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

Dr. Diego Bohórquez: The Science of Your Gut Sense & the Gut-Brain Axis - Sottotitoli bilingue

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 Dr.

Diego 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 experience,

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.

Borghe's expertise.

Dr.

Borghe's 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.

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 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 in order 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.

Borghez 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.

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.

Borca's upbringing in the Amazon jungle and how his knowledge and intuition about plants

has influenced his science and how the incredible science that his laboratory is doing relates to all of us

and our ability to better tap into our gut sense.

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

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And now for my discussion with Dr.

Diego Dr.

Diego Borgas.

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 be here.

I knew that since we met a few years ago,

there in So, there there there there that our our were were were of were a this ongoing conversation and a great conversation.

The gut and the brain,

you know, people call it an axis because traditionally it thought to be an imaginary line that was connected through hormones.

So since 1902,

when the first hormone secreting was reported by Bailey's and her It was known that when we eat,

then hormones,

these molecules in the gut are released and then they will enter the bloodstream and then eventually will have a cause in distant organs.

And for the next hundred or so years, the focus 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 say or we don't say the nose, brain axis, right?

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.

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 to get out.

Please don't do that anybody.

But is it still exposed to the surface?

You're right.

I 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 is just separated by some compartments that have all of these.

and the epiglores, the gastrosophageal junction, the pylorus, the ileosical junction, the rectum.

So these are the sequences of valves of chambers with valves between them that food passes through And within each,

as I understand it, there are different functions related to digestion.

But 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 we think about it 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 much that you can do at least in regular humans that you can do consciously expel something that perhaps is poisonous or toxic,

right?

It is the gut that has to make the distinction and then usually accommodate things for absorption or let them pass through

the digestion and then ultimately they will be secreted, right?

So, if you could describe

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 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 outcome.

but they also are like a touch in like a little membrane.

And they are the ones that interface with the inside of the body.

So in the 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 intestine, we have a little bit more of a more delicate epithelial layer.

And within this 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 Fader.

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

it into it.

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 us.

And so he named the diffuse endocrine system of the gut, and then he came up with his word, endocrine cell.

And these cells are dispersed at a ratio roughly speaking like 1,000 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 neuromodelators and the neuromodelators through the fusion 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 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 they 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.

A phone So,

in the gut,

this was not well described, there 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 them being studied is because the tools were not there.

And if you recall,

in 1990s,

with the advancement of green fluorescent sprouting as one of the main molecules to tag cells,

now all over the sun and there was a revolution in biology because you could identify the cells,

you take them out, you can do a transcriptomic analysis to see what genes they expressed.

stress, you can co-culture them, you can modify their genome, and 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 and everyone else are on board.

So, if I understand correctly, it's long been known that there are cells that are in these

layers of the 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 horn hormones into the bloodstream that could influence the brain, those hormones could travel and influence things far away.

In 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 and the current effects can also be local,

but by also understanding you 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 for 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 fitting how it is that I got into studying the system and as you

know between the 90s and the early 2000s there was an explosion in tools to

study the brain and neural circuitry and the connection of neurons and each one

of the neurons because up until the 1990s the tools were limited electrophysiology

you know behavior but then not only we had a green fluorescence protein with we

had optogenetics we had a rabies modified to be able to trace and how it is the neurons connect at one synapse.

which was a dream.

I that in fact that was the dream of Francis Crick when he was at the South King.

He talked about having a 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 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 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.

Yes, so then you could isolate

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 these cells.

In 2009,

Hans Cleaver's 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 that.

these papers coming out, when I was a PhD student, 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 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 effect.

Some of them had these very prominent arms at the base,

like literally like in the cysteine chapel, and I'm reaching out to God, right, like with a hand.

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 like, why would I sell?

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.

The the vasculature into the vessels to put the hormones into the bloodstream, right, grown.

Like, I couldn't find that direct connection.

So then I started to study, perhaps, they were associated with the nervous system.

And that's how we made some of the first observations.

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 we didn't name for this foot.

It kind of became organic and I want to highlight this because I think that as we go through the discovery trajectory,

we don't realize the need to also engineer language.

How we go about languages,

we start to attach words that we already knew, and we start to put them together to describe something that knew that we're observing.

Right right now.

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.

So we will call them axon-like because they look like a baby.

But then we call them also 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 that they are called a pod, a podia, or something like that.

So axon-like, pseudopod-like, basal process to describe that it was on the base.

So at some point, it so long that we couldn't fit it in an abstract, right?

So it's a bit of a mouthful.

So we began thinking about it.

And eventually I came up with the term I thought, like neuropod.

And I remember pitching it to my mentor, and said, let me think about the weekend.

And a Monday, he came in, and he said, you know, it has a ring to it.

I think that we should use it.

But essentially, the thought was that if these cells are contacting, then perhaps they are passing information directly onto the nervous system.

And that is very different than just spewing 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 modulate these terminals in a different space and time.

But the transmission, the neurotransmission is directly and more precise in space and time.

Could I just interrupt for a moment, please?

So signaling, endocrine signaling, generally is slower than the forms of communication directly between neurons, right?

It could be on the order of seconds,

sure, but typically on the orders of minutes or hours, whereas neural communication on the order of milliseconds.

So if I understand correctly,

these, what you decide to call neural pod cells, and thank you for shortening the name from the other description, line the gut.

But 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 the intestine?

Where does it exist?

This is where the conversation becomes expected.

because these neuropods are causing of these neuropods.

So these neuropods are simply specialized neuroepithelial cells,

meaning that are electrically excitable,

that can discharge electricity,

but 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 the test.

world, meaning that they can be exposed to fluctuations in temperature, fluctuations

in pH,

fluctuations concentrations,

and then they quickly can generate a chemo-electrical coat that they pass it on to the nervous system and

then ultimately the brain integrates that and says like, oh, my belly is feeling good but I'm feeling cold in the skin, right?

And that is thanks to all of these neuropithelial cells that they are even in tasting,

so to speak,

they are the cerebrospinal fluid inside of the spinal cord and 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 New Zealand.

and their whole concept is that there was not such a discrete distinction between an

entire neuron that lives inside of the brain or the central nervous system and a

neuroepithelial or a neuroendocrine cell that lives exposed to the outside.

simply that there is a continuum of adaptation so the organism can bring the

information from outside 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.

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.

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 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 spleen that is chasing this bacterium that got inside of the letters that we swallowed at launch, right?

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

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

Which the...

That's right.

So, you discovered...

pot cells.

That's right.

And you, or I describe them, you describe them.

Yeah.

And 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 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 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 I all bring data and showing just very simple immunohistochemistry 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 running, and I was thinking like, how you demonstrate connection between two cells?

And then I thought that since we had the ability to identify the cells by fluorescence, we could isolate them based on their fluorescence.

And what will happen if we put them in front of...

neuron and then just record them inside of a microscope over time.

And I thought maybe they will get close to each other and then we can go and do some more labeling.

are contacting or connecting.

But to our surprise,

we actually saw that in real time,

when you isolate them from the mouths 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 the gut and the brain in a dish.

Yeah, and that was an eye opener.

You know,

I still remember it was somewhere,

I think it like June 27, 2012, when I saw that experiment, because it opened my eyes to so many different things.

One was that these cells are not static, because since we have been seeing them for decades, just in a slices or fixed dishes.

And 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, then intestine.

They have intestine.

They reach a hand.

into the gut to sense whatever chemicals are there.

And have little cilia, little hair or microbili, 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, okay?

And sending a process.

By the way,

folks, any time you don't know whether or something is a dendrite or an axon, just call it a process, you'll get it right, a process up to the brain, underneath, that

will connect to the nervous system.

I see.

So 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, decisions.

That was the first experiment in addition, right?

The next experiment was, well, does it happen?

mouse.

And then through a series of,

I have a friend neuroscientist that actually calls these rabies gymnastics because you have to put in some genes and make things work.

Then 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 in what it was surprising is that the fluorescence from that rabies will show up

in the brainstem and in the bodies of the cells that are in the notos

ganglia which is this cluster where the cell bodies of the neurons of the baguos

nerve are located right underneath the neck meaning that there was just one stop between the surface of the and the brain stem.

The cells were connecting that space, you know.

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 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 as you mentioned,

develop an almost pathologic sense of interoception such that they have trouble navigating normal life because they're so aware of what's going

on inside their body.

This is actually an interesting issue in the field of psychiatry.

My colleagues in psychiatry at Stanford tell me that some people with a lot of anxiety for instance are so aware of their heartbeat that it becomes disruptive and distracting to them.

So it's not always the case that it's better to become more aware of your internal processing.

deleterious, other times it can be good for us.

Some people are very unaware of what's happening in their body and they need to develop more awareness of that.

I feel like as long as we're talking about rabies,

we should have a little bit of fun

and explain to people something about rabies viruses because what we've been talking about is the use of viruses as experimental tools.

in order to,

you know,

take a virus basically attach or put something in so that whatever cell is infected by it glows a certain color so you can see the cells and visualize

the circuitry.

But as long as we're talking about rabies,

I feel like it's such a word that has such salience, the rabies virus which exists in nature.

is amazing because it's,

I don't know if it has a consciousness, but it essentially propagates between animals by way of the animals that have it bite.

They become more aggressive.

They bite a target The virus gets in,

it's picked up by the nerve terminals and is carried back from one cell to the next across synaptic connections,

synapses that get little gaps between neurons.

And what Dr.

Diego has been telling us is is scientists have engineered the rabies virus so that it only jumps one station and then stops.

You can do this by modifying the coat protein.

There's a bunch of fun virology that can be done to do that.

But what I find amazing about rabies virus,

and there's a great book,

by the way,

called Rabid,

which is essentially a history of the study of rabies,

is that once it travels from the site of the bite up to the brain, what does it do?

It changes.

the now infected animal or person more aggressive so that then they go by somebody else.

So I mean in some ways that the viruses have a sort kind of unconscious genius to them, right?

What's the best way to get from one animal to the next?

Well, there are a of different ways, but one way is to just make that animal more aggressive so it goes and bites things.

Yeah, make that wild.

Make the animal work for you.

Make the animal work for you, right?

It's almost exploitive.

It exploits a certain circuitry in the nervous system.

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So you identified these, you said, described, but say discovered because that's what happened.

You discovered these cells,

you label their connections,

you see that there's just two stations between these cells or one station really between these cells and the

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?

So here it comes...

the key experiment,

and this was building obviously on the work of other scientists that had already described that the gut had some receptors for sugars,

specifically for glucose, for other nutrients.

