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

welcome to the huberman Lab podcast

where we discuss science and

science-based tools for everyday

[Music]

life I'm Andrew huberman and I'm a

professor of neurobiology and

Opthalmology at Stanford School of

Medicine my guest today is Dr Diego

borquez Dr Diego borquez is a professor

of medicine and neurobiology at Duke

University he did his training in

gastrointestinal physiology and

nutrition and later neuroscience and by

combining that unique training and EXP

expertise he is considered a Pioneer and

leader in so-called gut sensing or the

gut brain axis now when most people hear

the words gut brain axis they

immediately think of the so-called

microbiome which is extremely important

but that is not the topic of Dr borquez

expertise Dr borz focuses on the actual

sensing that occurs within one's gut

just as one would sense light with their

eyes or sound waves with their ears for

hearing our gut contains receptors that

respond to specific components of food

including amino acids fats sugars and

other aspects of food including

temperature acidity and other

micronutrients that are contained in

food that give our gut the clear picture

of what is happening at the level of the

types and qualities of food that we

ingest and then communicate that below

our conscious detection to our brain in

order to drive specific patterns of

thinking emotion and behavior and of

course everybody has heard of our

so-called gut sense or our ability to

believe or feel certain things based on

perceptions that are below or somehow

different from conventional language

today Dr borquez teaches us about all

aspects of gut sensing how it occurs at

the level of specific neurons and neural

circuits how the brain responds to that

how specific foods and components of

food impact not just our feeling of

digestion or feeling good or bad about

what we ate but indeed how we feel

overall how safe we feel how excited we

feel whether or not we feel depressed or

sad angry or happy today's discussion I

promise you is unique among all

discussions of neuroscience at least

that I've heard previously in that it

combines two seemingly disparate Fields

nutrition and Neuroscience indeed

today's discussion gets into how

different foods and food combinations

impact how we feel and what We crave and

what we tend to avoid we also get to

hear the absolutely extraordinary story

of Dr borz upbringing in the Amazon

jungle and how his knowledge and

intuition about plants has influenced

His science and how the incredible

science that his laboratory is doing

relates to all of us and our ability to

better tap into our gut sense before we

begin I'd like to emphasize that this

podcast is separate from my teaching and

research roles at Stanford it is however

part of my desire and effort to bring

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Dr Diego borz Dr Diego

borquez great to have you here thank you

for uh 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'll just want

to kick things off by asking you to

educate us explain you know what is this

gut brain axis that we hear about and

what's going on in our gut besides

digestion well uh Andrew thank you so

much for having me here uh thrilled to

be here I knew that since we met a few

years ago uh that we will have this

ongoing conversation and a great

conversation um the gut and the Brain

you know people call it an axis because

traditionally thought to be an IM

imaginary line that was connected

through hormones so since 1902 when uh

the first hormone secretion was uh a

reported by Bailey and Sterling uh

um it was known that uh when we eat then

hormones these molecules in the gut are

released and then they will enter the

bloodstream and then eventually will

have a cause in distant

organs uh and for the next 100 or so

years the the the the field focus on the

on the hormones and as a consequence

there was no direct line of

communication between the gut and the

Brain but as often I I say you don't you

don't say or we don't say the nose brain

axis right like or the eye brain axis

right uh and all of the organs are in

sync working in sync so H in the gut

there are also some sensory cells that

are able to detect the outside world

ER and then quickly communicate that

information to the brain and I say the

outside world because the gut is the

only organ that passes throughout our

body but it is still exposed to the

outside if you think about it uh if you

will swallow a marble it still has the

chance to get out um please don't do

that

anybody but uh but is still exposed to

the surface you're right I never thought

about the gut as the organ that is in

contact with the outside world unlike

our heart which is not in direct contact

with the outside world or our liver or

our pancreas but the gut is the gut is

uh and if you think about it it's just

separated by uh some compartments that

have all of these VVS you the epiglottis

the uh gastropa gel Junction the pylorus

The ilocal Junction the rectum so these

are the the sequences of valves of

Chambers with valves between them that

food passes through air passes through

and within each as I understand it there

are different functions related to

digestion but I think where you're

taking us is that there are different

modes of sensing what's coming through

and signaling to the brain and other

organs what's going on in the outside

world by what's sensed coming through

that passage is that correct that's

correct and uh if we think about it uh

um

the when we swallow something literally

we have to trust our gut perhaps that's

why we use this phrase trust your gut

right because after that there's not

much that you can do at least in uh

regular humans that you can do

consciously

to uh expel something that perhaps is

poisonous or toxic right um it is the

gut that has to make that distinction

and then usually accommodate things for

abortion or let them pass uh through

digestion and then ultimately they will

be secreted right so if you could

describe for us the architecture that is

the cells that respond to things in the

gut and where they send that information

and how they send that information what

what is this thing that we call Gut

sensing made up of what what's the parts

list so the parts uh list uh has been

evolving recently

and while some of the elements we have

known for for a while uh but in in

general what we're talking about because

is an external surface it is lined by a

single layer of cells that are called

epithelial cells and essentially these

cells are exposed to the outside world

but they also are like attached in like

a little membrane and they are the ones

that interface with the inside of the

body so in the stomach we have an try

toi a epithelium for instance that is uh

thicker so it can survive digestion

chemicals and other things like harsh

environment and in the intestine we have

a little bit more of a um uh more

delicate uh epithelia layer and within

this epithelia layer there are several

different cell types and one of those is

the so-called enteroendocrine cell to

put it in more simple terms is a gut

endocrine cell or a gut cell that

releases hormones the term was coined in

1938 by a German uh physician uh his

name was Frederick

fer and at that time it was a major

advancement in our understanding of

physiology because he came up with the

idea that the organs were not only

communicating to organs in fact there

were cells within the organs that were

communicating to other organs through

the release of some of these endocrine

factors these neuromodulators or these

neuropep that we know as hormones and uh

so he named uh the diffus endocrine

system of the gut and then he came up

with his word enteroendocrine cell and

these cells are dispar at a ratio of

roughly speaking like 1 to 1,000

epithelial uh cells throughout the

digestive

tract and we thought for the longest

time that these cells were not

connecting directly to the nervous

system that they will release these

neuromodulators and the neuromodulators

through diffusion will act on receptors

into some of the nerve Terminals and

that is true that is a very well

established uh system uh but in 2015 we

made an observation that some of these

cells anywhere from 1/3 to 2/3 of these

cells it depends on like the type of a

systems that you use to identify they

were contacting directly the nervous

system and that brought up a a a new

dimension of how it is that the gut

could be could be communicating to the

brain because as you know in the brain

the synapses are the ones that are most

predominant however there there is a lot

of neurom modulation from endocrine uh

functions in the brain too so in the gut

uh this was not well described there had

been historically uh a few examples that

these cells may be making synaptic

contacts but they had not been

studied and perhaps one of the main

reasons why they hadn't being studied is

because the the tools were not there and

if you recall in in the um in 1990s uh

with the advancement of green

fluorescence protein as uh one of the

main uh molecules to tag cells now all

of a sudden there was a revolution in

biology because you could identify the

cells you can take them out you can do a

a transcriptomic analysis to see what

genes they express uh you could

co-culture them you can modify their

genome and then you can start to

interrogate what is their contribution

to the entire body I'll just interrupt

you for a second just to make sure that

I never else is on board so if I

understand

correctly it's long been known that

there are cells that are in these layers

of the gut in the intestine and it's

long been appreciated that as food

passes through these cells somehow can

