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So first I wanted to thank everyone for being here.
This is a really exciting opportunity
to get to talk about something
that I am very passionate about,
which is the gut microbiota.
And when Wayne invited me to come speak here, I thought,
"Hmm, what can I talk about
that's going to be new cutting-edge science
that I will get to share with all of you?"
And not only is the microbiota
a aspect of cutting-edge science, it's also invisible,
so it's perfect.
And before we can really get into talking about
the gut microbiota and the gut-brain axis,
we have to understand what the gut-brain axis is.
So I know I'm here to talk about brain health,
but I'm actually gonna talk about your second brain,
and this is the brain that resides in your gut.
This is called your enteric nervous system.
With 500 million neurons, the enteric nervous system
is able to autonomously regulate itself.
It signals to the central nervous system
via afferent nerve fibers in the vagus nerve,
and is able to autonomously regulate its own blood flow,
mucosal secretions.
And maybe one of the best ways
of describing the communication that can go on
between the digestive system and the central nervous system
is by highlighting irritable bowel syndrome.
And people who suffer from irritable bowel syndrome
develop hypersensitivity to normal gas, normal bloating,
but they're hypersensitive to it.
And these signals of hypersensitivity
are then relayed to their central nervous system
and can impact their behavior as well as the way
that they feel and function in daily life.
People with irritable bowel syndrome
are much more likely to develop depression.
They have increased sensation of pain.
It's just one of the ways that the enteric nervous system
interacts with the central nervous system.
But really understanding the enteric nervous system
is only half of the story,
and thanks to advances in research in the last decade.
And this has to do with the ability
to rapidly sequence genomes of our gut microbiota,
and these are the bacteria that live in our gut.
You have trillions of bugs that are housed in your gut,
and thanks to the advances in technology in the last decade,
we have seen an explosion, a literal explosion,
of research involving the gut microbiota.
And this was published in "Nature Biotechnology" in 2013.
And in 2002, we had about 265 peer-reviewed papers
published about the gut microbiota.
By 2012, 2,683 papers.
In 10 years, a tenfold increase
in the number of papers published
in peer-reviewed journals about the gut microbiota.
I wouldn't be surprised if in 2015,
we're approaching 5,000 papers published
about the gut microbiota
and how it influences different aspects of health.
So what are we starting to learn about this gut microbiota,
about these bacteria that live on our skin
and that bacteria that reside in our gastrointestinal tract?
Well, at a cellular level, you, me, all of us,
we are more bacterial than we are human.
Think about that for a second.
Have you ever considered that?
You are only 10% human at a cellular level.
We are outnumbered 10 to 1
by the number of bacteria that live in our digestive tract.
It's kind of a scary thought.
Not only are you outnumbered
by the bacteria in your digestive tract,
but they are able to influence numerous aspects of health.
And the stomach houses some of them,
the small intestine, more,
but the vast majority of these bacteria,
a hundred trillion bacteria live in your large intestine,
in your colon.
Not only are we outnumbered, but metagenomic studies
looking at the total genomic material,
total genetic material, of these bacteria
have really started to shed some light
on the genetic potential of our bacteria.
We are actually outnumbered 100 to 1
when we look at the total genetic material
of the gut microbiota
compared to the genetic material in the human genome.
And these genes can be turned on or can be turned off
depending on what you're eating, on various inputs.
Antibiotics can turn on and turn off these genes.
Pesticides, heavy metals, prebiotics.
So if you're consuming fermentable starches,
these genes can be turned on, can be turned off.
And the availability of genes
is totally misunderstood right now.
It's totally underestimated
what the genetic potential of all these genes are
and how these genes could be actually influencing our health
and whether or not
we're able to turn them on or turn them off.
And this idea that we are vastly outnumbered
by the number of bacteria on our bodies,
the number of bacteria living in our gastrointestinal tract,
and the genetic material that these bacteria possess
have kind of changed the idea of what the human organism is.
Humans are now maybe thought of as a meta organism
or a super organism.
And this is an organism that is not just taking into account
the way that human cells are working,
but also taking into account
the symbiotic relationship we have to have
with our bacteria that are residing on us.
And I have good news for you guys. You never eat alone.
You'll never be eating alone again, right?
You have commensal bacteria,
which is what the gut microbiota is often referred to as,
that are gonna be eating everything that you're eating.
And that's something to think about before you go to lunch.
