like some of them. So eating ice cream, it tastes sweet. The tendency is to crave more.

    27. DBDiego Bohórquez58:47

        That's correct.

    28. AHAndrew Huberman58:48

        Right? I mean, you have to eat a lot of ice cream before you're truly full.

    29. DBDiego Bohórquez58:51

        Yeah.

    30. AHAndrew Huberman58:52

        Um, and most people self-regulate or their parents regulate for them-
11. 1:00:29 – 1:03:03

    Gut-Brain Disorders, Irritable Bowel Syndrome

    1. DBDiego Bohórquez1:00:29

       Uh, and then we did a couple more experiments in there. And what happens, uh, if we do the reverse, if we turn on these cells now?And the fascinating thing is that when we turn on the cells, now the, uh, uh, the mouse will eat the sweetener as if it will be sugar.

    2. AHAndrew Huberman1:00:46

       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?

    3. DBDiego Bohórquez1:01:04

       So here's another piece of information. If we will offer them water and we will turn on the cells, the animal will drink the water as if it will be sugar, like it will be appetizing.

    4. AHAndrew Huberman1:01:15

       Even though it's just plain water.

    5. DBDiego Bohórquez1:01:16

       Yes.

    6. AHAndrew Huberman1:01:16

       Interesting.

    7. DBDiego Bohórquez1:01:16

       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, um, in the salience of the stimulus is like how intense is the stimulus, and the other one is the valence of the stimulus is pleasurable or painful, so to speak, in like broad terms. And I say this because on the, on the pain side, um, Professor David Julius, Professor Holly Ingraham, Jim Byra 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 to nerve fibers of the spinal cord, and when they are activated, now all of a sudden they drive what we call in the clinical, uh, realm, visceral hypersensitivity. So they are responsible for triggering the hypersensitivity of the nerve fibers, the colonic nerve fibers because they detect nox- noxious stimuli and then ultimately they gate that noxious stimuli and pass it on to the nerve fiber as a, in broad terms, as a painful stimulus.

    8. AHAndrew Huberman1:02:44

       So is this irritable bowel syndrome?

    9. DBDiego Bohórquez1:02:47

       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, uh, they call them disorders of gut brain interactions

12. 1:03:03 – 1:04:04

    Sponsor: InsideTracker

    1. DBDiego Bohórquez1:03:03

       in the clinic.

    2. AHAndrew Huberman1:03:04

       I'd like to take a brief break and acknowledge our sponsor InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better meet your personal health goals. Now, I've long been a believer in getting regular blood work done for the simple reason that many of the factors that impact your immediate and long term health can only be analyzed with a quality blood test. Now, the problem with a lot of blood tests out there is that you get information back about metabolic factors, lipids and hormones and so forth, but you don't know what to do with that information. With InsideTracker, they have a very easy to use online platform that allows you to see the results of your blood test and then offers you various actionable tools such as behavioral tools, nutritional tools, and supplementation tools that can help you move those values from your tests into the ranges that are optimal for you. If you'd like to try InsideTracker, you can go to insidetracker.com/huberman to get 10% off their new subscription model, which has significantly reduced prices. Again, that's insidetracker.com/huberman to get 10% off.

13. 1:04:04 – 1:07:38

    Gut & Behavior; Gastric Bypass, Cravings & Alcohol

    1. AHAndrew Huberman1:04:04

       As a neuroscientist, I was trained to think about the neural retina, the light sensing tissue at the back of the eye, the cochlea, the essentially mechanosensory cells in the inner ear that respond to sound waves, not directly, but through a number of different transducers and this kind of thing. And then of course, we are all familiar with the skin and that it responds to pressure, light, touch, tickle, itch, et cetera. What I'm understanding based on what you're telling me is that all along the pathway from our mouth to our rectum, we have sensory cells that are evaluating the chemical constituents of the foods that we eat, emitting broad, kind of maybe even crude slow signals in the form of hormones to change our appetite, our feelings of wellbeing, maybe our feelings of not wellbeing, um, but also sending direct signals to the brain to drive certain types of thinking, emotions and behavior. What sorts of thoughts, emotions, and behaviors are foods known to evoke through this pathway from the gut? Because the story about the, your friend that had the gastric bypass and then changed the relationship completely to the craving of, or the aversion to sunny side up eggs, indicates that it's a pretty crude, as I'm describing it, system to begin with, but it ultimately converges on pretty fine scale decision making. You order this and you avoid that. Um, you really like this and you really are almost nauseous at the thought of something else. Th- that's pretty high level decisions. It might not seem like it to most, but, um, you know, it's impacting, you know, significant be- behavior or impacting behavior at a significant level.