sense the chemical constituents of the

of the food as it gets broken down and

then release hormones into the

bloodstream that could influence the

brain those hormones could travel and

influence things far away in fact um for

those that don't know endocrine

generally mean signaling at a distance

between cells so between gut and brain

or gut and liver it can also mean local

effects so uh hormones endocrine effects

can also be local

but if I also understand you correctly

it was only about 15 years ago when you

mentioned green fluorescent protein we

should probably just tell the Tale in a

few sentences this is an amazing story

in biology where if you've ever seen

fluorescing

jellyfish that's because they express a

gene for so called Green fluorescent

protein and biologists have hijacked

that Gene sequence and put it into mice

and now actually other organisms as well

which allows you to see individual cells

and cell types so these cells release

hormones the hormones influence the

brain and other organs and now I think

you're going to tell us that they also

are able to make direct communication

lines with other organs as well

correct uh so maybe here is feeling how

it is that I I got into a starting the

system and uh as you know between the

90s and the early 2000s there was an

explosion in tools to study uh the brain

and neural circuitry and the connection

of neurons and each one of the neurons

because up until the 1980s um the the

tools were were limited

electrophysiology you know

Behavior Uh but then not only we had a

green fluorescence protein we we had

optogenetics

we had uh a rabies modified to be able

to

trace how it is the the neurons connect

at one synapse which was a it was a

dream I think that in fact that was the

dream of Francis Creek when he was at

the Suk he he talked about that having

the way to control for those who don't

know Crick one uh was a co-recipient to

the Nobel Prize for the discovery of the

structured DNA but then later in his

career developed an obsession for

neuroscience and yeah he daydreamed out

loud about having tools to visualize

individual Connections in the nervous

system and as uh Diego is pointing out

scientists have hijacked the rabies

virus which hops between neurons labeled

the rabies virus with Things That Glow

fluorescent and in doing so we now

understand a lot about what Crick

dreamed for which was the ability to see

different specific Connections in the

nervous system yes uh so then you could

isolate the cells and then you could do

sequencing technology to see like what

are the genes that the cells are

expressing and then you can start to

understand the makeup of the cells uh in

2009 uh h cers a scientist u in the

Netherlands uh did a beautiful

experiment like he he discovered these

factors that will trigger a receptor of

the stem cells in the intestinal

epithelium and will form literally a

mini gut in a in a dish you know these

cells will be all lined up and then they

will have alumin and I remember like

seeing some of these papers coming out

uh when I was a PhD student and and I

was already studying the gut so it was

inspiring to see like all of the things

that all of a sudden you could do right

so when I began studying the cells um

immediately by isolating the cells and

simply observing the cells in the native

tissue of these um m

models it quickly became evident that

some of the cells had a very peculiar

Anatomy uh some of them had these very

prominent arms at the base like like

literally like um in the 16 Chapel uh

Adam reaching out to to God right like

with a hand uh the cells will have that

type of anatomical H features and even

ending with a little hand at the end of

that arm uh and obviously I I

immediately thought like why would a

cell that it is supposed to react to

food and release hormones into the

bloodstream or just in the vicinity will

invest so much energy into developing an

arm right so then I started to look well

perhaps it is because it's providing a

bridge directly into the vasculature

into the vessels to put the the hormones

into the bloodstream right uh grown you

know like a I couldn't find that that

direct connection uh so then I started

to study perhaps they were associated

with nervous system and that's how uh we

made some of the first observations that

some of them uh with the arm uh or

without the arm they will have a more

intimate

relationship with nerve

fibers and that of course open up um a

bunch of new

questions and but the first things that

the first thing that we had to do it was

to come up with a name for this foot and

it kind of became organic and I want to

highlight this because I think that as

we go through the discovery uh

trajectory we don't realize the need to

also engineer

language how we go about language is we

start to attach a words that we already

knew and we start to put them together

to describe something that new that

we're observing right and I say this

because at the very beginning uh with my

mentor we will start to call these

little feet first we call them axon

which is like uh the 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 a baby

axon but then we called them also like

Pudo po because it was like a pot but it

was

Pudo uh and at some point we and it was

coming from like some cells in the in

the kidneys that they are called uh po

podia or something like that so it was

axon like pseudo like basal process to

describe that it was on the base so at

some point it became so long that we

couldn't fit it in an abstract right so

a bit of a mouthful so we began thinking

about it and then eventually I came up

with a term I thought like ah

neurot um and I remember pitching it to

my mentor and I said like let me let me

think about the weekend and then on the

on a Monday he came in and he said like

you know it has a ring to it I think

that we should use it but but

essentially the the the thought was that

if these cells are contacting then

perhaps they are passing information

directly onto the nervous system and

that is very different than just

spewing a

neuromodulators in the vicinity and

hoping that some of those catch the

nervous system right and like I said

while that is still exist and I think

that is just like matter of space and

time like they they modulate these

terminals in a different space and time

the hormones but the transmission uh the

neurotransmission is directly and more

precise in space and time could I just

um interrupt for a moment please so

hormone signaling endocrine signaling

generally is slower than the forms of

communication directly between neurons

right um could be on the order of

seconds sure but typically on the orders

of minutes or hours uh whereas neural

communication on the order of

milliseconds correct so if I understand

correctly these what you decide to

called neurop pod cells and thank you

for shortening the name um from the

other description um line the gut are we

talking about everything from esophagus

down to the stomach to the intestine or

is it just at the level of the stomach

and intestine where where do they this

is uh this is where the conversation

becomes expansive because uh these

neopods or cins of these neurop pods so

these neurop pods are simply a

specialized neuro epithelial cells

meaning that are electrically excitable

that they can discharge electricity but

they are this type of cells are in every

single epithelial cell epithelial layer

of the body because that's how the body

creates a representation of the world

through sensor cells that are equipped

to detect the outside world meaning that

they can be exposed to fluctuations in

temperature fluctuations in PH

fluctuations in concentrations and then

they quickly can generate a chemo

electrical coat that they pass it onto

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

neuroepithelial cells that they are even

in um tasting so to speak the uh the

seru spinal fluid inside of the spinal

cord and the ventricles they are inside

of the the inner ears The Taste uh The

Taste SPS so it is and in fact there's a

beautiful book from the 70s uh from some

Japanese scientists uh fuet Canon

Kobayashi who uh called the cells Paran

neurons and their whole concept is that

there was not such a discrete

distinction between an entire a neuron

that lives inside of the brain or the

central nervous system and a A

neuroepithelial or a neuroendocrine cell

that leaves exposed to the outside

simply that there is a continuum of

adaptation so the the organism can bring

the information from outside inside into

the uh body to be able to process it and

then process it and then guide Behavior

So based on the way you describe it we

have these neurop pod cells that line

our gut and we also have these similar

cell types in the other organs of the

body and these cells are responding to

the chemical constituents of what we eat

as the food is broken down

also to the temperature of the

environment to the

pH the that is how relatively basic or

acidic something is that we ate and

presumably to other features in our

environment as well and all of that

information is activating these cells to

some degree or another and then we're

releasing hormones into our body as a

consequence but also there's a direct

line to the brain and we're not

necessarily aware of all of this

happening right I mean until you

describe it I think most of us are have

not been aware that this is happening

and we probably shouldn't be aware you

know like as I often say like um if you

and I are having a conversation we

probably shouldn't be aware of the

macras and the spleen that is chasing

this bacterium that got inside of the

lettuce that we swallowed in 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 is

