(upbeat music)
- I'm thrilled to be with
you tonight to share with you
a relatively new and I think
incredibly exciting field
of research that's really changing
our view of human biology.
The field of human microbiome research.
And that really describes
studying the intense diverse
communities of bacteria fungi and viruses
that live in and on the human body
and understanding how
they shape our health.
So what will we cover tonight?
Well, first things first.
How do you study entire
communities of microbes?
What tools do we have
and how do we understand
not just who's there
but what they're doing
and how they're interacting
with the human host.
And we'll go through a quick whirlwind
of the human microbiome.
Human microbiome 101.
And then I wanna shift
into some of the work
that we've been doing in
leveraging the very early life
gut microbiome to
understand an airway disease
that occurs years later in childhood.
So not your typical thinking
inside the box on this one.
And how we can use the
microbiome not just to predict
allergic asthma development
but to understand
why it develops in these
children in very early life
and to develop new
therapeutics to intervene early
to prevent disease development.
And then I wanna give you a
quick rundown of what's next.
What is in the future.
What's the crystal ball for this field,
what are we developing
here at UCSF and beyond
to leverage findings in
this field to really develop
what we see as a new field
of microbiome medicine.
And so when I begin my lectures,
I like to begin at the beginning.
The very very beginning:
the birth of the planets.
And point out that the first
and most successful organisms
on the planet are microbes.
They're bacteria.
They have been around the longest.
They are the most successful.
They're also the most numerous,
the most diverse and ubiquitous.
Everywhere we look on this
planet we can find microbes.
They have evolved and adapted to live
in the most extreme of environments.
That can be everything from an acid mine
to the incredible pressures
at the bottom of the ocean
to incredible extremes of heat
and chemical exposure for example.
So they're a depth.
They can live in the most
extreme environments.
And as I said, they are everywhere.
So we as well as every
other biological entity
on this planet have evolved
in a microbial soup.
And in fact we haven't just
evolved in a microbial soup,
we've co-evolved with microbes.
They live in and on us and
we actually rely on them
for functions that we
ourselves do not encode
in the human genome.
But how have we studied microbiology?
Well, we've taken a very
reductionist view traditionally.
What we've traditionally
done is taken microbes
out of their environment, grown
them under feast conditions
in laboratory media by themselves
and studied what they do.
And nothing could be
further from the truth
of how these microbes exist.
They're actually quite social.
They live like us in diverse communities.
They communicate with one another,
they use small molecules to sense
who's in their neighborhood
and respond those microbes
that are in their neighborhood.
So how do we get at these organisms,
many of which we've never cultured.
We don't know how to grow them,
we don't know what they eat,
we don't know what they subsist on.
We turn to molecular tools.
So the kind of workhorse of the
field of microbiome research
is using DNA based methods
to identify microbes
without ever having to grow them
or isolate them from a sample.
We'll take a sample, we'll
extract the DNA from it
and remember that DNA comes from
every microbial cell in that sample.
There could be various
different types of microbes
and then one approach we
have is really targeting
specific genes like this one
called the 16S ribosomal RNA gene.
This is a gene that's
only found in bacteria.
It's not found in any higher organisms
and it's a great biomarker
gene for identifying
which bacterium it came from
because it has these regions
in the gene that are really
highly conserved across
all known bacteria.
So we use those highly conserved regions
to kind of anchor an assay that we have
to basically make copies
of the region in between.
And the regions in between
those really conserved
regions of the gene are
what we call hyper variable.
There the sequence varies.
And it varies depending on which bacterium
the gene came from.
So we can make lots of
copies of these genes
and then sequence the
hyper variable region
to figure out who it came from.
And in that way we can generate
like what you would think of
as a fingerprint which bacteria are there
and in how much of each
bacterium is there.
What's the relative abundance.
And this is really useful for
comparing across very large
cohorts of samples
where we just wanna know
who's there and how it
differs, for example,
in health and disease.
We've got a similar tool
for looking at fungi.
There's a lot of various
regions we can look at
with the same type of technique
but we tend to use this one
called a interspacer region two.
Again, we amplify that piece
of the genome from fungi,
sequence it and then we
can tell which fungus
it actually arose from and in that way
look at fungal communities
and how they're composed.
Who's in that fungal community.