Around area in the early 2000s,

when we were starting to be able to identify some of these cells,

then it quickly became obvious that these cells,

these endocrine cells throughout the lining of the stomach intestine colon,

they had multiple receptors for multiple nutrients,

you like we have the macronutrients,

for instance,

sugars, fats, proteins, but within them we have, you know, a of molecules,

you know, multiple lipids, multiple types of sugars and so on and so forth.

depending on their location they will express a different type of receptors or a combination of those receptors.

And I said that depending on the location,

because when we're eating, let's say an apple, the apple is going to be partially undegested by the time that it enters in testing.

But by the time that it gets to the colon,

most of those nutrients have been absorbed, and perhaps only fibers are surviving to feed off most of the microbes that live in the colon.

So the gut has evolved to mirror and to become a velcro.

to the molecules that will be in that specific space,

so it will detect sugars more in the proximal intestine,

but fibers are fermented by products more in the distal intestine or in the colon,

like chain fatty acids, butyrate, propionate, And so on and so forth, you know.

What other kinds of nutrients do these neuropot cells detect from food?

So you mentioned sugars, you mentioned fermentation, presumably short and long chain fatty acids?

Yes, the short answer is that I think that in due time we are going to realize that they

detect just about every single thing that we put on our mouths every day,

you That they have some either an specific receptor that is dedicated to it or a combination of

receptors to be able to detect some of these compounds.

And not only the chemical compounds, but also an area that I think is going to be fascinating in the future is the mechanical distancing.

the adjustment in temperature as the time starts to flow from the mouth into the colon.

Like for instance,

I heard this from bioengineer and not long ago that was engineering artificial

gut and stomach and he shared with me a piece of information that I was not aware of that the sofagus has to,

adjust the temperature of the food very rapidly within seconds into physiological temperature of the inside of the body.

Like we're 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.

Amazing.

So if I understand correctly,

these neuropod cells have a variety of different receptors, depending on where they are located along the trajectory from the mouth to the rectum.

That's correct.

And some are sensing sugar, some are sensing temperature, some are sensing pH, so relative acidity.

Some are sensing amino acids, presumably.

I've heard it said, and I believe there's a researcher down in Australia who's been very bullish on the theory that we are.

not exclusively, but we are predominantly amino acid foraging machines because we need amino acids for all sorts of important biological processes.

And these cells essentially evaluating how much sugar,

how much leucine,

how much short-chain fatty acid,

how much,

you know,

essential fatty acids of different kinds, and then making changes to the gut itself, but then presumably signaling that information elsewhere in the body.

So here I'm going to give you something that will...

get your gut churning, so to speak.

So these cells have to make sense, not only of the molecule that had been adjusted, meaning the chemistry of the molecule.

Let's say with glucose it has to make sense.

A 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 adjusted inside of the to release ATP or some other compound, ATP energy, for instance.

That has also have to be taken into account, for instance, in glucose.

Glucose activates the TAS-1R3, 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 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 voltage and get it up a channel farther depolarizing the cell.

And then the cell releases, in turn, a for instance, glutamate.

That rapidly tells the vagus nerve, within milliseconds, you know, I got sugar.

And it tells it in two phases,

because that glutamate will activate two different type of receptors, ionotropic, which are very fast, and metatropic, which are a little bit more delayed.

But then the metabolism of that glucose that produces ATP and farther the pyloracids,

the we believe that it will cause the release of the hormone, of the neuropeptide.

So then the neuropeptide comes on top of that and gives you that full experience of what it to...

to consume sugar, right?

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.

So if I stand back from this picture,

what I get is there are very interesting cell types that line our gut that are evaluating all of the,

not just macronutrients,

proteins, fats and carbohydrates, but micronutrients within the food we eat, as well as some of the other qualitative features, temperature, for instance, maybe quality.

of the amino acids or the sugars, you know, simple versus complex sugars, etc.

If we could just further zoom out for a moment and take a human perspective on this at the level of experience.

I once heard you tell a story about someone you knew changed their gut radically and that changed their entire perceptual experience of food,

including certain cravings.

Would you mind sharing that story?

Yes.

Thank you for bringing that story, Andrew.

That story is very personal to me.

I often say when I get on stage that we are constantly influenced by two things in life,

the food that we eat and the people that we meet,

you like now we have known each other, but now we meet in person and we are knowing other people, right?

And I remember that when I was starting my PhD in nutrition at North Carolina State University.

I was, so I didn't grow up in the United States.

I grew up in Ecuador.

And was invited to my first Thanksgiving celebration.

So I sat at dinner and,

you know,

as we began chatting with the people that were next to each other,

all of a sudden I was in the enthrall in this conversation of a woman telling me this story about her experience

with gastric bypass surgery for treating obesity.

So gastric bypass surgery was begun to be developed by surgeons in the 60s.

And by the night he had become a male.

type of surgery for the treatment of chronic obesity.

So she told me that there were primarily three things that happened.

She said, well, within six months of the surgery, I had lost about 40% of body weight.

She said, like, I was about 300 pounds, you do the math, you know?

So was a significant amount.

She said, we think one week of the surgery, my diabetes was gone, she said, I did not need more insulin shots.

So I had the same reaction that you're having,

I was like, you know, I don't know much about diabetes, but I know that is a major health burden, right?

But the thing that really caught my eye was when she said, but since you're studying nutrition, I want you to answer this to me.

She said, why is he that before the surgery, I could not even look at Sony side up X.

Just looking at the yoke will make me queasy.

But after the surgery,

not only I can eat sonnyside up eggs,

I actually have a craving for the yolk,

every we go on Saturday to a restaurant for breakfast, I take the toast and I will actually clean the plate of the yolk.

So how is it that rewiring the gut?

After my perception of flavor, after my cravings and my mind to get the yoke, she said.

And even inverted her sense of what was aversive versus apeditive.

And guess for those of us that don't know,

meaning me, I understand the gastric bypass surgery involves the removal of a portion of the gut.

How much gut tissue do they actually take?

Is it centric?

I mean, the gut's a long distance, so what do do for gastric bypass?

In simple terms, the classic surgery is called roin-Y gastric bypass surgery, which involves a reduction of the stomach and short padding.

the connection of the stomach to the intestine.

So will cut one-third which will be the duodenum,

one-third of that will be cut,

and then that portion will be reconnected to the stomach meaning that you're short circu- And the whole idea was,

at the very beginning,

was like,

well, if we reduce the surface that is exposed to food, then we can reduce body weight by the simply reduction of surface

that is exposed to the right?

And what it became very clear is that well before the body weight changes got taken place,

there was already like some dramatic changes in physiology,

like the hormones, the neuropeptides that were released from the intestine in response to nutrients, you know, it will change very rapidly.

Then I mentioned,

the food choices will change,

diabetes will be resolved, So then it became obvious that it was not necessarily just the reduction in the surface of the gut.

So that's one of the main surgeries.

The other one,

as I understand,

is vertical is leaf gastrectomy,

and vertical is leaf gastrectomy is simply a reduction in the size of the So,

it now the stomach is very tiny and the idea is that we could hold less food and then the food will go very rapidly into the intestine.

And is becoming very obvious is that there is a rapid change in the sensory function of the gastrointestinal tract.

seems to rapidly shift, perhaps become more, such as speaking, general terms, more to the presence of nutrients, right?

Interesting.

So woman that you met at Thanksgiving gastric bypass surgery,

and presumably,

I think it's fair to assume,

A good number of these neuropot cells that sense different nutrients were removed and as a consequence

She completely shifted her craving of a particular food and is there any?

sense whether or not no pun intended the lack of sensing of what was in you know,

Sunnyside and was somehow related to a shift in appetite or something else,

or is it merely a qualitative, albeit a qualitative shift in what she craved?

So to a contextual pieces of information,

so I remember living in that dinner and I was like,

well, this is major, you know, like I'm sure that people have written about this or done research.

And I realized that it was very little was known, even a gastroenterologist knew very little about this.

The first clinical report that the alteration in food choices was common in came out,

I believe,

in 2011,

and then later on,

scientists replicated that even in rats or in mice,

we have done it in the laboratory and, consistently, they change their food preferences, their food choices.

So, in recent years, we have been...

And have been starting that system,

and I will tell you that in 2022, this is another important contextual piece that we have not gotten to it.

So after we...

found, and we describe that these cells were connecting to the nervous system and that they

were sending information up to the brain very rapidly, the challenge was, well, if this is a sense, what behavior is affecting, right?

Like, how is it that is affecting the responses of the organism?

And that took a little bit of a technical hurdle.

And here is where optogenetics comes in.

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

Yeah, so optogenetics 2005.

Professor Carl Dicer,

the Ed Boyden,

and other scientists had been able to make this dream of an experiment,

which was isolate the genes that encode for these opsins that are sensitive to specific wavelengths of light and put them into neurons.

And now, by turning that light, they could make the neuron activate.

And then, ultimately, later they went on to describe that that could be used to control...

that are regulating behavior and then by that define what cells are orchestrating certain type of behaviors like movement,

food intake, thirst, anxiety, so on and so forth.

So in 2014 we began trying to adapt that technology to the gut.

we realized that the way that light was brought into the brain was through a fiber optic cable that was rigid.

And in the brain, it helps that it's actually rigid.

But in the gut, it doesn't help because the gut is constantly moving and so on and so forth.

So it's not compatible for running those experiments.

And here's where I usually say, like, you know, we really don't know what is going on because some forces like move around us.

And in 2017, Professor Polinani Keva from MIT came to give a talk at Duke.

And reached out to And,

literally, she came and, as we were challenged, she like, Diego, I see that you're working between, in this interface of the gut and the brain.

And I have this fiber optic that is flexible, you know, will you have any use for it?

So with that fiber optic, that made a big difference to study, interrogate the function of these cells to behavior.

So, when we were able to put those offsings, the light-sensitive proteins inside of these neurons.

Now when we turn the light on to shut off these cells very rapidly.

We found something very So, normally animals, when you give them the choice between a sweetener, which is the void of caloric value.

So, like, like a, like, aspartame, or or Stevia, or something?

So, and you give them sugar, you know, table sugar, the animal invariably will go to sugar.

They prefer sugar.

They prefer sugar, you know.

If they have never seen sugar it will take them a little bit more time but regularly by the second day is

within 90 seconds that they detect what is sugar.

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.