the okay so you discovered these

neuropodial to selectively label them

what did that reveal about their

connectivity with you're referring to it

as the nervous system which I love

because a resounding theme on this

podcast as I always say you know brain

and spinal cord and all the connections

to the body and back again is the

nervous system but what what did you

discover in terms of the connections

with the brain proper here is where the

tools started to make a a big difference

you know all of the sudden you could see

the resolution of a receptor inside of a

cell using certain type of microscopes

right so I remember that one of the

first questions that I will always get

drill on you know how these uh laugh

meetings can get intense right like when

I will bring data and showing just very

simple um imunohistochemistry meaning

labeling to see how the cells were

interacting with uh the nervous

system um as and I will show some of the

images then uh the other scientists will

say well you know yeah those are nice

images but remember that contact does

not mean connection you know and I went

thinking about that like at the very

beginning I thought that it was silly

semantics you know um but I I

specifically remember that there was one

time I was running and I was thinking

like how do you demonstrate connection

between two cells and then I thought

that since we had the ability to

identify the cells by fluorescence we

could isolate them based on their

fluorescence and what will happen if we

put them in front of a sensory neuron

and then just record them inside of a

microscope right over

time and I thought maybe they will get

close to each other and then we can go

and do some more labeling and show that

they are H contacting or connecting but

much to our surprise we actually saw

that in real time they when you isolate

them from the mouth and you put them in

a dish they both look like these round

circles but after a few hours not only

they get close to each other but they

recapitulate the circuitry in the dish

literally they form like two brains in a

dish right like it's the gut and the

Brain in a dish amazing uh yeah and that

that was an eye opener you know I still

remember it was somewhere I think it was

like June 27 2012 when I saw that

experiment because um it opened my my

eyes to so many different things one was

that this cells are not

static because since we have been seeing

them for decades just in as slices or

fixed tissue and we have lost the notion

that this thing is constantly moving

right the cells are actually moving the

cells are actually moving so these cells

line the gut meaning they're along the

walls of the gut an intestine yeah the

intestine they reach a hand into the gut

to sense whatever chemicals are there

yeah they have Little Celia little hair

or micr that is literally like little

hair that is exposed to the Lumen M you

know so the Lumen folks is the the

cavity the empty cavity of the gut not

empty but you know the the the internal

part and so they're sensing the

chemicals there and you're saying they

can move okay and they're sending a

process by the way folks anytime you

don't know whether or not something is a

dendrite or an axon just call it a

process you you'll get it right uh a

process up to the brain underneath that

will connect to the nervous system I see

so through a series of of of stations

yeah okay um amazing so what we're

talking about here is Diego's discovery

of a pathway from the gut to the brain

that essentially allows sensing of

what's happening in the gut to inform

feelings decision correct yeah so that

that was uh the first experiment like

showing H in addition right the next

experiment was well does it happen in

the in the mouse and then through a

series of I have a friend neuroscientist

that she calls this Ravis gymnastics

because you have to put in some genes

and make things work then we

demonstrated that these uh

cells that the virus will be capable of

infecting these cells specifically

instead of infecting the other

epithelial cells it will infect these

new epithelial cells because ravies

likes

neurons and then it will jump from that

cell into a nerve

fiber and these ravies can only jump one

connection right and what it was uh

surprising is that the fluoresence from

that rabies will show up in the brain

stem and in the bodies of the cells that

are in the noos ganglia which is this

cluster where the cell bodies of the um

neurons of the begos nerve are located

right underneath the the

neck meaning that there was just one

stop between the surface of the

intestine

and the brain stem the two cells were

connecting that

um 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 right like we're not

necessarily aware of it although uh I've

read that there are some instances in

which people become more aware of it

either in uh a ag

typical uh fashion or with meditation

and other things that people can become

aware yes people definitely can become

more aware of their so-called

interoception what's going on at the

level of their heartbeat frequency or

their gut sensing if they spend time on

it some people as you mentioned develop

an almost pathologic sense of

interception 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 um some people with a lot

of anxiety for instance are so aware of

their heartbeat that it becomes um

disruptive and distracting to them so

it's not always the case that it's

better to become more aware of your

internal processing sometimes it can be

um dilus other times it can be good for

us um 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 uh 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 uh a word

that has such salience the rabies virus

which exists in nature um is amazing

because it's um 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 they

become more

aggressive they bite a um a Target

animal the virus gets in it's picked up

by the nerve Terminals and is carried

back from one ner cell to the next

across synaptic connections right

synapses the G little gaps between

neurons and what Dr Diego Boris has been

telling us is that scientists have

engineered the rabies virus so that it

only jumps one station and then stops

you can do this by modifying the coat

protein there's a bunch of fun virology

that can be done uh to do that but what

I find amazing about rabies virus and

there's a great book by the way called

rabid which is a a essentially a history

of the of the study of rabies um is that

once it travels from the S of the bite

up to the brain what does it do it

changes the brain to make the now

infected animal or person more

aggressive so that then they go bite

somebody else um 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 number of

different ways but one way is to just

make that animal more aggressive so it

goes and bites things yeah make wild

make the animal work for you right make

the animal work for you right it's it's

it's almost exploitive right it exploits

certain circuit in the nervous system

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so you uh identified these you said

described but you I'll say discovered

because um that's what happened you

discover these these cells you label

their connections you see that there's

just two Stations between these cells or

one station really between these cells

and the brain and so now these cells can

sense chemicals in the gut that are the

consequence of the breakdown of food and

send that information directly to the

brain what does the brain do with that

information all so here comes uh the key

experiment and this was building

obviously on the work of other

scientists that had already described

that the gut had some uh receptors for

uh sugars for specifically for glucose

for other nutrients around this area in

the early 2000s when we were starting to

be able to identify some of these cells

then uh it quickly became uh obvious

that uh these cells these

enteroendocrine cells throughout the

lining of the stomach intestine colon

they had multiple receptors for multiple

nutrients you know like we have the

macronutrients for instance sugars fats

proteins but within them we have you

know a repertoire of molecules you know

multiple uh lipids multiple types of

sugars and so on and so forth and these

cells depending on their location they

will Express a different type of

receptors or a combination of those

receptors and I said depending on the

location because when we're eating let's

say an apple you know the apple is going

to be partially undigested by the time

that it enters intestine but by the time

that it gets to the the colon most of

those nutrients have being absorbed and

perhaps only fibers are surviving to

feed off most of the microbes that live

in the colon right so the gut has

evolved to mirror and to become a velro

to the molecules that will be in that in

that specific space so it will detect so

um it will detect sugars more in the

proximal intestine but fibers or uh

fermented by products more in the distal

intestine or in the colon like shin

fatty acids beate prop propionate um and

so on and so forth you know what other

kinds of nutrients do these neurop pod

cells detect from food so you mentioned

sugars you mentioned ferment

fermentation so um presumably short and

longchain fatty acids yes the short

answer is that uh I think that in due

time we are going to realize that they

detect just about every single thing

that we put on our mouths every day you

know uh that they have some either an a

specific receptor that is dedicated to

it or a combination of receptors to be

able to detect um some of these

compounds and not only the chemical

compounds but also an area that I think

that is going to be fascinating in the

future is the mechanical distension plus

uh the the adjustment in temperature

as the Kim starts to flow

from the mouth into the colon like for

instance I I I heard this from a

bioengineer not long ago that was

engineering a artificial gut on a

stomach and he uh shared with me um a

piece of information that I was not

aware of that uh the esophagus has to

adjust the temperature of the food very

rapidly within seconds into

physiological temperature of the inside

of the the body like so we are having

hot coffee within couple of seconds it

has to be at the physiological

temperature of the body by the time that

it gets into the stomach right and all

of that happens in very rapidly amazing

suff right so if I understand correctly

these neurop pod 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 mean

I've heard it said and I believe there's

a a researcher down in Australia who's

been very bullish on the theory that we

are not exclusively but we are

predominantly amino acid foraging

machines because we need amino acids for

all sorts of important biological

processes um and these cells are

essentially evaluating how how much

sugar how much Lucine how much um uh

short chain fatty acid how much um you

know essential fatty acids of different

kinds and then making changes to the gut

itself but then presumably signaling

that information elsewhere in in the

body so um here I'm going to give you a

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 ingested meaning the

chemistry of the molecule let's say it's

glucose it has to make sense a little

bit of The Taste is it sweet right is it

bitter then it has to take into account

how much of the molecule is absorbed

inside of the cell right so that's the

second layer of integration then once

the cell has eaten that molecule so to

speak then that molecule will be

digested inside of the cell to release

ATP or some other uh compound ATP is for

energy for instance that has also have

to be taken into account for instance in

the in the in glucose glucose activates

the tas1 R3 which is a sweet taste

receptor then the glucose is absorbed by

some of the sodium glucose Transporters

which are active Transporters and these

Transporters uh depolarize the cell and

then once glucose gets inside of the

cell glucose enters the TCA cycle is

catabolized and then produces ATP and

the ATP further activates another uh

voltage gated Channel

further depolarizing the cell and then

the cell releases in turn a transmitter

for instance glutamate that very rapidly

tells the vus nerve within milliseconds

you know I got sugar uh and it tells it

in two phases because that glutamate

will activate two different type of

receptors ionotropic which are very fast

and metabotropic which are a little bit

more you know more delayed uh but then

the metabolism of that glucose that

produces the ATP and farther polarizes

the cell we believe that um it will

cause the release of the hormone of the

neuropeptide so then the neuropeptide

comes on top of that and gives you that

full experience of what it means to uh

consume sugar right um so that happens

at the level of one cell and at the

level of one molecule so imagine like

all of the computation that the gut has

to be making for each one of the

molecules throughout the digestive

tract so if I stand back from the

picture um what I get is there are very

interesting cell types that line our gut

that are

evaluating all of the not just

macronutrients proteins fats and

carbohydrates but micronutrients within

the food we eat as well as some of the

other qualitative features temperature

for instance maybe even quality of the

amino acids or the sugars 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 um someone you knew who changed