But the tools for
assessment of the microbiome
have rapidly evolved
and expanded in capacity
over the last several years.
And we now can, instead of just
looking at a biomarker gene,
actually take all of the DNA we extracted
and sequence all of that DNA
and then put those pieces back
together basically
reassembling the genomes
of all of the microbes in that sample.
And this is no small
feat as you can imagine.
I joke, although it's not really a joke,
and I say it's like me
handing you "War and peace"
by Tolstoy in pieces and
asking you to put it all
back together in a legible form.
That's the the computational
capacity that we need.
Is immense to do this
job but something that we
have developed very rapidly
over the last several years.
So while biomarker gene
sequencing tells us who's there,
shotgun metagenomics tells us
the genes that these organisms
encode and what they
have the capacity to do.
But we've pushed this field even further.
We can also extract RNA from a sample.
It's another type of nucleic acid.
And it basically it's the
transcription of those genes.
So it's what is that the
community of microbes
actually transcribing off their genomes.
Wow are they responding
to the current conditions.
And we can sequence those
pools of extracted RNA
by sequencing also and we call
this meta transcriptomics.
It gives us a snapshot into the genes
that are being expressed at
the time of sample collection
by organisms in the microbiome.
But what's even more exciting
is that we can look even deeper.
These are all next-generation
sequencing based tools
to look at microbiomes.
We can also use mass spectrometry,
the capacity to identify small molecules.
And we can use this to
look at protein pools
produced by the microbiome
to understand the proteins
that they produce and
that includes remember,
all of the enzymes and catalytic functions
of the microbiome.
But what's nearest and dearest
to my heart is metabolomics.
Looking at the small molecules.
Remember I said that that's how microbes
communicate with each other.
In fact, that's how cells
communicate with each other
irrespective of their microbial or host.
And this for me is the lexicon
that governs microbial-host
human host interactions
and this is where we think
the next frontier and
we're all already realizing
the next frontier in
this field really lies.
So the application of these tools
and in particular DNA based
tools, has massively expanded
our view of bacterial life on this planet.
This is the tree of life.
This is everything.
We're down in one of the
little branches down there
on the bottom with the eukaryotes.
These up here on the top are all bacteria.
And this is a study that
was published in 2016.
Everything in purple
are brand new bacteria
that were identified in this study alone
with molecular methods.
So we have immensely diversified
the bacterial tree of life
and we suspect that this is also true
for viruses and for fungi.
We just need to catch up
in developing the tools
for those realms of microbial life.
But what these tools have
told us is that there is
a much broader range of fungi and viruses.
Particularly those that
exist in the human body
than we previously were led to believe
based on culture-based approaches.
And in total, the application
of all of these tools
to interrogate the microbiome
has left us realizing
that we're not alone.
We are, in fact, super organisms.
We're a conglomerate of
microbial and mammalian cells
that have co-evolved over time
and we are colonized
inside and out by microbes.
This is just simply looking
at microbial diversity
across the surface of the skin.
Anything in red is kind
of higher diversity,
in blue is regions where there's
lower microbial diversity.
This is looking with mass
spectrometry at the molecules
made by those microbes on the skin.
And here you can see that
even where there's regions
for there's not so many microbes present,
there's a huge biochemical
diversity of molecules
that are produced at those sites.
Produced by the microbes,
produced by the host cells
in response to the microbes.
There's a rich molecular lexicon
occurring at these sites.
That's simply the skin.
And that's actually considered a very low
microbial burden sites.
We house the greatest burden and diversity
of microbes in our gut.
Particularly in the distal gut.
And these microbes are
not simply bystanders.
These microbes influence how
our gastrointestinal cells
behave and function and
respond to this microbial zoo
in the lower gut.
And I will say it's
not just the lower gut.
There are microbes obviously in the mouth
and the whole way down
through the GI tract.
They differ at different
sites along the GI tract.
And we think that that's
because of the prevailing
conditions that differ.
If you think about in the
stomach, the pH is very low.
in the lower gastrointestinal tract,
there's very little oxygen there.
These are strong selective
pressures that drive
the types of organisms that like to thrive
in these distinct niches along
the gastrointestinal tract.
But I think what's really
amazing is to think about
how much our microbiome
dwarfs our human genome
in terms of genetic capacity
and genes that it encodes.
This is one study of European
Asian and U.S. populations.