Everything you're going to eat is gonna be seen
by those gut bugs as it makes its way down there.
And commensal actually comes from the Latin com mensa,
which is table, and sal, together.
And this is to eat together.
So this is your opportunity to eat together,
and you just are always having this company with you
while you're eating food.
And so we are programmed from birth
to be colonized by bacteria.
The fetus is sterile,
largely sterile as far as we can tell, before birth.
Before the mother gives birth,
the bacteria in her vaginal canal begin to change
in for preparation for colonizing the baby
with specific microbes.
Once the baby's born, those microbes are inhaled by it.
They get covered in those microbes.
Breast milk contains galactooligosaccharides,
a specific prebiotic that can be used
in order to promote the growth of certain microbes
in the baby's digestive tract.
My point is, we have evolved,
we have this evolutionary need, this evolutionary niche
for these bacteria to grow on us, to grow in us,
and I think we're largely underestimating
the role that these bacteria do.
And we allow them to ride around in our digestive tract.
We provide them with food sources.
You know, there's between three and five pounds of bacteria
residing in everyone's gut right now.
Try not to grimace.
I know that's kind of gross, but it's interesting to think
that that's about the same weight as the human brain.
But, what do, yeah, right, thanks.
But what do they do for us in return?
What are these bacteria doing for us?
If I said this as a symbiotic relationship,
we've largely viewed this as a parasitic relationship.
We think of bacteria as bad.
We don't want bacteria,
but what are they doing for us in return?
And this is where the research gets really exciting
in starting to understand what these bacteria
that are residing in and on us are doing for us.
And thanks to advances in all these technologies
that I've been talking about,
we're much better able to understand
the symbiotic relationship we have with these gut bacteria.
So we know that the gut microbiota
actually synthesize vitamins in infants
in the first couple years of life.
Almost all their B vitamins
are obtained from their gut bacteria, as is vitamin K.
They educate our immune system.
So babies are born without almost any,
their immune system is totally naive.
It hasn't seen any pathogens, any microbes before,
so they help educate the immune system.
There's this huge interplay between your immune system
and your gut bacteria as you're developing.
They nourish epithelial cells.
They produce short-chain fatty acids
when they digest prebiotic starches
that are found in fruits and vegetables.
And these short-chain fatty acids
actually serve as an energy source
for the gut epithelial cells.
And importantly,
they interact with our central nervous system.
And I'm gonna introduce this concept
of what I like to call microbial mind control.
And that might sound kind of strange to you,
maybe sound kind of foreign,
but the idea of microbial mind control
shouldn't be that foreign to people.
We all are familiar with rabies.
Rabies is a viral infection where you're actually
more predisposed to aggressive behavior
because of this microbial mind control.
You also develop hydrophobia.
You're scared of water when you have rabies.
Other organisms such as Toxoplasma gondii,
which is a common bacteria found in cat poop, cat feces,
actually can infect rodents.
And when it infects rodents,
rodents becomes sexually attracted to cats.
This is microbial mind control.
Sexually attracted to cats so that the cats can eat them
and this organism can renew its lifecycle.
Now, these are more of a parasitic type of relationship,
but it just highlights the ability of microbes
to actually manipulate behaviors.
And so using germ-free mice, and these are mice
that are kept in sterile isolator bubbles,
totally plastic bubbles.
It's like "Bubble Boy," but for a mouse.
We're able to actually study
what the presence or complete absence of this gut microbiota
has on health.
So what's been observed in germ-free mice
is that they have all sorts of abnormal brain behavior,
brain activity.
They actually have decreased levels
of one of the growth hormones in the brain
that we were talking about earlier,
brain-derived neurotrophic factor.
They have increased levels of stress hormone, cortisol.
They also have a lot more propensity
to develop anxiety like behaviors.
And what's really interesting
is that you can actually ameliorate these behaviors,
these anxiety like behaviors, by taking these germ-free mice
and colonizing them with the microbiota
from a conventionally-housed mouse.
A mouse that's not kept in a sterile isolator bubble.
Now, there's been some research looking at how a probiotic
could colonize the germ-free mouse and manipulate behavior.
And it was found that Bifidobacterium infantis,
a common probiotic, is actually able to reduce
these anxiety like behaviors.
So the researchers who did this study
were starting to wonder,
"Well, is it just general sensing of microbes
that's required in the gut or is it specific microbes
having specific effects on behaviors?"