    2. DBDiego Bohórquez1:05:53

       That's correct. Um, and, uh, when I think about that specific example, uh, is that after there has been this rewiring of, uh, of the intestine, then now the intestine is very sensitive, so to speak, to the stimuli. And when those lipids from the yolk start to enter the intestine, if that sensitivity has changed, meaning it could have changed in how fast it reacts to the stimulus or how fast it communicates to the stimulus and, eh, how sens- sensitive it is to the saliency or like the, the strength of the stimulus, it could communicate that, ooh, what it used to be-... repulsive with a tiny little bit amount. Now, it is actually pleasurable with a tiny little wi- uh, bit of a- amount and here's a, a clear example. So it has been very well, um, oh, I will say that it has been documented, uh, in the clinic that patients that undergone gastric bypass surgery, they're actually more prone, I think that the, the, the, it goes from like two to seven-fold, uh, the likelihood that they become, uh, they, they will, they will develop alcoholism.

    3. AHAndrew Huberman1:07:08

       Really?

    4. DBDiego Bohórquez1:07:09

       Yes. Uh, because now, eh, the way that they describe it is like, "Well, you know, either before I didn't like wine, um, and then now I, uh, you know, after a few months of the surgery, I'll have one glass of wine and then all of a sudden I found myself going to two, three, four." You know, and then they will become either more sensitive. It's still not known, the entire biology, but they will become either not only more sensitive but more a- more attracted to that type of stimulus.

14. 1:07:38 – 1:11:46

    GLP-1, Ozempic, Neuropod Cells

    1. DBDiego Bohórquez1:07:38

    2. AHAndrew Huberman1:07:39

       I can't help but ask about Ozempic, Mounjaro and GLP-1, glucagon-like peptide 1, um, analogs, which are really kind of all the rage right now, at least for discussion, uh-

    3. DBDiego Bohórquez1:07:53

       Yeah.

    4. AHAndrew Huberman1:07:53

       ... but many, many, many millions of people are now taking this for treatment of diabetes and for weight loss. Um, my understanding is that GLP-1 acts at the level of the brain, the hypothalamus, to reduce hunger, but also at the level of the gut to give the sensation of more gastric distension. Is there any knowledge of whether or not GLP-1 interacts with the neuropod cells in this pathway that you're describing, given what these neuropod cells do for craving or aversion?

    5. DBDiego Bohórquez1:08:23

       Yes. That's, uh, a complementary question, and, uh, in fact when I got into, uh, uh, studying this field, uh, 15 years ago, uh, eh, the study among scientists in this area, uh, glucagon-like peptide was already very, uh, popular, uh, in the study. In, in fact, in this area it was, uh, people were very focused on, on the study of this peptide. And they were very focused on the study of, uh, this peptide because it was one of the most potent, um, eh, eh, stimulators of insulin release in the pancreas. Uh, after gastric bypass surgery, it will actually in- increase its amount in, uh, circulating levels. Uh, and there were already, like, uh, some, uh, studies suggesting that the, the effect of these gluco- glu- glucagon-like peptide, it was actually not through the circulation but more in a localized, uh, action onto nerve fibers, especially of the vagus nerve. So there was already, like, some ongoing, um, eh, discussion about this. Uh, and certainly some of these, uh, enteroendocrine cells, these, um, neuroendocrine cells, particularly at least in, uh, in animals I think it's more distal and, uh, eh, in the digestive tract that they do release these glucagon-like peptide, um, one, in response to primarily, like, uh, all of the macronutrients, but primarily sugar. And then, eh, these, uh, glucagon-like peptide one will act on re- specific receptors of the nerve terminals and then will trigger some other behaviors. It's also thought that, uh, it acts at, at the level of the, uh, the brain stem. And what it will, uh, potentiate is the reduction of, uh, appetite. So I say that this is a complementary question because what is happening in the first few milliseconds is the actual choice and the actual feeling of how you feel about food, and what is happening in the minutes to hours later is the amount, how much you can eat, right? And when you should stop, because after four hours, you're gonna come back and feel again the tickling of the gut because the gut starts, uh, to churn again, and it starts to call for food. Remember, it has to feed, uh, two giant organisms, the host itself but also the microbes that are inside, right? So it has to, eh, keep, uh, so to speak the, that hunger going every four hours or, or so, right? So that's why the hormones are more acting on the cy- cyclical, uh, circadian, eh, way, but the transmitters are acting in these very fast, uh, responsive way of, uh, the precise stimula- stimuli in specific, uh, regions of the gastrointestinal tract.