Just over 1,200 fecal samples
were sampled and examined
using shotgun metagenomics.
So looking at all of the
microbes and all of the genes
encoded by the microbiome in
those 1,200 or so samples.
And what staggering is, almost
10 million microbial genes
were found just across those 1,200 or so
individual fecal samples.
I wanna let you think
about that for a second.
That is incredible.
This is an ancillary microbial genome
that we carry around with us.
These genes are not silent.
They're actively expressed.
And we rely on these genes
for things like digesting
our dietary components,
for digesting metabolizing
our drugs, in fact
and for informing and
influencing our immune response.
So these are an important
part of our physiology.
An important part of what
makes us healthy or diseased.
And to add the complexity
that this is not just one type
of microbiome that we have in one site.
We develop our microbiome in early life.
We are born with the
very simple microbiome
that we inherit from our mothers.
It either arises in utero
or is contributed to
through the birthing process.
Babies who are born
through the vaginal canal,
have a preponderance of
lactobacillus species
which are the dominant organisms
in the female vaginal tract.
Babies who come at the
sunroof by cesarean section,
end up quite frequently with
organisms we find on the skin.
Staphylococcus and streptococcus.
Suggesting that very early
life postnatal exposures
influence those communities
of microbes that are found
in the very early gut.
And as we proceed through
very early life development,
we now know that a whole
range of factors influence
and shape the types of
microbes and activities
of the gut microbiome.
Things like early life nutrition,
antimicrobial exposure,
as I mentioned ceasarean section,
really strongly influenced
what type of microbes are there
and how they're functioning.
We continue to expand
the diversity of bacteria
that we have in the gut up
until about three years of age.
Around then the diversity
looks like that of an adult
but the functional
genes in that microbiome
at three years of age are quite different
from that of a healthy adult.
Throughout life we continue
to shape our microbiomes.
In fact, I view them as, in adulthood,
as a history of your exposures in life.
Things like pharmaceuticals,
diet, infection, sex hormones,
even environmental toxicants
can serve as strong
selective pressures on
which microbes are present
and what they're producing and therefore
how they're interacting with the host.
And to really reinforce this
and add to the complexity,
if we take a point in time
not all microbiomes are equal.
This is a study of the gut microbiome
in developing and developed
nations in adults in this case.
Here in red and green we have
gut microbiomes of Malawian
and Amerindian populations.
In blue we have the U.S. population.
And basically each spot is a profile
of what type of bacteria
were in the gut microbiome
of these individuals and how
we work through this immense
amount of data that we
generate is we ask how similar
is microbiome profile
A to all of the other
microbiome profiles in our cohort.
And we calculate a distance.
How similar is it, how close is it
in terms of which microbes are there
and what relative abundance,
how much of them are there.
And that's just a visualization
of this distance calculation.
So if we have two spots
representing two gut microbiomes
of individuals in these studies
that are closely plotted
beside one another, it means
that those two gut microbiomes
are very similar to one another.
But what you can starkly see in this,
is the U.S. gut microbiomes
are very different
from those of the Marindian
and the Malawian population.
And even though the Malawian
and the Merindian populations
are on two different continents,
their gut microbiomes
in these less developed nations
are more like each other
than they are like a U.S.
population gut microbiome.
To reinforce what we've done
to our microbiomes in the U.S.
this is just looking at the
number of types of bacteria
that are detected across
these populations.
We have severely reduced
the breadth of diversity
and the number of different
types of bacteria in the U.S.
population compared to the
in less developed nations.
And the really wonderful
thing about this study,
is we got indications why
this might be happening.
When the study examined
with shotgun metagenomics
looking at all the genes and the pathways
and these microbiomes,
what really differed
between these populations,
what was really striking,
is that the adult population
of Amerindian and Malawians
were really enriched for alpha-amylases.
So this is an enzyme
that breaks down complex
plant polysaccharides.
So the diet in Malawi and
in the Merindian population
is predominantly a plant
polysaccharide, a plant-based diet.
In the U.S. population, we see
huge enrichment of microbial
metabolic pathways for
processing simple sugars.
Found in processed foods, as we all know.
So at least one feature,
one thing that we know
is driving these differences
in the gut microbiome
across these populations
is differences in diet
in what we consume.
And this was reinforced even
more recently by Pete Turnbull
who is a faculty member here.