And what they found is that if they mono colonize
these germ-free mice with Bifidobacterium infantis,
they had a reduction in anxiety like behaviors.
If they mono colonize these germ-free mice with E. coli,
they didn't see any reduction
in those anxiety like behaviors.
So now we're seeing that this is very specific
to specific organisms.
Not only that, but if they were to sever the vagus nerve,
this line of communication between the gut and the brain,
they lost all the positive effects
of that probiotic supplementation.
Now, a lot of this research has been done in animals.
It's very difficult to study the microbiota in humans
to develop causative relationships.
However, there's some really interesting research
that's being done in the last couple years
looking at how probiotics
can actually modulate brain activity.
So this was a study where for 28 days
they had their study participants
consuming a fermented probiotic milk.
So this is just a fermented milk product,
probably like a kefir.
And what they found was that they did a brain scan
of these people after 28 days,
and they saw increased brain activity in areas of the brain
associated with emotion and cognitive function.
So now we're seeing that probiotics
are actually starting to work in humans.
A similar study was looking at self-reported feelings
after probiotic consumption, and they found
that there was reduced self-reported feelings of sadness,
reduced self-reported feelings of aggressive behaviors,
kind of similar to some other things we've talked about.
And these studies are ongoing right now.
This is a 2013 paper, and, you know,
these studies are brand new.
And that's one of the things
I think is really important to talk about with this field
is that this field is in its infancy.
Even though you saw that really fast increase
in the number of papers that have been published,
this field is still really far in its infancy.
And in humans, we can't really look at the mechanisms
of how these are working,
but we can look at the mechanisms in animals
and really start to understand how the gut microbiota
is actually influencing brain health and brain behaviors.
So what we're starting to find is that the gut microbiota
is actually capable of influencing behavior
in a variety of fashions.
There's this direct communication via the vagus nerve.
There's also the immunomodulation.
As someone said earlier,
70 to 80% of your total immune cells
are located in your gastrointestinal tract.
That represents a huge potential
for your gut bacteria to interact with your immune system
and perform immunomodulation.
So it's well known that certain probiotic bacteria,
as well as commensal bacteria, can induce the development
of anti-inflammatory or pro-inflammatory immune cells.
They also have all sorts of coats on.
The bacteria have coats on them
that interact with the immune system
and can cause production of different cytokines
as well as other inflammatory mediators.
And then we also see that there's this idea
of systemic communication between our gut bacteria
and the central nervous system in our brain.
And this is through production of neurotransmitters,
production of bacterial metabolites.
And some of the most important bacterial metabolites
produced by our gut microbiota
are these short-chain fatty acids.
Short-chain fatty acids were well known
for helping support gut health,
but once they do make their way into serum,
they actually can reach the blood-brain barrier
where they cause the blood-brain barrier
to increase injunction strength
so it's actually decreasing the permeability
of the blood-brain barrier.
This helps keep out toxins
and other potential harmful compounds.
Not only that, but once these short-chain fatty acids
make their way into the brain,
they're actually able to alter levels of neurotransmitters
directly in the brain.
There's some really interesting research done
by Jeff Gordon's lab,
and this was kind of a groundbreaking study
where he took the microbiota out of a obese mouse
and transferred it into a lean germ-free mouse.
That lean germ-free mouse
had this huge increase in appetite
because of neurotransmitters produced in the brain
due to changes in its microbiota, and it became obese.
These are just some of the ways that the gut microbiota
is actually able to influence behavior.
And we're starting to see that the gut microbiota
influences mood.
It's been associated with changing social behaviors,
anxiety-like effects as we talked about earlier
in germ-free mouse.
Not only that, but the neurophysiology.
It can stimulate the production
of growth hormones in the brain
that can help improve brain health or support brain health.
And also it can influence sleep patterns.
And there's a study looking at Lactobacillus brevis
where they actually administered Lactobacillus brevis
and they saw that the animals
that were given Lactobacillus brevis
actually slept through the night better,
well, slept through the day because mice are nocturnal.
But nonetheless, they were actually able to improve
their sleep patterns,
and the bacteria didn't even need to be alive.
They did a heat-killed bacteria
and they were still able to see this positive effect,
thinking that it's either related
to the coating of that bacteria
and how it's interacting with the immune system
or because it's simple administration of that bacteria
is causing changes in the genome
of the entire gut microbiota
that's then reflected in a better sleep pattern.