their gut

radically and that changed their entire

perceptual experience of food including

certain Cravings would you mind sharing

that story yes uh thank you for uh

bringing that story Andrew that story is

very personal to me I of 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 know like now I uh we have

known each other but now we meet in

person and we are knowing other people

right and I remember that when I was uh

starting my PhD in nutrition at North

Carolina State University I was uh so I

didn't grow up in the United States I uh

grew up in Ecuador and uh I was invited

to my first Thanksgiving celebration so

I sat at dinner and you know as we began

chatting with uh the people that were

next to each other uh all of a sudden I

was uh enthrall in this conversation of

a woman telling me this story about her

experience with gastric bipass surgery

for treating obesity so gastric bass

surgery uh was begun to be um developed

by surgeons uh in the 60s and by the 90s

it had become a mainstream uh type of

surgery for the treatment of uh chronic

obesity so she told me that there were

primarily three things that happened she

said well within uh six months of the

surgery I had lost about 40% of body

weight you know she said like I was

about 300 pounds you do the math you

know so it was a it was a significant

amount significant amount she said

within one week of the surgery my

diabetes was gone she said I did not

need more insulin shots so I had the

same reaction that that you're having I

was like that you know I don't know much

about diabetes but I know that is is a

major health uh burden

right but the thing that really caught

my eye was when she said but since

you're studying nutrition I want you to

answer this to me she said why is it

that before the surgery I could not even

look at sunic Side Up XG she said uh

just looking at the Yoke will make me

quizy you know but after the surgery no

not only I can eat sonide up eggs I

actually have a craving for the yolk she

said every time we go on Saturday to a

restaurant for breakfast I will take the

toast and will actually clean the plate

uh of the Yol so how is it that rewiring

the the gut uh alter my perception of uh

of flavor alter my my cravings and my

mind to to get the the Yol she said and

even inverted her sense of what was

aversive versus repetitive and and I

guess for those of us that don't know

meaning me um I understand the gastric

bypass surgery involves the removal of a

portion of the of the gut um how much

gut tissue do they actually take is it

centimeters inches I mean the guts a

long distance so what what what do they

do for gastri in in in simple terms the

most

um the classic surgery is called uh ruin

y gastric bypass surgery which involves

a a reduction of the stomach and short

cutting the uh connection of the stomach

to the intestine so you will cut you

know 1/3 which will be the dadum uh one

third of that will be uh cut and then

that portion will be reconnected to the

stomach meaning that you're short

circuiting the the gut and the whole

idea was at the very beginning was like

well if we reduce the surface that is

exposed to food then we can reduce body

weight by the simp L um reduction of

surface that is exposed to the food that

is absorbed right and uh what it became

very clear is that well before the body

weight uh changes got taken place uh

there was already like some dramatic

changes in physiology like like the

hormones the neuropeptides that we

release from uh the intestine in

response to nutrients you know will

change very rapidly then as I mentioned

the food choices will change diabetes

will be resolved um so then it became

obvious that it was not necessarily just

the the uh reduction in the surface of

of the gut so that's one of the main uh

surgeries the other one um as I

understand is vertical isaf gastrectomy

and this vertical s gastrectomy is

simply a a reduction in the size of the

stomach so is now the stomach is very

tiny and the idea is that will

accumulate uh less it could hold less

food and then the food will go very

rapid rapidly into the intestine and

what is very is becoming very obvious is

that there is a rapid change in the

sensory function of the gastrointestinal

tract so the gut seems to rapidly shift

perhaps become more so to speak in

general terms more sensitive to the

presence of nutrients right interesting

so this woman that you met at

Thanksgiving had G gastric bypass

surgery and presumably I think it's fair

to assume a good number of these neurop

hot 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 uh you know

Sunnyside egg yolks was somehow related

to a shift in appetite or something else

or is it merely a a a um a qualitative

albeit a dramatic qualitative sh in in

what she craved so two uh contextual

pieces of information uh so I remember

leaving that dinner and I was like wow

this is Major you know like I'm sure

that people have green about this or

don't research um and I realized that it

was very little was known even

gastroenterologists knew very little

about this the first clinical report

that um the alteration in food choices

was common in these patients uh came out

I believe in

2011 uh and then later on scientist

replicated that even in rats or in mice

uh we have done it in the laboratory and

consistently they they change their food

preferences their their um food choices

so er in in recent years we have been we

have been uh studying that that system

um and I will tell you that in

2022 this is another important

contextual piece that we have gotten

have not gotten to it so after we

uh 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 the

responses of the organism and that took

a little bit of a a technical hdle and

here is where optogenetics uh comes in

yeah please um explain for people what

optogenetics is in at least at a top

Contour level yeah so optogenetics uh

205

uh Professor Carl daero Ed boen and

other scientists had been able to make

this this dream of an experiment which

was uh isolate the the genes that encode

for these opsins that are sensitive to

specific wavelengths of light and put

them into neurons and now by turning

that light they could make the neuron

activate and then ultimately then later

on they went on to describe that that

could be used to control a specific

cells that are regulating behavior and

then by that Define what cells are

orchestrating certain type of behaviors

like movement food intake thirst anxiety

so on and so forth so in 2014 we we

began H trying to adapt that technology

to the

gut very quickly

we realized that the way that was that

light was brought into the brain was

through a fiber optic cable that was

rigid and uh and in the brain you know

it it helps that it's actually rigid but

in the gut it doesn't help because the

gut is constantly moving and so on and

so forth so it's not compatible for

running those experiments and here's

where I usually say like you know we

really don't know what is going on

because some some forces like move

around us and in 2017 uh Professor

Paulina Nika from MIT came to give a

talk at Duke and uh she reached out to

me and literally she came and as we were

chatting she said like Diego I see that

you're you're working between uh in this

interface of the gut and the brain and I

have this fiber optic that is flexible

you know would you have any use for it

so with that H fiber optic that made a

big difference to study interrogate the

function of these cells to

behavior so when we were able to put

those opsins the light sensitive uh

proteins inside of these neurop pods and

now when we turn the light on to shut

off these cells very

rapidly we found something very

interesting so normally animals when you

give them the choice between a suer

which is the void of caloric value so

like a like a aspartame or or Stevia or

something y uh and you give them

sugar table sugar the animal invariably

will go to Sugar they prefer sugar they

prefer sugar you know uh if they have

never seen sugar it will take them a

little bit more time but regularly um by

the second day is within 90 seconds that

they detect what is sugar 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

that's correct and uh people have

described this um this phenomenon for a

while and in fact in 2007 There Was An

Elegant experiment done by Professor Ian

Deo at Duke University in which the uh

sweet taste receptors were or the The

Taste uh receptors were genetically

erased and the animals um were not

capable of distinguishing the sugar the

sweetener from the water but they could

still distinguish sugar from uh water

meaning that there was something else

that was detecting that that 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 correct 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 uh then uh Professor ton