And people have described this phenomenon for a while,

and fact,

in 2007, there was an elegant experiment done by Professor Ivan Derajuco at Duke University in which the sweet taste receptors were all they...

receptors were genetically erased and the animals were not capable of distinguishing the sugar,

the sweetener from the water, but they could still distinguish sugar from water, meaning that there was something else that was detecting the sugar.

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.

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

Yes, and then Professor Tony Esclafani, he had been studying these behaviors and he went

in so far to suggest that perhaps the sodium glucose transporters are some of the

ones that are detecting there and the sugar has interest in testing and that's what is So,

we began working on the system and we wondered, could these cells be the ones that are guiding that behavior?

And around the time that we published this work, Professor Charles Zuker had a...

also further advanced that area by building on the previous work and demonstrating that

there were a population of neurons in the brainstem that were integrated in this information

from the gut and by that the gut and the brain were guiding these behaviors.

So, 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 see that in babies, even.

Correct.

And as I usually say,

I call it instinctively because our mother doesn't have to teach and Diego,

that is glucose,

you It may present us in some ways,

but at the end of the day, I have to go and get my glucose, get my amino acids, right?

Because is very simple.

We're just trying to solve this issue of getting our carbons, getting our nitrogen, getting our phosphorus, our potassium, our sodium, and our chloride.

in so many different ways, shape or forms, right?

So I went back to the experiment, the key experiment.

So when we were able to put these opsins and bring the light and shut off these cells very rapidly,

when we had presented the animal with a choice of sweetener, overshoot.

Then, all of a sudden, the animal became blind to the solutions.

It discern between the stevia, such as big or the sweetener, from the actual suver.

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

The intestine.

That's right.

Right the stomach.

It's just a small portion of the intestine.

So, if we make an attempt to transfer this to the human real-world experience, if I have some ice cream, it tastes sweet.

I like it and now I'm thinking about it and I'm craving it just to a little bit.

I don't have a huge craving for sweets, but I do like some of them.

So eating ice cream, it tastes sweet.

The tendency is to crave more.

That's correct, right?

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

Yeah.

And most people self-regulate or their parents regulate for them by limiting the number of scoops.

Um, and that sweet taste is part of the motivator, but what you're saying is that as the ice

cream enters the gut,

there are neuro pod cells there that are also sensing the sugar and signaling

to the brain is responding to pursue more of that sweet containing substance.

That's correct.

And it's happening below our awareness.

It independent from the sweet taste of the ice cream.

Correct.

The conscious sweet taste.

Whichever you think about it, it's not fully conscious, right?

You know I what we detect of the world,

it's just a very tiny little portion,

right, even side, you know, like, we think we are looking for light, but I don't know what is happening behind my back, I trust

that everything is going okay, right.

So, so when we shut off these cells, the animal and as I usually say it like became blind to the sugars because it's

kind of like a keen to have in turn of the cells that are able to detect light

the wavelength of light for us to be able to discern color.

And it's not that the animal is losing its memory, because then you remove the light and now the cells are functional again.

Then the animal, again, is able to distinguish one solution over the other.

And then we did a couple more experiments in there, and what happens if we do the reverse?

If we turn on the cells now.

And the fascinating thing is that when we turn on the cells now the mouse will eat the sweetener as if it will be sugar.

Interesting.

So activation of these cells makes the crave non-chloric sweetener or low-calorie sweetener as if it were sugar.

But is it blinding them to the difference between sugar and low-calorie sweetener?

So here's another piece of information.

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.

Even though it's just plain water.

Yes.

And what is becoming very obvious is that the gut has a descents at the most basic level

where the senses are doing is calculating a couple of things.

One is,

and the is of the stimulus is like how intense is the stimulus and the other one is the valence of the stimulus

is a pleasurable or painful so to speak in like broad terms and I say this because on the on the

pain side a professor David Julius,

professor Holly Ingram,

Jim Baira at UCSF they have done some in the column they have focused in the column that they coupled to a nerve fibers

of the spinal cord.

And when they are activated, now all of a sudden they drive what we call in the clinical realm, visceral hypersensitivity.

So they are responsible for triggering the hypersensitivity of the nerve fibers, the colonic nerve fibers because they detect noxious stimuli.

and then ultimately they gait that noxious stimuli and pass it on to the nerve fiber as in broad terms as a stimulus.

So is this irritable bowel syndrome?

It is,

we could call it as the biological basis of what could degenerate into They call them disorders of gut-brain interactions in the clinic.

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not directly,

but through a of different transducers and this kind of thing,

and then of course where you 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 that are evaluating the chemical constituents of the foods that we eat,

emitting broad,

maybe even crude, slow signals in the form of hormones to change our appetite, our feelings of well-being, maybe feelings of not well-being.

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 your friend had the gastric bypass and then changed the relationship completely to the craving of or the aversion to Sunnyside.

eggs indicates that it's a pretty crude as I'm describing a system to begin with, but it ultimately converges on pretty fine-scale decision-making.

You order this and you avoid that.

You really like this and you really are almost nauseous at the thought of something else.

That's pretty high-level decisions.

It might not seem like it to most, but it's impacting significant behavior or impacting behavior at a significant level.

That's correct.

And when I think about that specific example is that after there has been this rewiring 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 how sensitive it is to the saliency or the strength

of the stimulus, it could communicate that what it used to be repulsive with a tiny little bit of amount.

Now it is actually pleasurable with a tiny little bit of amount and here's a clear example.

So it has been very well, I will say that it has been documented.

in the clinic, the patients that undergone gastric bypass surgery, they're actually more prone.

I that it goes from like two to seven-fold.

The likelihood that they become and they will develop alcoholism.

Really?

Yes.

Because now the way that they describe it is like, well, you either before, I didn't like why.

And then now,

you know,

after a few months of a surgery,

I'll have one glass of wine,

and all of a I found myself going to 2, 3, 4, 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 attracted to that type of stimulus.

I can't help but ask about Ozempic,

Monjaro, and GLP-1, glucagon-like peptide-1 analogs, out of all the rage right now, at least for discussion about many, many, many millions

of people are now taking this for treatment of diabetes and for weight loss.

My understanding is that GLP1 acts at the level of the brain,

the hypothalamus to reduce hunger, but at the level of the gut to give the sensation of more gastric distension.

Is there any knowledge of whether or that GLP1 interacts with the neuropod cells and this pathway that you're describing,

given what these neuropod cells do for craving or aversion?

Yes, that's a complementary question.

And in fact,

when I got into a study in this field 15 years ago,

the among scientists in this area, glucagon-like peptide was already very popular in the study.

In fact, in this area, people were very focused on the study of this peptide.

And they were very focused on the study of this peptide because it was one of the most potent stimulators of insulin-like peptide.

in the pancreas.

After gastric bypass surgery, it will actually increase its amount in circulating levels.

There were already some studies suggesting the effect of this glucagon-like peptide.

It was actually not through the circulation.

but more in a localized action onto nerve fibers, especially of the vagus nerve.

So was already like someone going a discussion about this.

And certainly some of these enteroendocrine cells, these neuroendocrine cells, particularly, at least in animals, I think, is more distal.

in the digestive tract, that they do release these glucagon-like peptides, one in response to primarily all of the macronutrients, but primarily sugar.

And then these glucagonally peptide one will act on specific receptors of the nerve terminals and then will trigger some of the behaviors.

It thought that it acts at the level of the brainstem.

And what it will potentiate is the reduction of appetite.

So I said that this is a complimentary 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 two 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 to churn again and it starts to call for food.

Remember, it has to feed two giant organisms, the host itself, but also the microbes that are inside, right?

So it has to keep, So, to speak, that hunger going every four hours or so, right?

So that's why the hormones are more acting on the cyclical circadian way,

but the transmitters are acting in this very fast, responsive way of the precise stimuli in specific regions of the gastrointestinal tract.

So these neuroendocrine cells are releasing GLP1 or responding to GLP1.

They are releasing GLP1.

They're releasing GLP1 to show.

transiently shut down hunger and probably there is some interaction between the cells that they are having,

you know, the technical term is auto-cring or they are having like power-cring between the cells, you know, neuromodulation.

But primarily, let's say, they respond to the stimulus and release JLP1 onto the nerve fiber.

I have a theory for which I have no direct data,

but I'd like your thoughts on having spoken to a lot of people that work on nutrition,

but also gut-brain access today and 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 carbohydrate protein and fat.

the taste of that food, the amount of that food translated into calories, but also physical volume, and then the micronome.

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, sure people were making stews and soups and things for a long time.

Presumably sandwich came about through either desire for convenience or taste or both,

you putting meats protein in between two pieces of bread, something of that sort.

My definition of a sandwich, maybe some vegetables in there as well, some cheese.

What this whole pathway along the gut is trying to do,

it seems,

is 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.

That's correct.

And it seems pretty straightforward.

And this is a very classically described case, right?

You and you have the kung pao shrimp, or have the lentil soup at a given place.

And a few hours later you don't feel right.

Start some sweating, some...

And you develop a pretty broad aversion to that food,

or even the entire meal,

maybe the restaurant,

maybe even that entire type of cuisine, depending on how much of a lumper versus a splitter you are, as we say in science, right?

How much you, you make kind of a large bin decisions or fine bin decisions.

This is nerd speak for saying, you do you go back to the same restaurant but order something different?

Or do you decide to never go back again?

But.

That's a pretty extreme case, right?

The extreme would be you eat a food,

it's delicious, you feel wonderful, 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.

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 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 Metropolitan Museum

of Art and looking at a painting and trying to evaluate whether or you really like that painting or not.

In fact, it's much more complicated But it's what we do.

And I'm beginning to get the sense,

again, no pun intended, that this pathway that we call the gut brain axis is really a sixth sense of a very elaborate kind.

So, you just touched on an entire realm of a topic, which one of my favorite topics,

because at some point, you as scientists, we travel the world.

And it started to become very obvious to me that whatever I went,

we solved this issue of food in a very similar way,

whether it's a or two pieces of bread, which is another way of a tortilla.

you have your carbs and then you add a little bit of meat or a mushroom and now you have your protein.

or fish or chicken or fish or chicken the carnivores will say mushrooms not

approaching the vegans will say mushroom beans lentils great protein we're

not here to resolve that today do as you choose and then you add the letters or

the vegetables and here's the first stop in that come in the first stop

in that in that discussion because this is fascinating there are some recent work showing dot If you remove the protein from a diet,

the animal swallows that meal, they got evaloides, so there is no protein there, and it stops eating that meal.

So this is like ordering the vegetarian...