And I should note that those bacteria,
the administration of that bacteria,
also increased voluntary wheel running.
So maybe we just need to eat more dead bacteria
and we'll get rid of that obesity problem we have.
Now, I talked about the production of neurotransmitters.
The gut microbiota is starting to be accepted
as a major source of production of neurotransmitters,
and not only as a major source
of production of neurotransmitters,
but it also can manipulate and stimulate
the production of neurotransmitters in the gut.
A large amount of the body's serotonin and dopamine
is actually produced within our enteric system.
Not only that, but some of these rarer neurotransmitters
such as tryptamine, this is a neurotransmitter
that's not really considered very much
when you're talking about brain health,
but tryptamine is very commonly used as a drug,
like psychiatric, hallucinogenic drugs.
So, you know, the production of these neurotransmitters
cannot be underappreciated.
And again, we don't really fully understand
what these neurotransmitters are doing
when they're being produced by the gut microbiota.
The serotonin and its precursor 5-HT
that are produced in the gut
probably aren't making their way into the brain
and crossing the blood brain-barrier
and actually influencing
central nervous system function there,
but they can be interacting through the vagus nerve
and influencing function that way.
And the gut microbiota is producing tryptophan,
which is a precursor to serotonin,
and that can cross into the blood-brain barrier
and serve as more building blocks for serotonin.
Now, someone also mentioned earlier
that there is a very, very common association
between mental illness, psychiatric neurological illness,
and digestive problems.
Well, unsurprisingly, alterations to the gut microbiota
are also very common
in neurological illness and psychiatric illness.
Normally you have the small intestine
being predominantly colonized by Lactobacillus,
while the large intestine is predominantly colonized
by Bifidobacterium and Clostridium.
And changes to this makeup
can have a large influence on the genes
that are being expressed by this microbiota genome
as well as the things that are being produced
by this microbiota.
There was a study where they induced autism in mice
by causing immune reaction in the mother
before she gave birth.
And they were able to show that there was a metabolite
produced by these bacteria, 4-ethylphenyl sulfate,
that was increased in the autistic mice.
And if they were able to take either the bacteria
that produced it or administer it to healthy mice,
they could induce autism-like symptoms in healthy mice.
Speaking of of autism, this is a very common disorder
where we see changes to the gut microbiota.
There's a decrease in the number of Bifidobacteria
in autistic children, this is pretty common,
as well as an increase in the number of Lactobacillus.
And although this is kind of a maybe confusing paragraph
for those of you who aren't familiar
with the different families of bacteria,
all it's really meant to represent is that small changes
in the overall makeup of the gut bacteria
can have significant impacts on our overall health.
And I wanna stress that this is all very correlative.
These aren't causative studies really.
This is looking at correlation.
Changes to the gut microbiota
and also changes to overall different health outcomes.
And autistic children often display dietary aversions.
There's foods that they will or won't eat.
And the authors actually took this into account
when they were doing this study
to see if different changes in the gut bacteria
was just simply associated to dietary aversions.
And after controlling for all these variables,
they still saw these changes in the gut microbiota,
indicating that there's something else going on
other than just dietary aversions.
And so, you know, I'd just like to conclude
by reminding everyone
of the 2000-year-old Hippocratic statement,
"All diseases begin in the gut."
And I think this is maybe more true than ever
as we're starting to understand
what the role of the gut microbiota is.
And right now we are all present,
we're all taking part in the microbiome revolution.
This is a very fast growing field,
and we don't really understand
what our increased exposure to antibiotics,
our increased exposure to pesticides,
our increasingly hygienic world is doing to us
and is doing to our gut microbiota.
There are a lot of researchers
that are linking this overall overly hygienic lifestyle
to changes in health outcomes.
Cesarean section.
When babies are born, and born via cesarean section,
they're inoculated with a much different type of bacteria,
a skin bacteria, instead of vaginal and fecal bacteria.
And cesarean section is largely associated
with increased risk of allergy, asthma, and other diseases,
but also increased inflammation.
And everyone knows that inflammation
plays a major role in the development
of a lot of different neurological diseases as well.
So I just wanna remind everyone before lunch
that you're not gonna eat alone.
Take into account, you know,
I actually have to think about this now.
Every time I eat anything I'm like,
"Huh, I wonder what my gut bacteria think of this?"
And it's really, it's an amazing field,
and I think you should be excited to stay tuned
and watch what's gonna be happening in this field.
And so thank you.
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