clani he had been studying these uh

these behaviors and he went in so far to

suggest that perhaps the sodium glucose

Transporters are some of the ones that

are detecting the the sugar as it enters

the intestine and that's what is causing

the

behavior um so we began working on the

system and we we Wonder Could these

cells

be the ones that are guiding that

Behavior Uh and around the time that uh

we published this work uh Professor uh

Charles zuker at uh Colombia also

further uh Advanced that that area by uh

building on the on the previous work and

demonstrated that um there were a

population of neurons in the brain stem

that were integrating this information

from the gut uh and by that the gut and

the Brain were guiding this this

Behavior 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 you can see that in babies even

correct and as I usually say um I call

it instinctively because our mother

doesn't have to teach us hey uh Diego

that is glucose you know uh it may

present Us in some ways but uh at the

end of the day I have to go and get my

glucose get my am acids right because

eating is very simple we're just trying

to solve this issue of getting our

carbons getting our nitrogen getting our

phosphorus our potassium our sodium and

our chloride in so many different ways

shape or forms right so I went back to

the experiment the key experiment so

when we were able to put these opsins

and bring the light and shut off these

cells very rapidly when we had presented

the animal with the choice of sweetener

over sugar

then all of a sudden the animal became

blind to the solutions it couldn't

discern between the the the stevia so to

speak or the sweetener from the actual

sugar and the entire manipulation the

experimental manipulation that is is

occurring at the level of the gut the

intestine that's right right after the

stomach it's like just a small portion

of the intestine so if we make an

attempt to transfer this to the human

Real World Experience um um if

I have some ice cream it tastes sweet I

like it and now I'm thinking about it

and I'm craving it just a little bit I

don't have a huge craving for sweets but

um I do like some of them so eating ice

cream it tastes sweet the tendency is to

crave more that's correct right you have

to eat a lot of ice cream before you're

truly full yeah um and most people

self-regulate or their parents regulate

for them

um by limiting the number of Scoops or

something 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 neurop pod cells there that are also

sensing the sugar and signaling to the

brain and the brain is responding to

pursue more of that sweet containing

substance that's correct and it's

happening below our awareness it is

independent from the Sweet Taste of the

ice cream correct the the conscious

sweet taste the conscious sweet taste

which if you think about it it's not

fully conscious right you know as a what

we detect of the world it's just a very

tiny little portion right even sight you

know like we think we are looking for

light but I don't know what is happening

behind my my back I trust that

everything is going okay right so um so

when we shut off uh the

cells uh the animal and as I usually say

like became blind to the sugars because

it's kind of like uh a keing to having

turn off the cells that are able to

detect light the wav length of light for

us to be able to discern color right and

it's not that the animal is losing its

memory because then you if you remove

the light and now the the cells are

functional again then the animal again

is able to distinguish one solution over

over the

other uh and then we did a couple more

experiments in there and what happens uh

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 uh the

mouse will eat the sweetener as if it

will be sugar interesting so the

activation of these

cells makes them crave non-caloric

sweetener or low calorie sweetener as if

it were

sugar but is it blinding them to the

difference between sugar and low calorie

sweetener so here's another piece of

information if we will offer them water

and we will turn on the cells the animal

will drink the water as if it will be

sugar like it will be appetizing even

though it's just plain water yes and

what is becoming very obvious is that uh

the gut has this sense at the most basic

level

what the senses are uh doing is

calculating a couple of things one is um

in the salience of the stimulus is like

how intense is the stimulus and the

other one is the veilance 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

um uh Professor David Julius professor

hly in

uh jinra at UCSF they have done some

beautiful work demonstrating that there

are these serotonin releasing

cells specifically in the colon they

have focus in the colon that they couple

two 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 uh realm visceral hypers

sensitivity so they are responsible for

triggering the hypers sensitivity of the

nerve fibers the colonic nerve fibers

because they detect no noxious stimuli

and then ultimately they gate that

noxious stimulate and pass it on to the

nerve fiber as a in Broad terms as a

painful stimulus so is this irritable

bowel syndrome it is we could call it as

the biological basis of what could

degenerate into irritable bow syndrome

and so on and so forth or these

chronical GI uh they call them uh

disorders of gut brain interactions in

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neuroscientist I was trained to think

about the neural retina the light

sensing tissue at the back of the eye

the ca the essentially mechanos sensory

cells in the inner ear that respond to

sound waves not directly but through a

number of different transducers and this

kind of thing and then of course Where

You Are all familiar with the skin and

that it responds to pressure light touch

tickle itch

Etc what I'm understanding based on what

you're telling me is that all along the

pathway from our mouth to our rectum we

have sensory cells that are evaluating

the chemical constituents of the foods

that we

eat emitting broad kind of maybe even

crude slow signals in the form of

hormones to change our appetite our

feelings of well-being maybe our

feelings of not

wellbeing um but also sending direct

signals to the brain to drive certain

types of thinking emotions and behavior

what sorts of thoughts emotions and

behaviors are foods known to evoke

through this pathway from the gut

because the story about the your friend

that had the gastric bypass and then

changed the relationship completely to

the craving of or the aversion to uh

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 um 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 um you know it's

impacting you know significant be

Behavior or impacting Behavior at a

significant level that's correct um and

and uh when I think about that specific

example uh is

that after there has been this rewiring

of uh of the

intestine then now the intestine is very

sensitive so to speak to the stimuli and

when those lipids from the Yoke start to

enter the intestine if that sensitivity

has changed meaning it could have change

in how fast it reacts to the stimulus or

how fast it communicates to the stimulus

and how s sensitive it is to the

saliency or like the the the strength of

the stimulus it could communicate that o

what it used to be repulsive with a tiny

little bit of amount now it is actually

pleasurable with a tiny little uh bit of

amount and here's a a clear example so

it has been very well um I will say that

it has been documented uh in the clinic

that patients that undergone gastric

Bass surgery they're actually more prone

I think that the the the it goes from

like two to Sevenfold uh the likelihood

that they become and they they will they

will develop

alcoholism really yes uh because now the

way that they describe it is like well

you know either before I didn't like

wine um and then now I you know after a

few months of a surgery I'll have one

glass of wine and then all of a sudden I

found myself going to 2 three four you

know and then they will become either

more sensitive is still not known the

entire biology but they will become

either not only more sensitive but more

more attracted to that type of stimulus

I can't help but ask about OIC monjaro

and glp1 glucagon like

peptide one um analogues which are

really out of all the rage right now at

least for discussion but many many many

millions of people are now taking this

for treatment of diabetes and for weight

loss um my understanding is that glp1

acts at the level of the brain the

hypothalamus to reduce hunger but also

at the level of the gut to give the

sensation of more gastric distension is

there any knowledge of whether or not

glp1 interacts with the neurop Pod cells

and this pathway that you're describing

given what these neuropodia

complimentary question and uh in fact

when I got into uh studying in this

field uh 15 years ago uh the study among

scientists in this area uh glucagon like

peptide was already very uh popular uh

in the study in fact in this area it was

people were very focused on 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 um

stimulators of insulin release in the

pancreas uh after gastric bass surgery

it will actually increase its amount in

uh circulating levels uh and there were

already like uh some uh studies

suggesting that the the effect of this

gluc glucagon like peptide it was

actually not through the

circulation but more in a localized uh

action onto nerve fibers especially of

the vus nerve so there was already like

someone going um discussion about this

uh and certainly some of these

enteroendocrine cells these um

neuroendocrine cells particularly at

least in uh in animals I think it's more

distal and uh in the digestive tract

that they do release this glucagon like

peptide um one in response to primarily

like all of the macronutrients but

primarily

sugar and then

these glucagon Li peptide one will act

on specific receptors of the nerve

Terminals and then will trigger some of

the behaviors is also thought that uh it

acts at the level of the uh the brain

stem and what it will uh potentiate is

the reduction of uh

appetite so I say that this is a

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 going to

come back and feel again the tickling of

the gut because the gut starts uh to

churn again and it starts to call for

food remember it has to fit uh two giant

organisms the host itself but also the

microbes that are inside right so it has

to H keep uh so to speak that that

hunger going every 4 hours or so right

so that's why the hormones are more

acting on the

cyclical uh

circadian way but the transmitters are

acting in this very fast uh responsive

way of uh the precise stimul stimuli in

a specific uh regions of the

gastrointestinal

tract so these neuroendocrine cells are

releasing glp1 or responding to glp1

they're releasing uh glp1 they're

releasing glp1 to shut down transiently

shut down hunger and probably there is

some interaction between the cells that

they are they are having you know the

technical term is autoc 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 gp1 onto the nerve