This was a really
wonderful diet based study
of 10 individuals.
And what Peter did was
he took those individuals
and looked at how a plant-based
or an animal-based diet
may actually influence a
healthy gut microbiome.
And here we're just showing
you the amount of fiber
in their diet of these individuals
before they started the study,
then they got four days
of a plant-based diet,
the other participants got four
days of an animal-based diet
and as you would expect the fiber content
with the plant-based diet
or the plant polysaccharide
content goes up quite high
in an animal-based diet it's very low.
Also, the fat intake is
lower in the plant-based diet
compared to the animal-based
diet and the protein content
is also dramatically different
across these two diets
and he could track that
these key dietary component
really shift with the
introduction of either
a plant-based diet or
an animal-based diet.
What was really striking is
that when Peter calculated
again the distance, how
similar are the microbiomes
of the individuals after they
start their plant-based diet
compared to before they
started their plant-based diet,
didn't really see much
in the way of change.
Plant-based diet doesn't really
perturb the gut microbiome.
However, in comparison, the
animal-based diet introduction,
really increased this distance.
And what that tells us is that
microbiome is very different
from the microbiome that was
there before the introduction
of the plant-based diet.
But it's not just about
changing the composition
of the microbiome that matters.
What the study also
showed is that you change
the molecular output of the
microbiome by changing the diet.
And here we can see that two
key short chain fatty-acids
acetate and butyrate were
significantly reduced
in the animal-based diet
versus the plant-based diet.
And that makes sense because
these are the products
of microbial fermentation
of plants, of fiber.
And what's really critical is
these short chain fatty acids
are crucial energy sources for
the cells that line the gut,
they're antiproliferative and
they're anti-inflammatory.
And we think they have these activities
because we've co-evolved
with these microbes
who traditionally have
fermented our plant-based diets
into these small molecules
which quench inflammation
and promote kind of health in the system.
And so based on this, I'm sure
you're not gonna be surprised
that we're finding an
ever-increasing range of diseases
are related to perturbations
to the microbiome.
And things like the skin
microbiome is perturbed
in dermatological conditions
like psoriasis for example.
But what's really exciting is
that we are now saying that
conditions like obesity is also linked to
gut microbiome perturbation.
But what's most exciting for
me, is that we're finding
that conditions that are
very difficult to treat
and that we really don't have
a handle on like depression
and autism spectrum
disorder are also linked
to perturbations in the gut microbiome.
Suggesting that the gut microbiome
may actually influence remote organs.
And there's a couple of
really key seminal studies
that have shown this.
They've shown that perturbations
in the gut microbiome
are associated with
autism spectrum disorder
and also with cardiovascular disease.
But importantly what
these studies have shown,
is that it's microbial
metabolites, microbial products
that are responsible for these disorders
and much of this work
has been done in mice
with some follow-up work in humans.
So it suggests that the
gut is not like Vegas,
what happens in the gut
doesn't stay in the gut.
It actually enters the circulation
and these small molecules
and perhaps there's some
inklings even microbes themselves
may actually translocate to
other sites across the body
and change the physiology
of the organs there
contributing to the health or
disease of those remote organs
but how do we really know
that it's the gut microbiome
that's responsible for this?
Well, that evidence has come from
some really elegant mouse studies.
So in these studies, in this
case that I'm showing you,
the feces of obese individuals
and lean individuals
were transferred into germ-free mice.
These are mice that have
no existing microbiome.
They're bred to lack a microbiome.
They're not particularly healthy mice
but they're bred to not have a microbiome.
They're a wonderful vessel
for studying how microbial
introduction into kind
of a pristine environment
may shape the physiology of the host.
And that's what these
studies have shown us.
Transfer of the obese microbiome
into a germ-free mouse
sets up an obesogenic
microbiome in that animal
and those animals gain
weight at a much faster rate
than that of animals who
received the lean microbiome.
Suggesting that the
phenotype of the disease
can be transferred from the
patient by transferring the gut
microbiome of that patient to a mouse.
That's pretty incredible.
That means that the microbiome
is responsible in large part
for obesity in this case.
What's exciting is that
it's not just obesity.
This has also been shown for Kwashiorkor.
This is a wasting disease
with neurological deficits
that can be quite prevalent
in underdeveloped nations
like Bangladesh for example.
