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

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 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.

Before we begin I'd like to emphasize that this podcast is separate from my teaching and research walls 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.

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And now for my discussion with Dr. Diego Bortkis.

Dr. Diego Bortkis. Great to have you here.

Thank you for having me, Andrew.

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, you know, what is this gut brain axis that we hear about?

And what's going on in our gut besides digestion?

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, you know, people call it an axis because traditionally it's thought to be an imaginary line that was connected through hormones. So since 1902, when the first hormone secreting was reported by Bayley's and Stortling,

it was known that when we eat, then hormones, these molecules in the gut are released and then they will enter the bloodstream and 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, right, like all the eye brain axis, right.

And all of the organs are in sync, working in sync. So 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 a chance to get out.

Please don't do that anybody. But it is still exposed to the surface.

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.

The gut is. And if you think about it, it is just separated by some compartments that have all of these valves.

And they apply epiglories, they gastro-sophageal junction, the pylores, the iliocical junction, the rectum.

So these are the sequences of valves of chambers with valves between them that food passes through, error 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?

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, right?

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?

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?

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 this stomach, we have an stratified epithelium, for instance, that is thicker.

So it can survive digestion, chemicals, and other things like harsh environment. And in testing, we have a little bit more delicate epithelial layer.

And we think these epithelial layer, there are several different cell types. And one of those is the so-called endocrine 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 Fater.

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 neuromodolators, 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, enter endocrine cell.

And these cells are dispersed at a ratio roughly speaking, like 1 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 neuromodolators and the neuromodolators 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.

And 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 contacts, but they had not been studied.

And perhaps one of the main reasons why they had been being studied is because the tools were not there.

And if you recall, in the 1990s, with the advancement of green fluorescence, brought in 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 call culture them, you can modify their genome, and then you can start to interrogate what is their contribution to the entire body?

I'll just interrupt you for a second just to make sure that I never even 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 constitutes 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 more.

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 by 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 fluorescent 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 going to tell us that they also are able to make direct communication lines with other organs as well.

Correct. So maybe here is feeding cowards that I got into studying this system, and as you know, between the 90s and early 2000s, there was an explosion in tools to study the brain.

Neural circuitry and the connection of neurons and each one of the neurons, because up until the 1990s, the tools were limited, electrophysiology, you know, behavior.

But then not only we had green fluorescent protein, we had optogenetics, we had rabies modified to be able to trace and 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 a result, he talked about having the way to control.

For those who don't know, Crick one was a co-recipient to the Nobel Prize for the discovery of the structured DNA, but then later in his career developed in a recession for neuroscience, and he day dreamed out loud about having tools to visualize individual connections in the nervous system.

And then the scientist, Diego, was 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.

Yes, so then you could isolate the cells, and then you could do sequence in 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.

In 2009, Hans Cleaver is a scientist in the Netherlands, did a beautiful experiment, like he discovered these factors that will trigger a receptor of the stem cells in 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 starting the gut, so it was inspiring to see all of the things that all of a sudden you could do.

So when I began starting the 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 system chapel, Adam reaching out to gut, like with the hands, the cells will have that type of anatomical features, and even ending with a little hand at the end of that arm.

And 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.

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, right? I could find that direction.

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.

So now we go about languages, we start to attach words that we already knew, and we start to put them together to describe something that knew that we were 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 like the long extending branches of the neurons, the main branches of the neurons.

And then we call them axon like, because they look like a baby axon. But then we call them also like pseudo pot, because it was like a pot, but it was pseudo.

And at some point we, and it was coming from like some cells in the in the kidneys that they are called pod, pod, or something like that. So it was axon like pseudo pot like basal process to describe that it was on the base.

So at some point we came so long that we couldn't feel it in an abstract, right? So we began thinking about it, and then eventually came up with the term I thought like, uh, neuropath.

And I remember pitching it to my mentor and I said, like, let me, let me think about the weekend and the on the on the Monday he came in and he said, like, you know, it hasn't ring to it. I think that we should use it.

But, but essentially 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 a neuromodulators 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 new transmission is directly and more precise in space and time.

Could I just interrupt for a moment, please? So hormone signaling, endocrine signaling, generally is slower than the forms of communication directly between neurons.

Right? Um, 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. So if I understand correctly, these what you decide to call neuro pod cells. And thank you for shortening the name from the other description.

Um, line the gut. Are we talking about everything from the soft gets down to the stomach to the intestine or is it just at the level of the stomach and intestine?

Where does it? This is where the conversation becomes expensive because these neuro pods or costumes of these neuropods.

So these neuro pods are simply specialized neuro epithelial cells, meaning that are electrically excited, although 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 code 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.

Right. And that is thanks to all of these neuropetial cells that they are even in tasting so to speak, they are the zero respinal fluid inside of the spinal cord and the ventricles.

They are inside of the inner ears, the taste, the taste buds.

So it is, and in fact, there's a beautiful book from the 70s, from some Japanese scientists, Fujita Kanon Kobayashi, who called these cells parat neurons.

And their whole concept is that there was not such a discreet distinction between an entire neuron that lives inside of the brain or the central nervous system.

And a neuropetial 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 inside into the body to be able to process it and then process it and then guide behavior.

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.

And 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.

And there's a direct line to the brain and we're not necessarily aware of all of this happening.

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

And 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 and the splint that is chasing this bacterium that is inside of the letters that we swallow it in a launch, right?

Like it's just do your thing so we can keep communicating, right?

Except maybe don't eat more of that letters, right?

Which is the right.

Okay, so you discovered these neuropod cells.

That's right.

And you describe them.

And you had in hand some tools to selectively label them.

What did that reveal about their connectivity with your referring to it as the nervous system, which I love because of resounding theme on this podcast, as I always say, you know, brain and spinal cord and all the connections to the body and back again is the nervous system, which I love because of resounding theme on this podcast.

And 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 did you discover in terms of the connections with the brain proper?

Here is where the tools started to make a big difference.

You know, all of a sudden you could see 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 laugh meetings can get intense, right?

Like when I will bring data and show you just very simple immunochistochemistry, meaning labeling to see how these cells were interacting with the nervous system.

And then I will show some of the images, then 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.

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 grains in a dish, right, like it's the gut and the brain in a dish.

Yeah, and that was an eye opener, you know, I still remember 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 ecstatic 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?

The cells are actually moving. So these cells line the gut, meaning they're along the walls of the gut, and they're testing.

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

And they have little cilia, little hair or microbilli that is literally like little hair that is exposed to the lumen.

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.

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.

And their need that will connect to the nervous system. I see. So through a series of stations.

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.

That's right. 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.

And 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, right? And what it was surprising is that the fluorescence from that rabies will show up in the brain's team.

And in the bodies of the cells that are in the Nauros ganglia, which is this cluster where the cell bodies of the neurons of the bagus nerve are located right underneath the neck.

Meaning that there was just one stop between the surface of the intestine and the brain's 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, right? Like 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 a typical fashion or with meditation and other things that people can become aware.

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.

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[장-뇌 축(Gut-Brain Axis)과 장 감각의 신경과학: 디에고 보르케스 박사와의 대화]-[Dr. Diego Bohórquez: The Science of Your Gut Sense & the Gut-Brain Axis]

📋 Summary

장-뇌 축(Gut-Brain Axis)의 새로운 이해

1. 장 감각(Gut Sensing)이란 무엇인가?

2. 신경족(Neuro-pod) 세포의 발견

3. 과학적 도구의 발전과 발견의 여정

4. 감정과 본능의 생물학적 기초

🎯Key Sentences

📝Key Phrases

📖 Transcript