    6. AHAndrew Huberman1:11:15

       So these neuroendocrine cells are releasing GLP-1 or responding to GLP-1?

    7. DBDiego Bohórquez1:11:21

       They are releasing, uh, GLP-1.

    8. AHAndrew Huberman1:11:23

       They're releasing GLP-1 to shut down, transiently shut down hunger.

    9. DBDiego Bohórquez1:11:28

       And probably there is some interaction between the cells that they are, they are having, you know, the technical term is autocrine or they are having, like, paracrine between the cells, you know, neuromodulation, but primarily let's say they respond to the stimulus and release GLP-1 onto the nerve fiber.

15. 1:11:46 – 1:21:35

    Food Preference & Gut-Brain Axis, Protein

    1. AHAndrew Huberman1:11:46

       I have a theory, uh, for which I have no direct data, but I'd like your thoughts on, um, having spoken to a lot of people that work on nutrition, but also gut-brain access today, and, um, microbiome in previous episodes, that one of the key things that a human learns somewhat unconsciously, but also consciously, is the relationship between a given food, which macronutrients it contains, the ratios of, you know, carbohydrate, protein, and fat, the taste of that food, the amount of that food translated into calories, but also physical volume, and then the micronutrients. Why do I say this? Well, there are a growing number of studies showing that the ingestion of highly processed food leads to the intake of excess calories or more calories than if one consumes foods in their more natural form.... single ingredient foods or two ingredient foods are very different than a food that has a bunch of different things in it. And it seems to me that if we were to look back into our evolution, um, sure, people were making stews and soups and things for a long time. Um, presumably the sandwich came about through a either desire for convenience or taste or both.

    2. DBDiego Bohórquez1:13:03

       (laughs)

    3. AHAndrew Huberman1:13:03

       You know, putting meats, protein in between two pieces of bread, something of that sort. Um, by definition of a sandwich. Maybe some vegetables in there as well, some cheese. But that, what this whole pathway along the gut is trying to do it seems, is to deconstruct what's coming in, what's here, and shaping choices as you mentioned about food choice, including the amount of food to further consume and whether or not to return to that food or to avoid it.

    4. DBDiego Bohórquez1:13:34

       That's correct.

    5. AHAndrew Huberman1:13:34

       And at the extremes, it seems pretty straightforward. E- and this is a very classically described case, right? You, you go and you have the, um, you know, the Kung Pao shrimp or you have the lentil soup at a given place, and a few hours later you don't feel right, start some sweating, some gastric distress, and you develop a pretty broad aversion to that food or maybe even the entire meal, maybe the restaurant, maybe even that entire type of cuisine depending on how, um, how much of a lumper versus a splitter you are, as we say in science, right?