Same thing.
Transfer of the Kwashiorkor
gut microbiome or feces
to germ-free mice induces
wasting disease in those animals.
More recently it's actually been shown
for autism spectrum disorder.
Feces from patients with ASD
transferred into germ-free mice
induce neuro behavior that is consistent
with the symptomology of the disease .
So again, we're finding
multiple disease indications
where we can recapitulate
features of the disease in a mouse
who receives the
microbiome for the patients
with the disorder.
So what can we do?
Well, we call it yellow soup for the soul.
Fecal microbial transplant.
I'm sure you've all heard of it.
It's not new.
I call it yellow soup for the soul
because there are records in
5th century Chinese medicine,
of producing yellow soup
from feces as a treatment
for gastrointestinal conditions.
We've just recently rediscovered
fecal microbial transplant.
And what's very exciting is
that it is essentially doing
what we do in the mice but
instead it's transferring
the healthy gut microbiome
from a healthy donor
to the gut microbiome of
a patient with a disease
or condition or an infection
to try and reconstitute
the gut microbiome of the
patient and treat the disease.
So this has 92% efficacy in patients
with Clostridium difficile infection.
Antimicrobial treatment
for Clostridium difficile
is about 30% effective.
And in this trial that used
fecal microbial transplant
to treat the Clostridium
difficile infection,
they actually stopped the trial early
because it was really not, they
could not treat the patients
with this treatment because
they were seeing 92% efficacy
versus 30% in the vancomycin taper
and microbial treated patients.
It was unethical to continue the trial
and not use this to treat patients.
And we actually offer this
at UCSF as a treatment
for Clostridium difficile infection.
It's also been used in a small
pilot early study of children
with autism spectrum disorder.
It's about 18 or 19 children in the study.
There they saw significant reductions
in neurobehavioral
symptomology in those children.
In this case instead
of a single treatment,
where there's a colonoscopic delivery
of the fecal slurry into the diseased gut.
They did that initially but
then they followed it up
with a month of sustained
microbial pressure
in which the children actually consumed
freeze-dried fecal capsules
and that was sufficient,
a month of treatment,
to significantly reduce
the neurobehavioral
deficiencies in these patients.
They've also recently
followed up two years later
with these children and
this effect is sustained.
And in fact, they've seen
even greater improvements
across this small cohort
that has been treated.
And so now this is under
clinical trial in a much larger
placebo controlled
studies across the country
as a potential treatment for
autism spectrum disorder.
We at UCSF have been looking
at inflammatory bowel disease.
I'm in the gastroenterology division.
I can tell you that we
looked at Crohn's disease
and ulcerative colitis and
fecal microbial transplant
does not work for Crohn's disease.
At least the way that we tried it
with a single colonoscopy delivery.
We had several adverse events
and we shut down the study.
And I think it's important
for that message to get out
equally as the 92% Clostridium
difficile efficacy message.
It's not equal.
The microbiome is not the answer
to all of our patients' ailments.
And I think that it's
important that we're cautious
and that we are careful about
how we implement this field
and how we use this field
to treat our patients.
However, with an approach
very similar to that,
taken in the trial of autism
spectrum disorder patients,
we're now at about 40% response rate
in our ulcerative colitis patients.
And that's really exciting.
You know our biologics are
about maybe 20% efficacy
and we try different
biologics in patients to ask
what will work for them.
But we're seeing 40% response rate
with fecal microbial transplant.
We've got ideas how we can
even enhance this even more
and I'll talk a little bit about this
a little later in the study.
So for me, we're at a watershed
moment in human biology.
We've just discovered that we have this
ancillary microbial genome that
really influences our health
that shapes how our
cells work and influences
our health status.
And what I want to shift
now is talking about
how we leverage this field to
tackle a disease that I know,
probably everybody in the room
knows somebody with asthma.
Right, now in the U.S. we're
at about 11% of our population
diagnosed with the
disease and it's growing.
And you can see from this
map this is a disease
of westernized nations.
This is a disease of
lifestyle and environment.
This is not necessarily a genetic disease
in the typical sense.
What I think most alarming
for me is that the prevalence
of this disease has
increased most dramatically
in the pediatric population.
Children are disproportionately
affected by allergic asthma
which is the predominant form
of asthma in this country.