fiber right I have a theory uh for which

I have no direct data but I'd like your

thoughts on um having spoken to a lot of

people that work on nutrition but also

gut bra brain axis today and U

microbiome in previous episodes that one

of the key things that a human

learns somewhat unconsciously but also

consciously is the relationship between

a given food which macronutrients it

contains the ratios of you know

carbohydrate protein and fat the taste

of that

food the amount of that food translated

into to calories but also physical

volume and then the

micronutrients why do I say this well

there are a growing number of studies

showing that the ingestion of Highly

processed food leads to the intake of

excess calories or more calories than if

one consumes Foods in their more natural

form single ingredient Foods or two

ingredient foods are very different than

a food that has a bunch of different

things in it and it seems to me that if

we were to look back into our Evolution

um sure people were making stews soups

and things for a long time um presumably

the sandwich came about through a either

desire for convenience or taste or both

uh you know putting Meats protein in

between two pieces of bread something of

that sort um by definition of a

sandwich maybe some vegetables in there

as well some cheese but that what this

whole pathway along the gut is trying to

do it seems is to

deconstruct what's coming in what's here

and shaping choices as you mentioned

about food Choice including the amount

of food to further consume and whether

or not to return to that food or to

avoid it and at the extremes it seems

pretty

straightforward and this is a very

classically described case right you you

go and you have the um you know the

kungpow shrimp or you have the lentil

soup at a given place and a few hours

later you don't feel right start some

sweating some gastric distress and you

develop a pretty broad aversion to that

food or maybe the entire meal maybe the

restaurant maybe even that entire type

of Cuisine depending on how um how much

of a lumper or versus a splitter you are

as we say in science right how much you

you make uh kind of large large bin

decisions or fine bin decisions um this

is nerd speak for saying you know do you

do you go back to the same restaurant

but order something different or do you

just decide to never go back again but

that's a pretty extreme case right the

other extreme would be you eat a food

it's delicious you feel wonderful the

the restaurant the people it's wonderful

and you crave more of that food okay

there's all the contextual stuff too but

what we really are talking about here is

how one navigates this whole landscape

of what to put into one's body in terms

of nutrition and trying to understand

how that's impacting everything from how

we feel right away how it tastes whether

or not we conceive it as good or bad for

us whether or not we think it's

impacting our body composition and

health

in ways that we want or don't want I

mean it's pretty complex stuff right

this is at least as complex as going to

the Metropolitan Museum of Art and

looking at a painting and trying to

evaluate whether or not you really like

that painting or not in fact it's

probably much more complicated than that

but it's what we do and I'm beginning to

get the the asense again no pun intended

that this pathway that we call the gut

brain axis is really

it's a six sense of a very elaborate

kind so you just touch on a on an entire

realm of a topic which is one of my

favorite topics because at some point

you know uh we as scientists we travel

we travel the world and it started to

become very obvious to me that wherever

I

went we solve this issue of food in a

very similar way whether it's a tortilla

or two pieces of bread which is another

way of a

tortilla uh you have your

carbs and then you add a little bit of

meat or a mushroom and now you have your

protein or fish or chicken or fish your

chicken the the carnivores will say

Mushrooms not a protein the vegans will

say mushroom beans lentil great protein

we're not here to to resolve that debate

um do as you choose and then you add the

lettuce

or the

vegetables and here's the first stop in

that com the first uh stop in that in

that discussion because this is

fascinating there is some recent work

showing that if you remove the protein

from a diet the animal swallows that

that that

meal ER the gut evaluates that there is

no protein in there and it stops eating

that meal wow so this is like um

ordering the vegetarian Taco yeah or

burrito or sandwich and then avoiding

that particular taco 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 no and in fact

if the protein is low

not completely absent if the protein is

low the animal consumes more of the diet

because it's trying to compensate for

the lack of protein and obviously if it

has sugars or fats that are more

pleasurable it keeps eating that that

that meal right I see if the protein is

completely absent the animal

avoids that diet

unless unless the diet is very rich in

uh dietary fibers

and the study that uh that I saw uh

which I thought it was fascinating is

that because somehow the microorganisms

in the digestive tract if they have

enough highly digestible fiber now they

turn on the ability to synthesize

essential amino acids really yes

so 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 Etc the

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 acids

microorganisms excuse me 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 I'm an omnivore I love meat 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 compens protein 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 eggs Etc

you know 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 but

the people who are trying to limit their

meat intake are what hungrier in general

so you're better off either indulging it

or avoiding it but not having a small

amount of it is that the idea the the

idea is that uh the the the body or the

gut will be able to detect that and then

we'll try to compensate right I see and

this I I actually learned um recently

from a friend Laura dubal at Colombia

who works uh does some beautiful work on

mosquitoes and how it is that they they

feed on uh blood she came for the

gastronauts uh uh series is she from

Leslie V Vel yeah and what I learned is

that when the mosquitoes are not

reproducing they can leave off ATP which

is the energy molecule right uh but they

cannot lay X

they need the protein in order to be

able to lay

eggs otherwise the mosquitoes cannot lay

the egg you know so this leaves us with

a picture of the gut sensing cells these

neurop pod cells as

exquisitely sensitive to amino acid

content in our Foods um which makes

perfect sense and it has not been

published or demonstrated yet sure we're

now in the realm of of new incoming data

we want to highlight this bracket it

bold face and underline it as we're now

at The Cutting Edge of what's may be

coming um that's right right observation

um but nonetheless 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 Professor