Korean taco or burrito or sandwich, and then avoiding that particular...

or sandwich thereafter because it lacks protein because it lacks protein okay so

foods that lack animal-based proteins are tend to be avoided going forward

so here's the second part of that now 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, we have sugars or fats that are more pleasurable.

It keeps eating that milk, right?

I say.

If the protein is completely absent, the animal avoids the diet.

Unless, unless the diet is very rich in dietary fibers.

And the study that I saw,

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, really, yes.

Our gut, meaning the neurons in our gut, are essentially waiting for hoping, we give them a consciousness, proteins from animal sources.

That's correct.

If those animal proteins arrive in the form of meat, fish, eggs, et cetera.

cells signal to the brain craving more of those foods until satiety is reached.

But in the absence of that protein,

the animal quickly learns,

the person quickly learns to avoid that particular food,

unless there's fiber in it, in which case these gut cells are able to now synthesize the essential amino acid.

The microorganisms of the gut,

here we're talking about the microbiome now, can synthesize the essential amino acids that ordinarily would come from the meat, chicken, fish, or eggs.

That's right.

So, wow.

So, I'm an omnivore.

I love.

high-quality meat, but I also love vegetables, fruits, and starches of certain kinds.

But I have friends who are vegetarian vegan.

Many of them eat a vegetarian vegan diet that includes a lot of...

fiber, and you're saying that the fiber itself can trigger the gut microbiome to synthesize the essential amino acids that ordinarily would come from meat.

But you also said,

if I recall,

that if there's a small amount of protein,

so not zero protein, but a small amount of protein in there, then we crave more of that food in order to try and get.

Very interesting because this is the first thing that to me squares the

argument based on the observation that or the hypothesis that we are essentially amino acid foraging machines and

that complete proteins in the form of meat fish chicken and There are those that argue those are the,

quote unquote, best forms of protein, right, the most complete forms.

But there are many vegetarians and vegans who seem to thrive on a vegetarian vegan diet.

And you're telling me that perhaps their body is, their gut microbiome is compensating for the lack of whole animal protein.

That's right.

And the people who are trying to limit their meat intake are what, hungrier in general.

So you're better off either.

either indulging it or avoiding it, but not having a small amount of it.

Is the idea?

The idea is that the body or the gut will be able to detect that and they will try to I see.

And these I actually learned recently from a friend Laura Dubal with Columbia who works,

does some beautiful work on mosquitoes and how it is that they feed on a blotch.

She for the Gastronauts series.

Is she from Lesley Valsal?

Yeah, Valsal.

And what I learned is that when the mosquitoes are not reproducing,

they can leave off ATP,

which is right but they cannot lay X they need the protein in order to be able to

lay X otherwise the mosquitoes cannot lay on the egg you know So this leaves us with a picture of the gut-sensing cells,

these neuropot cells, as exquisitely sensitive to amino acid content in our foods.

which makes perfect sense to me.

It not been published or demonstrated yet.

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

In Kim, yeah.

We want to highlight this bracket, bold face and underline it as we're now at the cutting edge of what may be coming.

That's right.

Right, observation.

But very interesting.

But there is this,

fairly long-standing 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.

And in fact there is evidence on that and a professor Steven Simpson in Australia in the nutrition research institute at Sydney University he is

main proponent of these protein leverage hypothesis you know that and in fact

protein is the most se seeding a macronutrient so that that has been

established and that's why normally we have focus on sugars and fats but we have

neglected a little bit of on the protein because it's not as pleasurable as the

sugars or fats but what is fascinating is that is the most se seeding and nutrient

and as you know it's like the most limiting and also like even commercial is the most Yeah,

I certainly have had the experience of at one time in my life really enjoying and even craving sweet foods,

desserts and sugars and things of that sort.

And I notice that over time if I eat sufficient amounts of meat, chicken, eggs, fish, which is not to say that I consume it.

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 other shares well.

But I promise you that this was a fun topic, right?

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 complement each other.

Like, instance, a classic, especially in native communities, it's called the Three Marys.

I believe it's a...

pumpkins on some type of fibers with corn,

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

That's right.

And I grew up in a farm, my parents got farms, and I remember when they would plant.

They will also throw in there the beans, and the beans will wrap around 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 agriculturally,

and probably in the subconscious,

to call way or perhaps the plants taught us how to cultivate them in such a way that now when

we put them in the plate, it just makes sense at the nutritional level.

Because if you think about it, every time that we go to eat, how is it that we arrange that plate, right?

There It has some beings,

and then there are some letters,

and if we have, for omnipores people would put made or you would put other types of protein in there.

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

As long as we're talking about your upbringing.

You have a fascinating story.

So maybe we could discuss that for a few minutes.

Where were you born?

I was born in the Amazonia of Ecuador, a town called El Chaco in Ecuador.

It's on the slopes of the eastern slopes of the Andes on the way to the Amazonia in the Napo province.

Incidentally, it was like through the path from where Francisco, the origin in 1542 March on its way to the discovery of the Amazon.

It actually through a trail that later on reading.

I that native people had all of these trails between the Amazonia and the Andes and the coastal line for thousands of years.

You grew up in a very rural.

Yes.

Oil had been detected in the 1920s in Ecuador.

It was first explored in 1964 in the first oil well was in a town called La Vaguario,

which now is only like three or four hours from the town where I grew up.

But that time it was like eight hours, the roads were not good.

And the first road passed through it in 1974, I was born in 1983.

But remember that we used to have like a giant diesel engine that we electricity only from 7 to 9 p.m.

I remember when my father bought the first color television in the town,

and then neighbors will come to our living room and then we will watch movies.

Wow, and this was in the 80s.

That was in the 80s, right?

Such an interesting upbringing.

So, did you eat a purely vegetarian diet, or you meats as well?

What did those meats come from if you did?

Primarily from a cattle, a goat's ship.

So, how do you go from to a study of nutrition and ultimately neuroscience.

Yeah, that's the question, right?

Like deeper I go,

the more I question this,

I used to think that,

oh, I was very simple, you know, like when I was, specifically when I was 11 years

old, my father, he was born in 19th,

By 19,

he lost his father, my grandfather, when he was six years old, and he was given a way, and he had to go on like...

built his life.

He was a very successful entrepreneur.

But in the process, he had made a lot of friends and acquaintances.

So, when I was 11 years old, I remember specifically that a friend of his who was in the special forces stopped by a

Because that was the main road that we go into the Amazon jungle where the folks in the special forces in the military will be trained.

And he stopped by and said, like, hey, Rogelio, what are you going to do with Diego?

I think that it's about time that I think that you should send him to the military school.

And I remember in a matter of literally a couple of weeks or three weeks,

I taken the tests and I was accepted into the military school and then I ended up in military school.

At that time, it was the premier military school in the country.

That alone, with you start to understand the context in which you developed.

Because it was a very interesting context for a child, like just to give you an idea.

This cool.

had the first and the only zoo in the country.

So from my classroom,

I will literally look at the Then, I think that was by the second year that I was in the school, second or third year.

That became, because the city started to grow and then the military school was wrong.

Then they separated the higher education for military officers.

They them and they put them in a different place.

But that zoo actually became the first zoo of the capital of keto.

You had a zoo with lions at your school.

Yes.

You said you could see the lions in your classroom.

And they could see you presumably.

I probably know them.

I assume could see you.

Lion Vision is pretty good.

I know what the resolution is, but I'm guessing that their vision is.

Yeah, they definitely use their old faction, but they are site-based hunters as well, so.

But I have a specifically one memory, like climbing up.

I think it was like from there,

because we had an Olympic pool and we had all of these,

events, the field was the field where the national team will go and train on because they didn't have their own training grounds.

Later on, they had their own training grounds.

So, But that was something that you just grow into it, right?

But was with the years and now especially like that I get to reflect on it.

I was extremely fortunate through that experience and that education.

And I'm here sharing some of the story.

And through that, inspiring some people, especially young people.

people that would like to go and chase their dreams, you know?

So you went to military school in Ecuador,

you graduated and you decided to go to,

yeah, so I want to become a, so in the military school, they will select the top cadets.

like I think it was the top 10%

and they will select them and they will put them through a special training so you have essentially being half like what was a

normal summer vacation you know I will go into military training So,

for me,

it going to be very,

not easy, but relatively straightforward to transition into officers' academy, like four more years, like West Point here, and then become an officer, right?

In fact, I had a Reserves Officer degree when I graduated.

But two years before graduating, a friend of mine.

who he preferred other types of careers, he said, like, you're not going to become a military, right?

You're not going to go into the military.

And he said, you should probably study something that will help your parents.

And then I said, what will that be?

And he said, like, perhaps agriculture.

And I didn't think of that time.

It didn't dawn on me in that people can study for agriculture.

And agriculture is like the base of food for all of us.

And then I said, where?

And then he mentioned for the first time this university in Zamorano, which was founded with Zoma.

some funds that were donated by the founder of the Standard Fruit Company, which eventually became, I think, Chiquita Banana, Zam Zemorai.

And is a noise that is in Honduras, outside of Tebus Galpa.

So it's a boarding school, you wear uniforms, so it was kind of like military, it's very strict.

You can not accumulate more than 12 demerits, otherwise they will send you home.

how do you get a demerit?

You show up two minutes late to work in the morning at 6 a.m.

in field and then you just get two minutes late one demerit 12 of those you're out to demerit two demerits you're out yeah you get a we

use they will check your room.

So for instance, I guess like you, if you will go there, like they will give you every Wednesday, they had 7 p.m.

They will check your room, but like very meticulously, right?

And if they found a little bit of dust on the window or something to the merits, then you're going home.

If you accumulate enough, you will go home, right?

So it really And then do that with your kids?

Nah, I think that I can become very...

Do make their beds?

They do make their bets, yeah.

But that was the context.

And was then where I learned about two things.

One is where this idea of getting a PhD,

because I noticed that most of the leaders will have a PhD, most of the leaders in the university.

And I realized in the United States is one of the training grants, main training grants, for PhDs.

And the other one was nutrition.

I was a little bit more keen on perhaps going into veterinary school.

And then I had an experience in a day re-farming.

where I learned the value of nutrition, there was more prophylactic rather than a palliative or like treating the cow, right?

That kind of convinced me to look for training in nutrition.

And then a friend of mine,

the late Abel Gernath, he was able to connect me with some friends and my mentor at North Carolina State University.

And where I ended up doing my PhD in nutrition.

That's where the career became.

And then maybe another detail in there is that I was so excited about taking,

that's where I took my first physiology class and all of the sudden I realized that in a way the body was like a machine,

right?

Like it's a limited way of thinking, but it was the body was like a machine.