And for those maybe a little
less familiar with the disease,
it's characterized by a pretty
specific immune dysfunction.
Children with allergic
asthma have far fewer
of the specific type of T-cells
called regulatory T-cells.
They produce this molecule called IL-10.
And you wanna think about these cells
as putting the brakes on inflammation.
We need them to dial down inflammation.
So children with asthma have
far fewer of these cells
and instead they have
much more of these ones.
These are another type of
T-cells called T2 cells.
And they produce three
other molecules called
IL-4, IL-5, IL-13 and
they ramp up inflammation.
These children are also
characterized by having very high
concentrations of this antibody
IgE in their circulation.
So they're the Cardinal immune
dysfunctional features of allergic asthma.
Something to remember as we move through
the rest of the presentation.
I think what's also striking to me is that
while we can treat our
patients with corticosteroids,
long-acting beta
agonists, we have no cure.
And that's what really
drove me into this field
and start thinking about very early life
and what are the factors that
influence disease development
and could the microbiome be
the canary in the coalmine
for asthma and allergy
development in childhood.
And what drove me towards
that idea was really
the opportunity to stand
on the shoulders of giants.
There's many many studies
that have tried to figure out
the genesis or the developmental origins
of allergy and asthma.
So there's been lots
of very large studies,
birth cohort studies
where babies are followed
into childhood from birth.
You know their early life exposures
and you know whether they
developed allergy or asthma
years later in childhood.
And these studies are really
consistent in the factors
that we know increase the risk of disease.
There are things like formula-feeding,
antimicrobial administration
and cesarean section.
And if those factors sound familiar,
they are amongst the things
I told you at the outset
of this presentation,
shaped the composition
and the activities of the gut microbiome.
On the flip side, decreased
risk of allergies and asthma
in childhood are associated
with breastfeeding,
with exposure to livestock and animals.
And in fact we've shown in
the inner-city environment
to cats, mice and cockroaches.
All vectors for microbes and they increase
the microbial diversity
and microbial exposure
for babies in very early life.
And we think that's important
because we think the
environment of the baby serves
as the library of microbes
that are available
for accumulation into the
gut microbiome and elsewhere
as we develop our microbiome
in that critical window
of the first few years of life.
But we were still,
before we really launched into this field,
interested in asking questions in models.
Can the gut microbiome
really impact the airways?
Because no one had really shown that.
And so to do this we did
a pretty simple study
in which we took mice
and daily we fed them
this lactobacillus species.
We did that for a week before
we sensitize the airways
of the animals with cockroach antigens.
So IT stands for intratracheal
and CRA is cockroach antigen.
So we expose the airways
of these mice to an antigen
that induces allergic inflammation.
As a control group, we had
animals who didn't receive
the Lactobacillus johnsonii.
And what we found was that
in the animals that received
the Lactobacillus johnsonii,
you can see that they have
significant we reduced
IL-4, IL-5 and IL-13,
the three molecules I told
you that the the group
of cells, the T-cells produce that promote
allergic inflammation.
And this was true whether we looked at the
expression of these genes or
the protein of these genes.
And what was even more compelling is
this is what the airways
of these animals look like.
These are the animals whose
airways we've sensitized,
who got no lactobacillus into the gut.
Here are the airways
of those that received
the lactobacillus supplementation.
The airspaces of these
animals are absolutely pink
and occluded with mucin.
That pink staining stains mucin.
So they are completely full of mucin.
These are highly inflamed
airways and this does not occur
in the animals who received an oral
lactobacillus supplementation.
We began to start thinking about this.
Is this just about
allergy or is this really
a more profound airway protection
that occurs when we change
the microbiome by introducing
microbes into the gut.
And so we asked the same question
but here we didn't use allergen.
Now we used respiratory
syncytial virus or RSV.
We think of that as an asthmagenic virus.
Children who have an infection
with RSV in the first
few months of life that
requires hospitalization,
are significantly more likely
to go on to develop asthma.
It's kind of a red flag for asthma.
And so we have this model
in which here we used
live lactobacillus johnsonii
or heat-killed lactobacillus.
Do we need a metabolically active microbe
to engender protection in these animals.
And PBS is just saline.
That's the control in this study.
And we know that when we
infect these mice with RSV,
they have this very predictable
kind of infection dynamic
and by day eight we can see
profound pathology in the airways.