Steven Simpson in Australia uh in uh the

uh in nutrition uh Research Institute at

Sydney University he is uh main

proponent of these protein leverage

hypothesis you know that and in fact

protein is the most assing uh

macronutrient so that that has been

established and that's why uh normally

we have focused on sugars and fats but

we have neglected a little bit of on the

protein because it's not as pleasurable

as the sugars or fats but what is

fascinating is that is the most suting

um nutrient and as you know it's like

the most limiting and also like even

commercially is the most expensive right

yeah I certainly have had the experience

of um at one time in my life really

enjoying and even craving sweet Foods

desserts and sugars and things of that

sort and I noticed that over time if I

eat sufficient amounts of meat chicken

eggs fish and which is not to say that I

consume excess amounts of them that my

sugar Cravings go way way down that's

just my personal experience but I know

it's an experience that family members

of mine and others share as well but I

promise you that this was a a fun um a

fun topic right I couldn't uh we

couldn't stop at like just layer number

one layer number two is that in

agriculture we have this instinct to

plant plants that a complement each

other like for instance a classic um

especially native among native

communities is called like the three

Marys uh I believe is a a um pumpkins or

some type of fibers with corn

carbohydrates and Bings so in purely

plant-based diets there's an effort to

get the fiber the sugar and the amino

acids that's right and I grew up uh in a

in a farm my my parents had farms and I

remember when they will plant they will

also like throw in there the the beans

and the beans will wrap around the the

corn and it just seem like so natural

and that's what you will do because that

what you learn to do but if you think

about it's an instin that we have

developed even agriculturally probably

in the subconscious to cultivate them in

such a way or perhaps the plants taught

us how to cultivate cultivate them in

such a way that now when we put them in

the

plate it just makes

sense ER 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 is some

rice which is very deficient in in some

essential amino acids but is rich in

carbohydrates right it has some beans

right uh and then there's some lettuce

you know and sometimes we have like for

omnivores people will put meat or you

will put other types of protein in there

right and certainly it varies by culture

time of year food availability and

things of that sort as long as we're

talking about um your upbringing um you

have a fascinating story um so maybe we

could could discuss that for a few

minutes uh where were you born uh I was

born in the Amazonia of Ecuador a small

town called el Cho in Ecuador uh is on

the slopes of um the Eastern slopes of

uh the Andes on the way to the

Amazonia uh in the Napo Province uh

coincidentally was like through the path

from where uh Francisco the Orana in uh

1542 march on its way to the discovery

of the the Amazon actually passed

through a a trail that later on reading

I realized that uh Native people had all

of these Trails between the Amazonia and

the Andes and the coastal line for

thousands of years so you grew up in a

very rural yes uh the uh oil had been

detected in the 1920s in Ecuador uh it

was first explorer in

1964 in uh the first uh ER oil um um

well was uh in a town called lag Wago

which now is only like three or four

hours from the town where I grew up but

at that time it was like eight hours the

roads were not good and the first road

passed through it uh in uh

1974 uh I was born in 1983 but I

remember that we used to have like a a

giant um diesel T engine that will give

us a light electricity only from uh 7 to

900 p.m. you know uh I remember when my

father bought the the first uh a um

color television in the in the town and

then neighbors will come to the our

living room and then we will watch

movies wow and this was in the 80s that

was in the 80s right um such an

interesting upbringing so um did you eat

a purely vegetarian diet or you ate

Meats as well where did those meats come

from if you did primarily from a cattle

uh goats ship so how do you go from the

Amazon to a study of nutrition and

ultimately Neuroscience um yeah uh

that's the question right like the

deeper I go the more I question I used

to think that oh it was very simple you

know like when I was um uh specifically

when I was 11 years old

uh my father he was born in

1932 uh by

19 he lost uh his father my grandfather

when he was six years old then he was

given away and he had to go and like

build his his his life uh he was a very

successful entrepreneur but in the

process he had made a lot of uh a lot of

friends and acquaintances so when I was

11 years old I remember specifically

that a friend of of his who was in the

Special Forces stopped by uh our home

because that was the main road that we

go into the Amazon jungle where the uh

folks in the special forces in the in

the military will will be trained and he

stopped by and said like hey roio like

what are you going to do with Diego you

know like I think that is about time

that you know I think that you should

send him to the military school and I

remember in a matter of like literally a

couple of weeks or three weeks I had

given the taken the tests and um I was

accepted into the military school and

then uh I ended up in a military school

and this was the at that time it was the

premier uh military school in the in the

country that alone it was uh with years

you start to understand the context in

which you you developed uh because it

was a a it was a very interesting

context for for a child like just to

give you an idea uh these these uh this

school had the first and the only zoo in

the country so from my uh classroom I

would literally look at the at the at

the Lions and then I think that was by

the second year that I was in the school

second or third year that became that

because the the the city start to grow

and then the the military school is

wrong and then they separated the higher

education for Military Officers they

separated them and they put them in a

different place but that Zoo actually

became the first zoo of the capital of

Kiton wait so you had a zoo with lions

at your school yes and you said you

could could see the lions from your

classroom and they could see you

presumably probably know yeah well I

assume they could see you uh lion vision

is pretty good I don't know what the

resolution is but I'm guessing that

their Vision yeah they they definitely

use their old faction but they are uh

sight sight based Hunters as well so but

I I have a specifically uh one memory

like climbing up I think was like from

the because we had an Olympic pool and

we had all of these events um they they

they the the soccer field uh was the the

field where the uh national team will go

and train on because they didn't have

their own their own um H training

grounds later on they had their own

training grounds so but that was

something that you just grow into it

right like but you it was with the years

and now especially like that I get to

reflect on it I was extremely fortunate

uh through that experience and that

education and now I'm I'm I'm here

sharing some of the story and hopefully

uh through that inspiring some people uh

especially young people that would like

to go and chase their dreams you know so

you you went to military school in

Ecuador yeah you graduated and you

decided to go to to uh yeah so I was

allowed to become

a so in the military school they will

select uh the top uh Cadets um like I

think was the top 10% and they will

select them and they will put them

through a special training um so you

have essentially didn't have like what

was a normal summer vacation you know I

will go into a military

training uh ER so for me it was going to

be very not easy but relatively

straightforward to transition into

officers Academy right like do four more

years like West Point here and then like

become an officer right in fact I I had

a reserves officer degree when I

graduated but two years before

graduating a friend man who uh he prefer

other types of uh 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 uh perhaps

agriculture uh and I didn't think at

that time it didn't dawn on me uh that

uh you know people can study for

agriculture and agriculture is like the

base of food um er for all of us right

and then I said where and then he

mentioned for the first time this

University in zamorano which was founded

with some uh uh some funds that were

donated by um the founder of the

Standard fruit company which eventually

became I think chikita banana Zam

zamurai and that is an oasis that is in

Honduras outside of tusi Alpa so it's a

boarding school you wear uniform so it

was kind of like military it's very

strict uh you cannot accumulate more

than uh 12 de merits otherwise uh they

will send you home how do you get a Dem

Merit um hey you show up uh two minutes

late to uh work in the morning at 6:00

a.m. in the field and then you just get

to two minutes late one De Mer 12 of

those you're out two demerits two

demerits you're out yeah you get a we

used to get a um they they will check

your room so for instance a guest like

you if you will go there like they will

give you a every Wednesday they they had

at seven M they will check your room but

like very meticulously right and if they

found a little bit of a dust on the

window or something to the merits um and

you're going home if you accumulate

enough you will go home right wow um so

it really forms character right and then

do you do that with your kids no I think

that I have become do they make their

beds they do make their beds yeah okay

but that's that was the context and it

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 runs main training runs for

phds and the other one was nutrition I

was a little bit more King on perhaps

going into a Veterinary um uh

school and then uh I had an experience

in a a dairy farm in uh California where

I learned the value of uh nutrition

there was more prophylactic rather than

uh a paliative or like treating the the

cow right um and that kind of convinced

me like to look for a uh training in

nutrition and then a friend of mine uh

the late uh AEL gnat he was able to

connect me with um some uh some friends

and my mentor at uh North Carolina State

University and that's where I ended up

doing my PhD nutrition you know and

that's where like the career be became

and then maybe another detailing there

is that that I uh I was so excited about

taking uh that's where I took my first

physiology class and all of a sudden I

realized that in a way the body was like

a machine right like obviously is a

limited way of thinking but the body was

like a machine and one of the professors

was um a

neuroscientist uh and I took two

physiologies two human physiologies with

uh with him and I was just thrilled by

when he will explain how is it that in

the synaptic terminal there were these

vesicles that had like these proteins

that will walk that vesicle in the

preoptic active Zone and that's how we

make movement you know or something like

that um and I guess I kept that in the

background of my head and when I had the

opportunity to work in the gut uh I

applied that so you were Enchanted by

the nervous system yes yeah as as I was

too I I'm um 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 essentially govern our entire

experience of life it's just amazing um

well that's quite a journey from uh the

Amazon to uh well this table and and

much and much more of course um thank

you for sharing that uh so you grew up

in a uh let's call it a plr environment

the Amazon at least from the pictures

I've seen very um let's talk about plant

Botanicals and um the idea that maybe

plants for lack of a better way to put

it have a certain intelligence or a

composition that is not random with

respect to our interactions with them

right uh 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 you said

the pumpkin or the squash the corn and

the beans um what are your thoughts on

Plants perhaps from the Amazon but

elsewhere um too and their capacity to

have things in them um chemicals that

can be uh good for us at the level of

the gut but perhaps at the level of the

the brain or other organs as well yeah

how do you think about plants these days

so the first thing you you you mentioned

there like uh intelligence right I mean

I don't know like if that exact

terminology applies but I I do like this

word wisdom because it's reflected uh

experience right and I said reflected

experience because somehow we are uh

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 they don't know what is going on um