    6. DBDiego Bohórquez1:14:05

       (laughs)

    7. AHAndrew Huberman1:14:05

       How much you, you make, uh, kind of large, large bin decisions or fine bin decisions. Um, this is nerd speak for saying, you know, do you, do you go back to the same restaurant but order something different or do you just decide to never go back again? But that's a pretty extreme case, right? The other extreme would be you eat a food, it's delicious, you feel wonderful, the, the restaurant, the people, it's wonderful, and you crave more of that food. Okay? There's all the contextual stuff too. But what we really are talking about here is how one navigates this whole landscape of what to put into one's body in terms of nutrition and trying to understand how that's impacting everything from how we feel right away, how it tastes, whether or not we conceive it as good or bad for us, whether or not we think it's impacting our body composition and health in ways that we want or don't want. I mean, it's pretty complex stuff, right? This is at least as complex as going to a Metropolitan Museum of Art and looking at a painting and trying to evaluate whether or not you really like that painting or not.

    8. DBDiego Bohórquez1:15:10

       Absolutely. (laughs)

    9. AHAndrew Huberman1:15:10

       In fact, it's probably much more complicated than that.

    10. DBDiego Bohórquez1:15:13

        Yeah.

    11. AHAndrew Huberman1:15:14

        But it's what we do. And, uh, I'm beginning to get the, the sense, again, no pun intended, that this pathway that we call the gut-brain axis is really, it's a sixth sense of a very elaborate kind.

    12. DBDiego Bohórquez1:15:31

        So you just touched on a, on an entire realm of a topic, which is one of my favorite topics, because at some point, you know, uh, we, as scientists, we travel, we travel the world. And it started to become very obvious to me that wherever I went, we solved this issue of food in a very similar way, whether it is a tortilla or two pieces of bread, which is another way of a tortilla, uh, you have your carbs. And then you add a little bit of meat or a mushroom, and now you have your protein.

    13. AHAndrew Huberman1:16:09

        Or fish or chicken.

    14. DBDiego Bohórquez1:16:10

        Or fish or chicken.

    15. AHAndrew Huberman1:16:12

        Yeah. The, the carnivores will say, "Mushroom's not a protein." And the vegans will say, "Mushroom, beans, lentils, great protein."

    16. DBDiego Bohórquez1:16:17

        (laughs)

    17. AHAndrew Huberman1:16:17

        We're not here to, to resolve that debate. Do as you choose.

    18. DBDiego Bohórquez1:16:21

        And then you add the lettuce-

    19. AHAndrew Huberman1:16:24

        Mm-hmm.

    20. DBDiego Bohórquez1:16:25

        ... or the vegetables. And here's the first stop in that com- uh, the first, uh, stop in that, in that discussion, because this is fascinating. There is some recent work showing that if you remove the protein from a diet, the animal swallows that, that, that meal, eh, the gut evaluates that there is no protein in there and it stops eating that meal.

    21. AHAndrew Huberman1:16:55

        Wow, so this is like, um, ordering the vegetarian taco-

    22. DBDiego Bohórquez1:16:59

        Yeah.

    23. AHAndrew Huberman1:17:00

        ... or burrito or sandwich, and then avoiding that particular taco or sandwich thereafter because it lacks protein.

    24. DBDiego Bohórquez1:17:12

        Because it lacks protein.

    25. AHAndrew Huberman1:17:13

        Okay, so foods that lack animal-based proteins are, tend to be avoided going forward.

    26. DBDiego Bohórquez1:17:18

        So here's the second part of that now. Uh, and in fact, if the protein is low, not completely absent, if the protein is low, the animal consumes more of the diet because it's trying to compensate for the lack of protein. And obviously if it has sugars or fats that are more pleasurable, it keeps eating that pro- that, that meal, right?

    27. AHAndrew Huberman1:17:39

        I see.

    28. DBDiego Bohórquez1:17:40

        If the protein is completely absent, the animal avoids that diet, unless, unless that diet is very rich in, uh, eh, dietary fibers. And the study that, uh, that I saw, uh, which I thought it was fascinating, is that because somehow the microorganisms in the digestive tract, if they have enough highly digestible fiber, now they turn on the ability to synthesize essential amino acids.

    29. AHAndrew Huberman1:18:16

        Really?

    30. DBDiego Bohórquez1:18:17

        Yes.
16. 1:21:35 – 1:25:16

    Protein & Sugar, Agriculture & ‘Three Sisters’

    1. AHAndrew Huberman1:21:35

       So this leaves us with a picture of the gut sensing cells, these neuropod cells as exquisitely, uh, sensitive to amino acid content in our foods, um, which makes perfect sense to me.