And so what we found is that
when we tested the airways
of these animals for how
responsive they were,
only the animals that received
the live lactobacillus johnsonii
had significantly
reduced reactive airways.
And also they were the
only animals that had
significant reductions in
allergic inflammatory markers
and molecules in their airways.
Again, IL-4, IL-5 and IL-13.
So this told us that we needed
a live microbe to actually
confer protection in the airways.
Which is what this is pointing out.
But we began to think
about how does this happen.
What's actually happening
before we get to that stage
where we can see differences
in airway pathology.
And so we rolled back the
timeline on this model
and simply asked with
the same type of model,
now we're just looking
at animals supplemented
with live Lactobacillus
johnsonii versus PBS,
what happens at day two.
And we were particularly
interested in whether there were
metabolic changes in these animals.
Whether the small molecules produced
by an altered gut microbiome
could hold the secret
to the response to the viral infection.
And I don't expect you
to read all of this.
Here's where we use that mass spectrometry
to look at all the small
molecules that are produced
in these animals in their
serum, in their circulation.
this is what we see in the
control animals two days
after we infect them with
respiratory syncytial virus.
Anything in blue has
gone down from baseline,
anything in red has gone up.
Not a whole lot going on.
And I think you'll agree that
that's true when I show you
what happens in the animals that receive
the live lactobacillus johnsonii.
Now we see two days after the
viral infection in the airways
this immense capacity
to produce a whole range
of amino acids, peptides
but in particular lipids
and when we saw this list of lipids,
we got super excited.
Because in this list of lipids
are a whole range of things
like polyunsaturated fatty acids
that we know dial down inflammation.
And so that suggested
to us that when we alter
the gut microbiome of these mice,
we change the metabolic output
not just of what's in the gut
but what's in the
circulation of these animals
and that that's what
leads to the protection
against the viral infection in the airway.
But we wanted a little bit
more evidence for this.
So we did one more experiment.
We took what we call bone
marrow derived dendritic cells.
So these are immune cells
that are really critical
in response to viral infection.
And we incubated those
immune cells with the blood,
the plasma of the animals
who received either
the control PBS and were
subsequently infected
or the ones that had the
lactobacillus johnsonii
introduced into the gut
and then were infected.
So those ones that had that two-day
lipid onslaught that we saw.
And then we took those dendritic
cells, those immune cells
and asked how did they
now respond to the virus
when they encounter it.
Could the products that
we see in the circulation
change the activity of the immune cells
and that's indeed what we found.
The immune cells that we know
incubated with the plasma
from the animals who had
the lactobacillus johnsonii
now are significantly less inflammatory
and they're significantly less activated
and they have significantly
less lower capacity
to present antigen to engage
in an inflammatory response.
So what this tells us is that
by changing the gut microbiome
we can change the metabolic
output of the system
from the gut and we can actually protect
the airways of those animals.
And it looks like some of this
is through the production
of these metabolites.
What I neglected to tell
you is we started looking
at some of those
metabolites and we did find
that one of those polyunsaturated
fatty acid conferred
this phenotype in the cells.
So we were right in thinking that those
anti-inflammatory lipids
are perhaps the ones
that are driving this change
in how our immune cells
are functioning in this mouse model.
So that's all in mice.
That's great.
But that's a model system.
Could the early-life gut
microbiome actually be perturbed
in babies who go on to
develop allergies and asthma.
And maybe it's just beyond a
perturbation to who's there,
could the metabolites being
produced by the early life
gut microbiome actually
be the key to priming
the immune cell
differentially in children,
in babies who go on to
be children with asthma.
And so we really wanted to ground this
in something that was very kind of solid.
And so we think of early
life microbiome development
no differently from how any
other ecosystem develops.
And we've studied ecosystem development
for a couple of hundred years.
So they're pretty good framework.
We know how ecosystems develop.
And one of the things we know
about ecosystem development,
is that the first
colonizers, the first species
into a previously pristine
ecosystem can actually shape
the conditions in that ecosystem
and species accumulation
trajectories over time.
So What this suggested to us is perhaps
there's different types
of seed microbiomes.
Different types of micro
biomes in early life
that lead to different trajectories
of microbiome development.
And remember, the microbiome
educates the immune response.
And we think that that
could lead to distinct
immune maturation and give
rise to health or asthma
and allergy development
years later in childhood.