I think it's a little bit uh perhaps

naive is the word I went to um the the

the main Court of the

uh these Mayan um ruins of kopan at the

junction between Honduras and uh

Guatemala uh this was a very special

city of the of the Mayans and in the

main Court you see like all of the EST

Stellas which are like the main uh

stones of the of the kings of several

dynasties and at the top of one of the

uh the the the stairs of on these

pyramids there is this giant uh

SAA uh tree which is like 650 years

old something like that so that tree was

there before the spers uh landed in

there when the um Mayans perhaps were

still celebrating things or perhaps

right after right so imagine how much

information that a organism has in there

and we will be able to just tap somehow

into that information like

climate uh

fluxuations organisms interactions

movements I mean like so many different

things right like that right now I don't

think that we even have the the language

of being able to understand at the

organismic uh level of how much

information that is stor in one single

one of those organisms but then think

about uh a um uh a chloroplast for

instance or like one of the

photosynthetic uh organel inside of the

the the cells uh how is it that they

have been shaped for hundreds of years

in those organisms right um and I think

that perhaps in the

future uh this is more of a Sci-Fi right

now but perhaps in the future we we will

be able to harvest that type of wisdom

we will be able to understand a lot

about the uh about the the place or the

Earth that we live in that's Point

number one uh Point number

two is that this 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 right like here driving

in in La uh or driving in a major uh

City uh for some of us is just like

second nature right 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 the the

jungle is uh the makeup of the Jungle is

in there I've seen uh Native people

walking through the jungle without shoes

and right before for stepping on a leaf

stopping and then pointing out like look

underneath that leaf and then like

lifting it out and then a tarantula

right there like how do you even uh make

sense of that like I don't have the

sensory acuity or the wisdom to be able

to figure that out uh but they do right

and certainly that is a is is just a

level of um sensory perception that uh I

am not equipped with uh 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 uh and for many

other uh

functions uh these plants have been part

of the ecosystem of how these people

navigate uh their world all the way from

making a canoe to uh making a backpack

to carry a fish from the river into the

house right so how do you think we

evolved food choices and flavor

preferences I imagine humans you know um

that existed long before

us being hungry the gut starts rumbling

and there are all these plants

everywhere and some nuts and some

berries and things and so they had

presumably no choice but to consume them

and decide at the level of the the mouth

like that's bitter no that's not good

maybe eventually cook those and see if

that changes the relationship yeah I'm

thinking raw Acorn versus cooked Acorn

you know yeah um but that ultimately

there was a lot of trial and error and

that these neurop pod cells which surely

existed for a very long time prior to us

played a key role in Discerning what's

in these plants 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 what is not 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

propagate one imagines that you know

this is like almost as essential as

breathing you know and that and that

this

path of in our nervous system of the

neurop Pod cells to the brain for sake

of decision making of yum yuck or

me is perhaps one of the most important

core functions of the nervous system

once you get past the elements that

control breathing heart rate um you know

temperature regulation things of that

sort I see it is some among the senses

it's at least as important as vision and

perhaps more in terms of making sure

that we survive from dayto day that's

correct and uh here's where I think that

is a large vacuum in

biology uh if I will 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 uh even if you just go to a

Botanical Garden here uh in you know in

the city I will be really hard to figure

out um you know what plant is for what

right yeah what safe to e what safe to

eat not you know uh maybe like the Coti

you are able to figure that out by touch

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 ER

ER botanists that were studying the

plants um were exploring the jungles not

only the Amazon uh but Borneo Sri Lanka

and so on and so forth and studying the

interaction of native people with the

plants and if uh going through the

literature that

literature there is a pattern that

emerges and like uh the native people

they talk about how it is that they

actually learned from the plants that

the plants were the ones that were uh

teach them you know so that's why I said

from the biological perspective like how

can we make reconcile that uh I think

that there is still quite a bit of uh to

learn what does that mean to to learn

from the plants I mean there's something

that intuitively makes sense uh and when

you say that I've heard about um you

know looking at plants as teachers about

the local environment you know when

they're open right they're light sensing

when they're closed um but you know in

terms of trans ating some of that to you

know how humans have learned to navigate

given environments navigate meaning you

sort of thrive in those environments um

how do we go about that does it mean

taking plants grinding them up and

figuring out the constituent parts or is

that too reductionist is that going to

leave us with a parts list that doesn't

mean anything sort of like if I split

out all the pieces of a a car or an

airplane um in front of us it doesn't

really tell us anything about that

except what parts make up the thing that

flies yes and that's why I said like

this is more on the anthropological um

studies that have uh you know especially

from scientists that have gone there

learned the language leave with the

natives as natives you know and then

start to understand the dynamic of uh

their culture and their

interactions um then that's when like

for instance uh how it is that they

classify uh plants the way that they

classify plants is like several levels

more richer than our classification our

our scientific classification by um the

two name system or the variety right

like for instance they take into account

not only the the flavor but also the

shape uh the

location uh how they uh interact over

the year how they react over the year uh

for instance there's this beautiful

plant that

um people call it a the lips plant I

don't know if you have a very if you

Google it you will see it uh it's like

lips literally like lips it has like

these red beautiful lips like uh the the

the plant just looks like lips um and

then people use it for uh pain for some

rashes skin rashes and also like in some

rituals and like most of these plants um

the the way that the natives interact

with the plants is in a sacred uh level

you know there is this respect for the

plant right um

so yeah I think that uh biologically I

think that there is quite a bit in there

to um 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 in a t perhaps is

to uh reductionist it could be a

beginning of a understanding but it is

reductionist seems like nowadays in the

field of bioed research and clinical

research that there's a lot of interest

in uh plant-based

psychedelics um you know LSD from Urgot

and

psilocybin

mushroom um and so on and so forth

iasa iboga um so it seems like science

and plants have merged at that level in

terms of clinical implications of course

there are entire fields of plant biology

that are extremely important I think

most people probably don't realize this

but a lot of what we understand about

circadian rhythms

grew nope pun intended out of our

understanding of plant circadian rhythms

first and then it was translated to

mammals your beautiful work by Steve Kay

and and others um seeing the circadian

rhythms in leaf opening and orientation

of the whole plant and and other

features of plants that are mirrored by

the changes in um arousal level in in

mammals including us which is why I'm

always telling people to get sunlight in

their eyes early in the day and to avoid

bright light um in the evening and night

time um so what are your thoughts on

Plants as a source of medicine

psychedelic or

otherwise I think that uh well

traditionally that's where medicine was

um developed from I was at uh the Oxford

uh botanical gardens uh last year with

the family and uh we went into the

gardens and they have a beautiful garden

was established in 1621 I think was the

first uh Botanical Gardens in England

and they have a beautiful uh medicinal

plant collection and there was this very

humble uh a um uh what little sign with

a description in there uh that said in

there that about 80% of medicine it

still comes straight from Plants really

yes uh and if you think about it uh it

kind of makes sense right like because

you know when we think about like the

the medicines that we have been able to

develop which have been phenomenal for

especially for certain chronic

diseases uh but we don't have like a

broad uh repertoire uh of it right um so

I think that has

been obviously a great Advance um in in

our society that we have been able to

identify the molecules uh synthesize the

molecules package the molecules render

them by available in a specific sites uh

and I think that when we are able to

couple that with the rest of the

molecules that the plants through their

I keep saying their wisdom because

somehow they develop their ability to

have not only one molecule but like a

combination of other things that will

provide the full experience of of the

plant right uh for instance uh Gera

mattive you know it's not only caffeine

right because it's very different than a

shot of espresso you know if you take

the whole thing uh it not only gives you

energy but it gives you a full range of

experience that is specific to the

yamatic which is a is a leaf right yeah

it's a distinctly different um sub

subjective experience than coffee and I

I enjoy both coffee and espresso and yum

mate you um were the one who introduced

me to gu guayusa which is a is a causing

of jate because jate is parensis WUSA is

elix WUSA and it's not as bitter as mate

but it has uh almost as much caffeine as

coffee and it has antioxidants and other