    2. DBDiego Bohórquez1:21:48

       And it has not been published or demonstrated yet, so.

    3. AHAndrew Huberman1:21:51

       Sure. We're, we're now in the realm of, of new incoming data.

    4. DBDiego Bohórquez1:21:54

       Incom- yeah.

    5. AHAndrew Huberman1:21:55

       So we wanna highlight this, bracket it, boldface and underline it as we're now at the cutting edge of what's l- may be coming. Um-

    6. DBDiego Bohórquez1:22:02

       That's right.

    7. AHAndrew Huberman1:22:02

       ... right? Observation.

    8. DBDiego Bohórquez1:22:04

       (laughs)

    9. AHAndrew Huberman1:22:04

       Um, but nonetheless, very interesting. But there is this fairly longstanding hypothesis that we are foraging for essential amino acids because they are the building blocks of so many important things in the brain and body.

    10. DBDiego Bohórquez1:22:15

        And, in fact, there is evidence on that. And, uh, eh, eh, Professor Steven Simpson at, uh, in Australia at, uh, in, uh, the, uh, eh, Nutrition, uh, Research Institute at Sydney University, he is a main proponent of this protein leverage hypothesis, you know that. And, in fact, protein is, uh, the most satiating, uh, eh, uh, macronutrient. So that, that has been established and that's why, uh, normally we have focused on sugars and fats, but we have neglected a little bit of, uh, on the protein because it's not as pleasurable as, uh, the sugars or fats. But what is fascinating is that it's the most satiating, um, eh, nutrient, and as you know, it's like the most limiting and also, like, even commercially is the most expensive right now.

    11. AHAndrew Huberman1:22:59

        Yeah. I certainly have had the experience of, um, at one time in my life really enjoying and even craving sweet foods, desserts and sugars and things of that sort. And I noticed that over time, if I eat sufficient amounts of meat, chicken, eggs, fish, and which is not to say that I consume excess amounts of them, that my sugar cravings go way, way down. That's just my personal experience, but I know it's an experience that family members of mine and others share as well.

    12. DBDiego Bohórquez1:23:28

        But I promise you that this was a, a fun, um, a fun topic, right? I couldn't, uh, we couldn't stop at, like, just layer number one. Layer number two is that in agriculture we have this instinct to plant plants that, eh, complement each other. Like, for instance, a classic, um, especially native, uh, among, uh, native communities is called, like, the Three Marys, uh, eh, I believe is, uh, eh, um, eh, pumpkins or some type of fibers with corn, carbohydrates, and beans.

    13. AHAndrew Huberman1:24:03

        So in purely pla- plant-based diets, there's an effort to get the fiber, the sugar, and the amino acids.

    14. DBDiego Bohórquez1:24:11

        That's right. And I grew up, uh, in a, in a farm. My, uh, my parents had farms, and I remember when they would plant, they would also, like, throw in there the, the beans and the beans will wrap around the, the corn, and it just seemed like so natural and that's what you will do because that's what you learn to do. But if you think about it, it's an instinct that we have developed even, eh, agriculturally and probably in the subconscious, to cultivate them in such a way, or perhaps the plants taught us how to cultivate, cultivate them in such a way that now when we put them in the plate, it just makes sense.... eh, at the nutritional level. 'Cause if you think about it, every time that we go to eat, how's it that we arrange that plate, right? There is some rice which is very deficient in, uh, in some, uh, essential amino acids, but it's rich in carbohydrates, right? It has some beans, right? Uh, and then there's some lettuce, you know. And sometimes we have, like for omnivores, people will put meat or you would put other types of protein in there, right?

    15. AHAndrew Huberman1:25:11

        And certainly it varies by culture, time of year, food availability and things of that sort. As long

17. 1:25:16 – 1:36:15

    Childhood, Military School; Academics, Nutrition & Nervous System

    1. AHAndrew Huberman1:25:16

       as we're talking about, um, your upbringing, um, you have a fascinating story. Um, so maybe we could discuss that for a few minutes. Uh, where were you born?