And one of the professors was a neuroscientist and I took two human physiologists with him

and I was just

Thrilled by when he will explain how is he that in the synaptic terminal there were these

Bessicles that had like these proteins that will walk the Bessicle in the presynaptic actives on and that's how we make movement,

you know Something like that

And I guess I kept that in the background on my hair and when I had the opportunity to work in the garden

I applied that so you were enchanted by the nervous system yes as as I was too I'm

nothing to me is more um spectacular than the realization that we are made up of these little

tiny cells many different types but that the neurons is govern our entire experience of life.

That's just amazing.

Well, that's quite a journey from the Amazon to, well, this table and much more, of course.

Thank you for sharing that.

So you grew up in a, let's call it a plant-rich environment, the Amazon, at least from the pictures I've seen.

Let's talk about plants,

botanicals, and the idea that maybe plants, for lack of a better way to put it, have a certain intelligence or a composition that

is random with respect to our interactions with them, right?

You described how agriculture in some places has evolved to include and ensure the different macronutrients and essential amino acid intake,

even in the absence of animal proteins, is it the pumpkin or the squash, the corn and the beans.

What are your thoughts on plants,

perhaps from the Amazon,

but elsewhere too,

and their capacity to have things in them,

chemicals that can be good for us at the level of the we've got, but perhaps at the level.

The brain or other organs as well.

Yeah, how do you think about plants these days?

So the first thing you mentioned there like intelligence, right?

I mean, I don't know like if that exact terminology applies But I do like this work wisdom because it's reflective experience, right?

And I said reflective experience because somehow we are going over the

experience and plants have been many more millions years of age on Earth than any other animal, right?

Therefore, they have had way more time to actually experience the ground.

So, to think that they don't know what is going on, I think it's a little bit perhaps naive as the world.

I went to the main court of the Mayan ruins of Copan,

the junction between Honduras and This was a very special city of the Mayans,

and in the main court you see like all of these stelas,

which are like the main stones of the kings of several dynasties, and at the top of one of the stairs on these pyramids.

There is this giant seva tree, which is like 650 years old, something like that.

So that tree was there before the Spaniards landed in there, when Mayans perhaps were still celebrating things.

or perhaps right after, right?

So imagine how much information that an organism has in there.

And we will be able to just tap somehow into that information, like climate, fluctuations, organisms, interactions, movements, like so many different things, right?

Like right now, I don't think that we even have the language.

of being able to understand at the organismic level of how much information that is stored in one single one of those organisms.

But then think about a chloroplast, for instance, over one of the photosynthetic organelles inside of the organism.

How is it that they have been shaped for hundreds of years in those organisms, right?

And I think that perhaps in the future this is more of a sci-fi right now,

but perhaps in the future we will be able to harvest that type of wisdom,

we be able to understand a lot about the place or the earth that we live in.

That's point number one.

Point number two is that these plants have been interacting and we have been interacting with plants for hundreds of years, right?

And obviously,

we are a consequence of the environment,

like here, driving in LA or driving in a major city for some of us is just like second nature.

But if you go into a jungle, then all of a sudden it will not be the same thing, right?

But for somebody that has been in the jungle for hundreds of years,

now all of a sudden they are able to describe with such a sensitivity of like how it is that the jungle is,

the makeup of the jungle is in there.

I've seen native people walking through the jungle without shoes,

and right before stepping stopping and then pointing out,

like, look underneath that leaf and then I'm lifting it out and then a tarantula right there.

Like, how do you even make sense of that?

Like, I don't have the sensory acuity or the wisdom to be able to figure that out.

But they do, right, and certainly that is just a level of sensory perception that I am not equipped with.

But I do think that there's quite a bit of that interaction in there to learn.

And then of course,

not only for food,

but also for medicine,

for textiles,

and for many These plants have been part of the ecosystem of how these people navigate the world all the way from making a canoe to making a backpack to carry fish from the river into

the house, right?

How do you think we evolved food choices and flavor preferences?

I imagine humans, you that existed long before us.

The gut starts rumbling,

and there are all these plants everywhere,

some nuts and some berries and things,

and they had presumably no choice but to consume them,

and decide at the level of the mouth, like, mmm, that's bitter, nope, that's not good.

maybe eventually cook those and see if that changes the relationship.

Yeah, I'm raw acorn versus cooked acorn, you know, but that ultimately there

was a lot of trial and error and that these neural pod cells,

which surely existed for a very long time prior to us, played a key role in discerning what's in the of barks, roots, nuts, berries.

We're setting aside meats for the moment and other animal proteins and making decisions about what's nutritious, what is safe.

And that's a pretty complex process, given that some things might taste okay, go down okay, but then you run into serious trouble later.

But given the critical importance of ingesting sufficient amounts of macronutrients and the need for micronutrients to survive on a day-to-day basis,

much less reproduce and propagate,

one imagines that you know this is almost as essential as breathing,

you know,

and that this path in our nervous system of the neuropot cells to the brain for sake of decision-making of yum,

yuck, or is perhaps one of the most important core functions of the nervous system once you

gets past the elements that control breathing, heart rate, temperature regulation, things of that sort.

I it as somewhat among the senses,

it's at least as important as vision and perhaps more in terms of making sure that we survive from

that's correct and here's where I think that is a large vacuum in biology.

If I would be with my biological,

my training in biology,

if I would put my my hat of the training in biology,

I wouldn't be able to explain much of like how is it that we figure it out because

Because even if you just go to Botanic Algarden here in the city, it would be really hard to figure out.

but you know, what plant is for what, right?

Yeah, what's safe to eat.

is safe to eat?

What To or not.

You know, maybe like the cacti, you are able to figure that out by torture, right?

So from the biological perspective, I think that there is quite a bit in there to explore and to learn.

There is some very interesting work from the anthropological perspective.

So anthropologists and botanists, that's right.

where exploring the jungles,

not only the Amazon, but Borneo, Sri Lanka, and on and so forth, and studying the interaction of native people with the plants.

And if going through the literature,

the literature,

there is a pattern that emerges, and like the native people they talk about, how it is that they actually learn from the planet.

plants, that the plants were the ones that would teach them.

So that's why I said from the biological perspective, like can we make, reconcile that?

I think that there is still quite a bit to learn.

What does that mean to learn from the plants?

I there's something that intuitively makes sense.

When you say that, I've heard about looking at plants as teachers about the local environment.

When they're open,

they're light sensing, when they're closed, but terms of translating some of that, you know how humans have learned to navigate given environments.

Navigate meaning sort of thrive in those environments.

How do we go about that?

Does it mean taking plants, grinding them up and figuring out the constituent parts?

Or that two reductionists?

Is that going to leave us with a parts list that doesn't mean anything?

Sort of like if I splayed out all the pieces of a car or an aeroplane.

In front of us it doesn't really tell us anything about that except what parts make up to the thing that flies Yes,

and that's why I say that like this is more on the anthropological Studies that have you know,

especially from scientists that have gone there and learned the language leaf with the natives as natives you know and then start to understand the dynamic of

their culture and their interactions then that's when like for instance how

is that they classify plants the way that they classify plants is like several

than our classification or scientific classification by the two-name system or the variety, right?

Like, for instance, they take into account

only the flavor, but also the shape, where the location, how they interact over the year, how they react over the year.

For instance, there is this beautiful plant that people call it a, plant.

I don't know if you have a very heavy google that you will see it.

Literally like lips, it has like these red beautiful lips like the the plant just looks like lips.

And people use it for a pain for some rashes,

skin rashes and also like in some rituals and like most of these plants and the way that the natives interact with the plants is in a sacred level

You know,

there is this respect for the plant So,

yeah, I think biologically I think that there is quite a bit in there to understand and explore and define.

I do agree with you that like just thinking about grinding it up and like just putting

it in a tip perhaps is to a reductionist.

It could be a beginning of understanding, but it is a reductionist.

Seems like nowadays in the field.

medical research and clinical research that there's a lot of interest in plant-based psychedelics.

You LSD from ergot and a psilocybin mushroom and so on and so forth.

Ayahuasca, Iboga.

So, it seems like science and plants have merged at that level in terms of clinical implications.

Of there are entire fields of plant biology that are extremely important.

I most people probably don't realize this, but a lot of what we understand about circadian rhythms.

grew, no pun intended, out of our understanding of plant circadian rhythms first and then it

was translated to mammals,

beautiful work by Steve Kay and others,

seeing the circadian rhythms in leaf opening and orientation of the whole plant and other features of

plants that are mirrored by the changes in arousal level in mammals, including us, which is why we're telling people to.

early in the day and to avoid bright light in the evening and nighttime.

So what are your thoughts on plants as a source of medicine, psychedelic or otherwise?

I think that, well, traditionally that's where medicine was a developer.

I was at the Oxford Botanical Gardens last year with the family and we went into the gardens and they have a beautiful garden.

It established in 1621.

I think it was the first Botanical Gardens in England and they have a beautiful medicinal

And there was this very humble little sign with a description in there that said in there that about 80%

of medicine still comes straight from plants.

Really?

Yes, and if you think about it, it kind of makes sense, right?

Because we think about the medicines that we have been able to develop,

which have been phenomenal,

especially for certain chronic diseases,

but we don't have a broad repertoire So,

I think that has been obviously a great advance in our society that we have been able to identify the molecules,

synthesize the molecules, package the molecules, render them by available in specific sites.

And I think that when we are able to couple that with the rest of the molecules that it plants through their,

I keep saying,

their wisdom because somehow they develop their ability to have have have have their their have not only one molecule,

but like a combination of other things that will provide the full experience of the plant, right?

For instance, a germatium, you know, is not only caffeine, right?

Because very different than a shot of espresso,

you know,

if you take the whole of the thing,

it not only gives you energy,

but it gives you a full range of an experience that is specific to the yeramata, which is a leaf, right?

Yeah, it's a distinctly different subjective experience than coffee, and I enjoy both coffee and espresso and yeramata.

You were the one who introduced me to Guayusa, which is...

Which causing of Geromata, because Geromata is ill-exparable gences.

Guayusa is ill-exparable.

and it's not as bitter as a matte,

but it has almost as much caffeine as coffee and it has antioxidants and other compounds, which give you these various mood experiences.

So, in the Amazon, they take a drink of what you use every morning.

around 4 a.m.

between 4 and 6 a.m.

They call it yes.

It like Jocko willing, curly.

Some people understand that joke.

He wakes up every morning and he posts a picture of his Casio watch.

Yep.

And he's already training 4.30.