    2. DBDiego Bohórquez1:25:28

       Uh, I was born in, uh, the Amazonia of Ecuador, a small town called El Chaco in Ecuador. Uh, it's on the slopes of, um, the eastern slopes of, uh, the Andes on the way to the Amazonia, uh, in the Napo Province. Uh, coincidentally was, like through the path from where, uh, eh, Francisco de Orellana in, uh, 1542, uh, march on its way to the discovery of the, the Amazon, actually passed through, um, a trail that later on reading I realized that, uh, native people had all of these trails between, uh, the Amazonia and the Andes and the coastal line for thousands of years.

    3. AHAndrew Huberman1:26:07

       So you grew up in a very rural place?

    4. DBDiego Bohórquez1:26:09

       Yes. Uh, eh, the, uh, oil had been detected in the 1920s in Ecuador. Uh, it was first explored in 1964 in, uh, the first, uh, eh, oil, um, um, eh, well was, uh, in a town called Lago Agrio, which now is only like three or four hours from, uh, the town where I grew up. But at that time it was like, uh, eight hours. The roads were not good, and the first road passed through it, uh, in, uh, 1974. Uh, I was born in 1983, but I remember that we used to have like, um, a giant, um, eh, diesel ti- eh, engine that will give us a light, eh, electricity only from, uh, 7:00 to 9:00 PM you know. Uh, I remember when my father bought the, the first, uh, eh, um, color television in the, in the town, and then neighbors will come to the, our living room and then we will watch movies. (laughs)

    5. AHAndrew Huberman1:27:13

       Wow. And this was in the '80s?

    6. DBDiego Bohórquez1:27:15

       That was in the '80s, right. (laughs)

    7. AHAndrew Huberman1:27:17

       Wow, s- um, such an interesting upbringing. So, um, did you eat a purely vegetarian diet or you ate meats as well?

    8. DBDiego Bohórquez1:27:25

       Uh...

    9. AHAndrew Huberman1:27:25

       Where did those meats come from if you did?

    10. DBDiego Bohórquez1:27:27

        Primarily from, uh, cattle, uh, eh, goats, sheep.

    11. AHAndrew Huberman1:27:32

        So how do you go from the Amazon to a study of nutrition and ultimately neuroscience?

    12. DBDiego Bohórquez1:27:40

        (laughs)

    13. AHAndrew Huberman1:27:41

        Um...

    14. DBDiego Bohórquez1:27:41

        Yeah. Uh, that's the question, right? Like, uh, the deeper I go, the more I question this. I, I used to think that, oh, it was very simple, you know, like when I was, um, uh, eh, specifically when I was 11 years old, uh, my father, he was born in 1932. Uh, by, eh, 19... Eh, he lost, uh, his father, my grandfather when he was six years old, and he was given away and, uh, he had to go and, like build his, his, his life. Uh, he was a very successful entrepreneur, but in the process he had, uh, made a lot of, uh, eh, a lot of friends and, uh, acquaintances. So when I was 11 years old, I remember, eh, specifically that a friend of his who was in the Special Forces stopped by, uh, eh, our home because that was the main road that we go into the Amazon jungle, where the, uh, folks in the Special Forces in the, in the military will, will be trained. And he stopped by and said like, "Hey, Rogelio, like what are you gonna do with Diego? You know, like, I think that it is about time that, uh, you know, I, I think that you should send him to the military school." And I remember in a matter of like literally a couple of weeks or three weeks, I had given the, taken the tests and, um, eh, I was accepted into the military school and then, uh, I ended up in a military school. And this was the, at that time, it was the premier, uh, military school in the, in the country. That alone, it was, uh... With years you start to understand the context in which you, you developed, uh, because it was, uh, eh, it was a very interesting context for, for a child. Like, just to give you an idea, uh, this, this, uh, this school had the first and the only zoo in the country. So from my, uh, classroom, I would literally look at the, at the, at the lions, and then I think that was by the second year that I was in the school, second or third year, that became that... Because the, the, the city start to grow and then the, the military school is wrong. And then they separated the higher education for military officers. They separated them and they put them in a different place. But that zoo actually became the first zoo of the capital of Quito.

Episode duration: 2:42:12