So no Guayusa required for Jocko.

And they call it the Wysa Upina.

the hour of the Yousa and is ritualistic, drinking of the Yousa in the morning and where they talk as a family.

Or the issues that they have had the days before or the weeks before,

like either with other communities within the family if they have to represent or represent one of the children

or talk to them about some mistakes that they are making.

And then they plan the full day of activities by drinking water.

And around 5.30, because they will boil, they will use it, right?

And they keep boiling, they will use it, and just keep adding water to it.

And then around 5.30, then they will have what is called, it's a bowl of Chonta.

And Chonta is this pound date, very rich in lipids and fiber.

So, they will have the Yousa, because the Yousa, they say, that gives them energy.

It heals any pain, it shuts down appetite, so will eat at like 3 p.m., you know, shuts down, modulates appetite.

As does your bromate.

Yes, that's are one of the more potent effects, actually, of Mate and Gua Yousa, is a mild to moderate appetite suppression.

And then if you combine that to Chonta,

which gives you the lipids,

and then it's like a full meal for until 3 p.m., and then they go and work in the fields.

Interesting.

So, they're essentially starting the day with hydration, caffeine, and they, what in

some circles they call fat fasting, meaning consuming lipids in order to stave off hunger.

I it's the density source of calories among macronutrients.

And is a vegetable-based diet, I guess, right?

Are they a healthy culture?

Do live a long time?

I am not a nation.

probably do more reading that.

I'm not well educated in what are the studies that have follow up on the, you know, and the health status of the communities.

But I can tell you is that at least colloquially, I say that diabetes, those type of issues are not as prevalent.

But they do have obviously through like social exposure, they have other things, you know?

Fascinating this morning ritual of conversation about family and culture and what's needed planning the day.

We had on this podcast as a guest, Dr.

Sachin Panda,

who is at the Salk Institute for Biological Studies,

often known for his work on intermittent fasting, time-restricted feeding, but also has done beautiful circadian biology.

And he talked about the use of fireside chats, not the sword on stage, but you know, gathering around fire at night.

It's something that has existed in many cultures where people reflect on the previous day and discuss issues,

social and work issues, and of dissect what's happened and talk, and it's about building and repairing relationships, sounds like in this, is it true?

What is this group?

Is a role, is this a native community?

Because there are like about 70 or so communities that have been documented in the Amazonia with their own language,

with their own traditions, and many of them share the same type of traditions.

And if you think about it, like a podcast is one way of an evolution of that conversation, right?

Like where we can have this extended conversation and get this,

the more primordial things,

the ones that we have them in the prefrontal cortex right away and like this cause of a like,

well, you know, this discovers these identifications.

But then we get to the part of like, what does it mean for the whole community?

Yeah, there's doing.

and then there's resting and recovering, right?

And there is something about, like, I in death for the next generation, right?

Yeah, passing on of lessons, better learn from the mistakes and successes of others, if you can, as you go forward.

Very interesting.

If we could, I'd like to now return to the biology, the nervous system.

And thank you for that voyage through some of your background in Ecuador, fascinating I do for a mug of Guayusa.

Sometimes I'll mix the two, the loose leaf yerba, maté.

And as you said, what time does it feel?

I really like it.

Most of the it's loose leaf yerba mate or cobra yerba mate.

But I'll mix in the guayusa leaves.

And I do like,

as you mentioned,

is can continue to pour water over them for many hours,

and it tastes different as the time of And I guess as you're extracting different things from it and different concentrations as time goes on,

I realize it's not a precise science.

It's interesting today we're talking

about very precise neurons and methods of tracing neurons and sensing of specific amino acids and lipids at the level of the gut.

And then we're also going to more macroscopic view,

a broader scale view of the plants,

having many things that need to coexist in certain ratios that the plants have evolved to create for us.

So sort of straddling both ends the continuum.

And if I could fit in their story,

no long ago,

I visited a friend,

a native friend,

in a nearby town,

and he produces some of the best chocolate,

what I will say, in the planet, you know, because actually the plants of the Ubroma cacao was recently documented.

There a paper in science.

And not long ago that it was domesticated in Ecuador in Europe where I grew up and they have done some tracing and genetic tracing.

So he produced some of the best chocolate, like literally he harvested in there and then he roasted.

Grinde and then he prepared for us in there and he the Swiss are saying with the Belgians right I claim the best chocolate,

but we know Ecuador is the place for the best chocolate I think I just got a lot of Swiss and Belgians angry at me for saying that but

It is do they have a very dark variety?

I the extreme dark varieties, you know 95% even a hundred percent chocolate if it comes from a really quality absolutely delicious.

There's like milka straight from the cow right like and what he did is like he said like Diego you have to try it with Yusa.

and he makes the chocolate the way the way you serve.

As a drink, like as a drink, boy, like that will give you wings in.

Guayusa hot chocolate.

Yes, and it's a very smooth experience, right?

Like you're mixing this tea, which is for energy with chocolate, you know, over the best quality.

So we're not talking about eating chocolate and drinking tea, we're talking about melting the the chocolate in the Guayusa.

It was something like one other kind, you know.

Of I couldn't sleep until like 3am, I think.

Right, there's something to do.

Maybe this is why these groups drink the Guayusa so early in the day.

That's right.

Yeah, and I have to imagine I would need caffeine at 4am, 5am.

otherwise we'll be falling back asleep.

So back in the gut and nervous system, in particular within the brain, we haven't talked about the brain so much.

So information from the gut is sent via these neurons.

Up to,

you mentioned the no-dose ganglion,

such a cool name for a brain,

and a ganglion, in this instance, is aggregate of neurons, so it's like a batch of neurons, that then send a connection into the brain.

What, what brain areas?

They send it to, and maybe we could describe these by name, but also by function, what they generally are responsible for.

And probably should be prefaced with, ultimately we'll go to the entire brain.

Everything ultimately connects to everything.

It's like Google Maps, everything to everything.

But what are some of the primary recipients of that information?

into, of sensory integration are in the brain stem, you know, and for instance, the nucleus

tractors, solitary, is in a specific region within the brain.

The is one area.

And NTS, for those that don't know, is involved in regulating hunger and appetite?

That's correct.

Other functions perhaps, but like for instance, that seems to be an area of sensory integration for nutrients.

And when we say drives hunger,

appetite, sensory integration for nutrients, I what would be great is if, you know, people can understand, you know, the language of the nervous system

is chemical and electrical.

So when these neurons are active, We tend to crave certain foods, you know, seek them, literally, go to the refrigerator.

Among different choices, go to that thing and select that and put it into our mouth.

So presumably it's driving reward systems, motor systems.

I what we call hunger and appetite is really a kind of a domino effect of a lot of different brain circuits.

Do we know whether or the nucleus tractus solitaire projects to the areas of the brain involved in dopamine release and craving?

Yes.

And there has been some elegant work from several different neuroscientists in this area like tracking the circuitry from there onto many other different areas,

the for instance, very basic behavioral functions and the striatum where there is dopamine release and then there is this pleasurable sensation and reward.

There are several other areas in there that are involved in this sensory integration.

There is quite a bit of work still to be done specifically from the neural pods.

There is like some evidence that they are connecting directly to or they're

if you put two papers together is obvious that they are connecting to like some of these areas of

dopamine release basal ganglia in the brain and that's why they are causing this reinforcing effect like in the lateral hypothalamus and other areas.

I do think that And there is quite a bit of a gap in like different regions of the digestive tract.

Today we just talked about the Sophogus, right?

Like the Sophogus I think that is still...

There is a little bit of work,

perhaps I think that I still believe our list has worked in that area,

another neuroscientist doing some very fine, detailed work in sensory biology in the Sophovus.

There is quite a bit of a lack of precise biology in how it is that The esophagus,

the specific cells of the esophagus are innervated or like making sense of the environment.

Same thing for the stomach and how it is that ultimately each one of those regions are feeding into different regions of the brain.

Even how each one of these valves,

I'm fascinated by the each one of the valves that we talk early on like, The gastrosophageal sphincter or the pylorus or the leocecal junction.

Yeah, we should illustrate for people.

I'm an expert in the gut by any means, but what Dr.

Borges is referring to is that the gut, you know, the gut.

as it extends from the mouth to the rectum is not just a of tubes of different uh...

diameters uh...

but Rather,

they have valves,

chambers, and these sphincters that cut off, you know, everyone hears the word sphincter, and they always think, oh, you anal sphincter, and then

they, ah, you know, it's like, you know, elementary school, middle school humor.

But are that they literally can close and open to varying extent in order to

allow passage or prohibit passage from one compartment to the next, such that the certain things can take place over time.

one region like the esophagus or within the stomach or before passing to other chambers.

And so I hear you saying that critical processing is happening at each of these chambers.

The sphincters are determining how long that processing occurs and that distinct sets of

neuropod cells are likely detecting distinct qualities and quantities within the food, chemical qualities and quantities within the food.

And that, to the brain.

That's correct.

And here is something that,

since we're getting into the future of this area,

and while there is not direct publish evidence yet, I think that is going to be a fun area.

As the brain also generates these electrical patterns.

Those electrical patterns change depending on fasting versus feeding and circadian rhythms.

Probably can realize jet lag.

The God is asking you for a burger at 3am and your brain is telling the God, can you please go to sleep, right?

So, these electrical patterns, these electrical waves that are going into, that are being

propagated by the gastrointestinal tract, there are like several different cells like the enterica neurons are coordinating these cells.

There are also these interstitial cells of Cajal.

So Santiago Ramón Cajal, the greatest neurobiologist of all time.

That's right.

It was named after him.

He actually has...

the second volume of his classic book on the histology of the nervous system,

one of the last figure stocks, like the innervation of the villa in the intestine.

So beautiful.

For those that don't know, Kahal shared the Nobel Prize with Camila Golgi in 1906.

They together developed tools and mapped the structure of the nervous system.

And it's fair to say that Kahal Supernatural levels of insight into the nervous system.

He looked at the nervous systems of so many different animals in dead specimens the joke,

even though it's not funny, is that many animal species entered his laboratory, very few walked out.

But by looking at fixed specimens under the microscope and then drawing them in select elements within them essentially came up with most of the major hypotheses

about how the nervous system works, not just its structure, but neuroplasticity, the failure of mammalian central nervous system neurons to regenerate.

This is why after traumatic brain injury or stroke, there's often loss of function that doesn't recover.

Sometimes it recovers.

And that people who have injuries younger often can recover certain functions.

Everything from the direction of electrical flow through the nervous system,

all from looking at tissue that was not alive, no electrophysiology, no behavioral experiments, just but incredible, supernatural, seemingly.

levels of intuition and insight.

Yes, there is some quote in one of his books that when he got invited to

When I was,

of his friends to England,

I don't remember,

it was a famous neuroscientist at the time in the late 1800s that Kuchar helped him to expose his work to other audiences,

you and invited him to England.

So he said in there that it took like three months to go to that podcast, right?

Like, it was a three-month trip.

So he said that he brought his microscope.

with him with him and in the in the role he will be able to do some of these

Observations yeah peculiar guy also known for carrying a very heavy iron umbrella In order to do physical exercise on the way to the lab.

He a he was a very very fit physical specimen also reportedly,

I don't know which pick which one, a pretty gruff person, not terribly pleasant to be around.

Ran tight ship,

but in any event So,

the cells of the gut are named after,

some of them are named after called interstitial cells of the They're you got a waltz into some neuroscience history, but history.

So, they have this emanating electricity, right?

And far, these, and it seems like the spinters.

modulate the emanation of this electricity.

Oh, like an instrument.

And you probably think like that is because the intestine,

and maybe here we get a little bit even deeper into this,

and I read some work from a philosopher in the UK who was,

and I'm on a paraphrase that very largely,

you know,

so please don't quote,

something along the lines that if we are what we eat,

the place where food becomes us and we become food, it should be in testing, right, because that is where food is actually absorbed, right?

So that is a very fascinating point.

Number is that the food enters us at a frequency.

that it will modulate the entire body, right?

Therefore, like the body through these electricity, these electrical waves should be in sync with also the electricity of the entire nervous system.

So I think that here's where,

in the future,

I think that there's going to be a fascinating realm

of understanding how it

is of the body and the brain are synchronized with each other because as we know like

for instance sometimes when we don't we are hungry we become angry you know like

we become irritated by the fact that we don't have food and perhaps it's

this dissonance in the emanation of the electrical waves between the digestive tract and the nervous system.

So I think that is that's just like one of the one of the realms of how it is that the brain is connected to the gut at a more

organ to organ level to be able to make us function ultimately, right?

Because that's how we are integrating the outside world, the food, into our entire system so we can maintain the entire organism.

Well, certainly our level of alertness is linked to our level of health.

of anticipation, and a lot of our food anticipation impacts our levels of arousal, aka alertness.

So as you mentioned in the, we're a diurnal species, so in the middle of the night it's unusual to get hungry, right?

A lot of are shut down,

digestion is happening at different rates and typically our appetite is greater during the day than it is in the middle of the night.

But in addition to that,

it makes good sense to me that what is going on at the level Is going to tell the brain did we get enough nutrients from the previous day?

Are we in a place of abundance?

There's also the psychological aspect of gut sensing and we haven't really touched on that

What are your thoughts as both a and a human with a with a gut brain access on this notion of a kind of gut

Intuition you meet certain people and it sort of relaxes and warms you and you want to get to know them more other people for whatever reason

You just feel like I don't know something doesn't feel quite right that we can sense things at the level of the body

that inform our brain and No one really understands that process yet,

but we do know that the vagus nerve,

which is a you know multi pronged pathway big pathway it's major branch of the nervous system,

really, is sending by directional communication between brain and body.

And when we're around somebody or something that doesn't, quote unquote, feel right, the Vegas is involved.

A few interesting things in the work of Carl Jung talks about it,

about subconscious and how it is that we're accumulating all of these experiences that we have

been passing through in life is not that they are not a store anymore,

it's just that they are back in the subconscious, right, and then ultimately they become part of the so-called intuition.

We have this gut feeling that if we analyze some of the languages,

I think that in past people have told me in so many different languages that There is this phrase for God-filings in so many,

like, for instance, in, think, Portuguese is free of the Barriga, you know, like, cold in the, in the, in the stomach, you get a cold.

In Spanish we call it a pre-sentimento, like a pre-filling.

Or pre-sensation or feeling, it will be more feeling if you translate that as if it arrives first before you're able to articulate it.

So there is this storage in the entire body that gives you, depending on the context, it gives you a certain type of feeling.

talk about intuition.

There's also like this other aspect of how it is that food synchronizes that intuition.

It seems to synchronize among two or more people, because if you think about it, we have this ritualistic way of serving something.

When commonly say, or colloquially say, let's go for a cup of coffee.

And often what we mean is,

let's go and talk about business,

the future,

result when you're but we're talking about the cup of coffee and we have to share and people I think there are some

psychologists that have run some of these studies in which they say that if the food that we these

more alike we are more likely to to connect at least on the moment right so there is this aspect,

and that's why we share the food.

Interesting.

So, is the idea that it's the actual chemical constituents of the food that's creating a common

experience that then allows people to bond more readily, or it that the specific constituents of the food are actually driving?

bonding per se.

We go back to if we are what we eat, then we eat the same thing, we should be more alike to each other.

That's why in communities, you share the food.

In fact, if go into certain specific communities, you pass around the food, you pass around the drinks, And it's very common to share, right?

Yeah, and certainly in romantic bonding, there are many factors, of course, but the kind

of more basic functions of food, sex, and sleep represent the common places of bonding.

initially, right?

And conversation, of course, and values, et cetera, right?

Not dismiss any of those.

They're essential as well.

But terms of, you know, feelings safety.

That's right.

Feelings of communing with somebody, right?

These basic biological functions.

Yeah, and in business too, right, like there has been a study like behavioral economists that they talk about how it is that the business are more likely to happen when they are like made over

food or lunch or things like that.

Right.

Like this synchronicity in the decision making.

And here is a third dimension on this area that it has.

well-explorer, but I suspected in the near future it will begin to be explored.

I read a while ago a very elegant paper from Walter Cannon.

So you may want to expand on who Walter Cannon was.

one of the founding figures of the study of physiology.

Autodomics, physiology, right?

A of physiology at Harvard in 1920s, 1930s, an author of the wisdom of the body.

He has a paper.

Okay, publish a paper I will leave in the 1930s.

It's called voodoo death voodoo death.

And I remember when I found that title, I like, ooh, this is something to sit down and dissect, you know.

Yeah, good title.

Good title.

If you want somebody to read it, good title.

And he essentially the gist of it,

let me see if I can do a little bit of justice, but I obviously will chop most of the details.

But is that in some observations,

in some native tribes,

I believe it was in Africa,

that if young people,

especially young, youngsters, if they were frightened by a shot, that they will not perform a certain thing, a certain task, right?

The intro, a level of psychosis, so to speak, that could cause death, like the cast and spell, right?

And that's why it's called guru death.

What kind of goes on this question?

that is an activation of the vagus nerve and the peripheral nervous system that is a hyper-activation

that is going through the subtreshold level of consciousness.

And in some of these tribes, at least that's what he explains that is happening.

And believe that he did some experiments in some animals.

But what he was saying is that these are hypertonic activation of...

system, when there are these spells that are casted by a member of the tribe that is

in higher or more superior or more influential position, that if the other member especially with this pair with something, right?

Like you say,

like, if you go outside and don't listen to what I just told you and you see a black cat, those two things match together.

Now you're hyper-activated, right?

And become super-stitious about it.

What Walter Cannon goes to explain is that there is a hyper activation of the peripheral nervous system or is there is probably more details in there?

But the the the paper Really highlights an area of exploration that we don't know about these a threshold of subconsciousness of the nervous system,

how it is driving us to have superstition, to drive instinctively to go and consume certain things, or behave in certain ways, right?

Yeah, so it sounds like it's paired association learning

through statements, cognition, but that's enacted through the Vegas in order to control the organs of their periphery.

That's nerd speak for, if we hear and believe it.

certain events will cause certain changes in our physiology.

They in some instances become capable of that.

Eat this food at this location and you'll get sick.

Eat this food at this location, you'll feel better.

And learned association.

There's not, and ultimately it's physiological, but it sounds like it's subject to a lot of learning effects.

As long as we're talking about the Vegas,

I think it's a great opportunity to just mention

that a lot of people understandably think that the Vegas nerve activation is always about calming of the nervous system.

And indeed, the Vegas is placed under the umbrella of a parasympathetic pathway.

But I think it's very important for people to know that both experimentally and clinically,

if the vagus nerve is stimulated, you get exactly the opposite effect.

You get aroused.

This is commonly known in labs that do physiology of different kinds.

It's in the clinical context.

People with depression are sometimes treated with vagal nerve stimulators, and it certainly isn't driving more sedation, more depression of the nervous system.

It drives alertness and arousal.

So have to,

I think,

make sure that we look at the vagus system and describe the vagal pathway as one that can both induce states of calm,

of ease, rest and digest, as sometimes called, but also states of arousal and alertness, even fear.

And so I think of the Vegas as a superhighway of a bunch of different pathways with lots of inputs and outputs that's highly subject to learning.

And indeed, the Vegas can slow heart.

you know, down through a number of things like long exhale breathing.

Earlier we were talking about stress modulation, something my labs worked on.

Extend your exhale.

So that's the most basic way.

Physiological size, two inhales followed by a full exhale to lungs empty.

These are core physiological mechanisms known to activate the vagus and lead to calming.

But I look at the Vegas as kind of including both an accelerator of sorts,

accelerator-based pathways in terms of arousal and breaks,

and probably our basal level of vagal activation reflects sort of the RPM of our system,

how much are we are very calm, are we humming at a higher level of activity.

Such an interesting path.

area of the nervous system.

And don't really understand yet.

Even the major branches and pathways are just now finally beginning to be understood.

We're on virgin beaches.

Yes, right now that I hear you bringing up the humming,

for instance, there is a branch of the vegas that innervates the ear, the inner ear, you know?

And that's why it is believed.

And I think there is a little bit of evidence out there

that how it is certain music at a certain frequency will calm you down because it is immediately left.

brings the...

it to make the bagels vibrate at a certain frequency.

Yeah, and humming has been linked to vasodilation, which is associated with a calming effect,

whereas activation of the sympathetic arm or the autonomic nervous system or the kind of...

sometimes is referred to as fight or flight, but it's involved in other things.

And if you think about it, like in several religious practices, there is the humming, right?

There is the singing, there is the sound, the sound plays a big role in running.

There is a certain frequency that makes you run, makes comes you more and makes you run better.

Is that right?

Yeah.

There is some evidence that Lisa, I'm they prefer a certain type of frequency for the running, right?

So a certain pace of running or breathing, and they sound.

Specifically the sound.

The sound of their feet.

No, the sound of the music.

Like if you play certain music, right?

And probably the sound of their feet too, right?

Like it's just that it has not been explored, right?

It's fascinating.

And know,

so much of what I think about when I think about the nervous system is the fine grain processing of,

you know, of color or light or what but when it comes to our feelings of well-being, our levels of arousal, sleep, etc.

It's the rather I don't want to call them crude because they're really sophisticated.

They to be sophisticated but these kind of macroscopic signals like light coming in in the morning has these,

you know, long wavelength and short wavelength contrast.

That's what tells our That's right.

It's the orange, red, blue contrast, even if there's cloud cover, it's the difference between those two different qualities of light that says it's morning.

And when the sun is overhead, you don't see that yellow, blue or orange, blue, red, blue contrast.

But you see it again at sunset and it informs.

It sounds like the combination of specific chemicals in the gut tell us this is good.

Pursue more of this and maybe even the place where you found it is a good place,

as opposed and in the opposite is probably also true.

Yes.

Like that's an entire new domain of the digestive, the sensory system in the digestive tract that we haven't even been to articulate yet.

memory.

How do we remember like what was that first meal?

Like the Ratatouille movie from when we were children, right?

Like was very different.

Like I still remember like some of the very simple humble meals that my mother would make, but it's just priceless for me, right?

Whenever I go home, it's like, without asking, sometimes my mother will prepare those for me.

And like, it just brings you back when you were that age, right?

Yeah, the memory system is tightly linked to taste and smell.

There's no question about it.

And then, like, how it is that they got triggers that those sensations or farther reinforces those sensations.

We even begin to articulate.

And I said articulate, because we don't even have the language to refer to these things.

You know, that's why at the very beginning, we were talking in our conversations about the axis.

You know, and that we don't say like the nose brain and the nose brain axis, right?

Like just went for what we had at that time.

And I do think that the language we continue to evolve for us to be able to articulate more precisely more richly more elegant more,

you know, in so many different ways.

How it is that the organs communicate with each other to make us who we are.

And there, in one of our papers, we quoted these beautiful passages from the book, Memories of a Stomach.

It was greeting in 1853, by a French person, by what it says in the first page.

by the Minister of Interior, because all of those who eat may read or something like that.

And then on page 21 it goes to describe the dialogue between the gut and the brain.

And it says like that how it is that the gut communicates to the brain with the rapidity

through these two sets of electrical wires that communicate the arrivals of the day

with the precision and rapidity to the brain is so the brain will make its own feelings and impressions.

And then he said that when he's talking from the perspective of the stomach,

he says like when I grew more rose,

like meaning I'm not working in the Then the brain also grew irritable and petulant, you I agree.

It's so interesting to look at human experience from the directionality of gut to brain rather than brain to gut.

That's right.

And, you know, as I...

do from time to time, you know, pay attention to what's happening in the landscape of wellness and mental health and physical health.

A lot of what you see out there in terms of,

you know,

highly educated people who have thought very deeply about how to navigate decision-making

in lots of different domains of life and to do it in a way that really honors our own individual preferences and needs.

People will like Martha Beck.

I don't know if you've heard of her,

but she exists in the,

she has tripled the greed from Harvard,

but has talked a lot about learning to sense one's way into and decisions, through intuition that is more of the body.

and is more of a particular brain circuits than our analytic,

like, you know, pros and cons lists, you know, because pros and cons lists and obviously important metrics like objective

metrics like,

oh, is this the right salary, the right location, the right, you know, you know, all the, all the things that matter for decision making.

And we're trained in that in,

in school,

in, in, many areas of the world as well, of course, and that's critical, but that

there's this other training,

there's this other learning of self that can be extremely useful and it almost always comes back to body first,

then to cognition and decision-making,

and I feel like modern humans are trying to learn how to run the analysis of life decision-making through this,

I guess, more ancient axis.

So, again, the intelligence of these, what used to be called more primitive systems.

But don't think they're primitive at all,

and talking with you today,

it's clear to me that these are highly sophisticated systems, just as sophisticated as any forebrain pathway involved in analyzing, say, like or something.

And that's why I like to highlight the example of having a nice meal and having a nice conversation at the same time.

If you go to a nice restaurant,

and have a nice meal while you're having a nice conversation,

and if you pay attention to it,

it, then it brings humility to your body to know how much your body is doing for you to

be able to just express a tiny little bit of and having some sort of highly intellectual

sophisticated conversation while you're able to put in the precise amount of letters inside

of your mouth and chew it in the right way and adjust it with a little bit of water and

maybe a bit of wine and understand what is cleansing your palate and putting down the napkin and so on and so forth.

Or without going to the restaurant every time that you feel like going to it, right?

There is an entire sophistication of the body just to have something like a simple as a catch up conversation, you know.

Do you think that our ability to sense into gut sensing more?

to really hear and respond to the signals from the gut is something that we can learn even as adults simply by paying more attention.

Yes, and I think that here's the concept that usually, you know, that when we talk about

topics like meditation,

you know,

is that self-care,

and that self-care is listening to your own body,

right, how it is that the body is feeling, like, I don't know, you know, I grew up and my mother will tell me, like, or, you know, family will tell

me.

tell you,

if you feel like going to the restroom and to pee for a biobrake,

don't hold it for too long because it may be bad, right?

Like, and I think that just learning that part of like listening to, to the body is an essential aspect.

It's just that we're not constantly doing it over learning about how we are moving our career forward.

Yeah, so much of what we're taught in order to,

high achieving and forward moving in life in modern culture is about learning to override the signals from the body.

But it seems that learning to listen to the signals from the body is key to being a healthy human being.

Yes and I here I have an example a years ago I used to run quite a bit and I remember that after I had ran a marathon,

on.

I took a break for like a few weeks and then I got back on the on the trail and I began running and I was like,

you know, I don't need to warm up for three or four weeks up to like get back into speed, right?

And I remember that I started to feel like that my right,

the soul of my right food was a bit like bothering me like that.

imperceptible.

And I was like, no, you just have to keep going.

My wife Elaine told me like, you know, you should pay attention, take a break, you know, and I just kept running.

And I remember specifically that one time I went to run.

I said, like, I can put in 80 miles, I think that I was running at like seven minutes, 715.

a mile or something like that.

And I began running it.

And a mile,

I feeling pumped at two miles,

three miles, I like, and then I usually will go and do four miles and then turn around and come back.

I got a mile four and I fell quick.

and I could not walk anymore.

There was a hair fracture that is almost imperceptible in the next ray,

but whether you cannot move your food anymore,

I had to limp for four miles all the way back to the car, because I didn't even have my phone.

And I never forgot that for the next time you get a pay attention to your body,

your body is simply telling you, something is a little bit off, just don't keep pushing it.

And I specifically remember because I kept running and I had to literally limp all the way back to the car.

Well Diego.

I must say that among the many things that you've shared with us today and taught us about the gut and its ability to influence the brain

And the incredible things that are happening at the level of biology and physiology of the gut

Chief among them is the message that we should all pay more attention to our sensing at the level of our gut.

And we hear so much about the gut microbiome such that fortunately I think most people are starting to appreciate

that the gut microbiome is vital for all aspects of health and that there are things that we

can do to feed that microbiome fiber intake, fermented food intake and so forth.

clearly based on what you've told us today,

that even just paying a little bit more attention to what our gut is telling us at the level of feeling good,

feeling less good, because the signs and signals are subtle, I realize, can really help us make better decisions, help us.

Decide not just what foods to eat or not eat,

how much to eat or not eat,

but also how to navigate higher order decisions,

if you will, about who to spend time with, what to do, what not to do, moving along the decision tree of life.

Along those lines, I want to thank you for making the decision to come here today.

I certainly am happy that we decided to do it.

It's something that's been a long time coming.

I really see you as one of the true pioneers in this area of trying to dissect the understanding of the gut brain axis,

heal the brain through the gut, understand and modulate our emotions at the level of gut sensing.

other researchers in this area,

I refer to you as a pioneer because you really undergone this incredible trajectory from the Amazon,

through nutrition science, into neuroscience, and now we're getting a little bit into psychological science, and I'm excited for what comes next.

I only ask one thing,

which is that as you make these discoveries,

that you come back and talk to us about them so that we can learn more about your incredible work.

So, Andrew, I want to say a few things.

The first thing is that I feel deeply honored by your invitation, and thank you so much for the opportunity.

I am just simply a...

of the people that work with me and work with us.

You I'm just an ambassador and they get the majority of the credit for their dedication to help us understand a little bit more.

of the body and how it is helped us to navigate the world that we live in.

So I want to thank you for the opportunity.

I want to thank the people that have made this possible.

Also like the people that are along the way or the institutions that are along the way have a fund these,

and they were,

you know,

my home institution,

I took,

I'm deeply grateful because my career has developed there,

and some of my mentors, Roger Little, Andrew Muir, and the people that have helped me along the way.

And they find

I think you and your team and congratulate you for the work that you do and that you have

created this window for us to come and share with the public some of the, a little bit of the work that we do.

perhaps some of that is obviously is based on evidence.

Some portion of that is thinking about the future,

but I do think that through maintaining the dialogue with the public that we can continue to understand the world that we live in,

and for that I have to thank you for having creating this platform.

Well, it's a labor of love and I'm honored to be able to do it and in no small part because

I get to sit down and have beautiful, intimate conversations about biology and life with you.

So, thank you so much.

Thank you for joining me for today's discussion about sensing with the gut and the gut brain axis with Dr.

Diego To learn more about Dr.

Borges' research and also to see a link to his fabulous podcast called The Gastronauts, please see the show note captions.

If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel.

That's a terrific zero cost way to support us.

In addition, please follow the podcast on both Spotify and Apple and on both Spotify and Apple.

up to a five star review.

I am Huberman Lab on all social media platforms, so that's Instagram X formerly known as Twitter, LinkedIn, Threads, and Facebook.

And all of those platforms,

I cover science and science-based tools,

some of which overlaps with the content of the Huberman Lab podcast,

but much of which is distinct from the content of the Huberman Lab podcast.

Again, that's Huberman Lab on all social media channels.

If you're not already following our newsletter,

the neural network newsletter is the Huberman Lab zero cost monthly newsletter that includes podcast summaries as well as protocols in

the form of one to three page PDFs.

The protocols cover topics such as how to improve and even optimize your sleep, how to regulate dopamine, deliberate cold exposure, deliberate heat exposure.

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Thank you.

once again for joining me for today's discussion with Dr.

Diego And but certainly not least, thank you for your interest in science.

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