And again as I mentioned,
we began to think about
how this might work.
And we began to think of what we've seen
in the neurology field
or the gut microbiome
or the cardiology field that
gut microbial metabolites
can shape remote organ behavior.
And we've seen that in our
mice so we thought that
it's not just about a perturbed
gut microbiome in early life
it's perhaps the molecules
that that got microbiome
is producing really skew immune
development in those babies.
And so one of the first studies
that we address this in,
was a study of the gut
microbiome of healthy babies
and high risk for asthma babies.
And they're designated
high risk for asthma babies
because they have at least
one parent who has asthma
and this is the meconium microbiome.
This is the first bowel
movement of newborn babies.
This forms in utero.
And here I'm showing you
another one of those plots
where it's one of those distance plots.
In red, are the high-risk babies,
in green are the healthy babies.
And you can see they're kind
of segregated along this axis.
They're spatially separated.
They're actually significantly different.
So high risk for asthma babies start life
with a very different
microbiome from healthy babies.
And what's exciting and
consistent with what ecosystem
theory would predict, those babies follow
a different trajectory of
microbiome development.
These are the healthy
babies and they accumulate
bacterial diversity at a pretty quick clip
over the first year of life.
In contrast, the high risk
for asthma and allergy babies,
have delayed diversification
of their gut microbiome.
And remember, each species
of microbe brings with it
its own genome and its
own repertoire of genes
into the gut microbiome.
So these babies will
have a very functionally
distinct gut microbiome.
They just don't have the
same microbial capacity
that a healthy gut microbiome has.
But that's simply one study.
Can we see this in a population?
These are high risk
versus healthy controls.
This is the extreme.
Can we actually spot this just
in a population of babies?
And so to do this we studied
a large birth cohort.
Again, this is one of
these studies where samples
are collected in very early
life and the babies are followed
out through life and we know
whether they, in this case,
developed allergy at two years of age
or asthma at four years of age.
and the part of the study
I'm going to tell you about,
we had 130 one-month old babies
from whom we had fecal samples.
So we profiled their microbiota
using the the gene-based approach
I told you about at the outset,
to find out which bacteria
and which fungi were
present in these microbiomes
of these 130 babies.
And then this is quite
a large amount of data.
We became hands-off at this stage.
We asked an algorithm can you
find significantly distinct
gut microbiomes amongst these 130 babies?
And the answer was three.
The answer always seems to be three.
Here again, I'm showing you
one of these distance plots.
And here you can see that
what the algorithm called
the three different gut
microbiomes, we've labeled them,
neonatal gut microbiome
one, two and three.
Shown in blue, green and red.
And again they're spatially segregated.
They're significantly
different in their composition
and actually calling them
neonatal gut microbiome
one, two and three.
Those classifications explain
about 9% of the variants
in microbiota as we see
in these 130 babies.
But the key question is does
starting life at one month
of age with one of these
gut microbiomes relate to
the clinical outcomes we
see at age two and age four.
And the answer was a resounding yes.
Babies with the one-month
old NGM3 gut microbiome
were at significantly
higher risk of developing
atopial allergies at age
two and asthma years later
at age four about three times more likely
to develop these diseases.
What was different about
these gut microbiomes?
Well, we found was it wasn't
just a loss of bacteria
that we saw on the high-risk
NGM3 baby gut microbiome.
We also saw that they
were highly increased for,
what we consider to be allergenic fungi,
rodatorola and Candida.
So this isn't just about
a loss of bacteria,
it's also about an increase in fungi
in the gut microbiome of these babies.
And using mass spectrometry,
we asked is the metabolic
output of this gut microbiome distinct?
And we found that yes it
is and I'm not showing you
another one of those crazy plots
where you can't read anything
but I'm gonna summarize
and tell you, just like
we saw in our mice,
the babies who went on to
develop allergies and asthma
had significantly reduced
polyunsaturated fatty acids
amongst many other lipids.
And they also were highly
increased for this one lipid,
12,13 DiHOME, a diet oxyfatty acid.
So what all of this pulled
together suggests to us
is that the NGM one and two microbiomes
are actually tolerogenic.
They might be educating
the immune response
in a very different way from
the NGM3 microbiome in the gut
which is full of potential pathogens
and is metabolically very much altered.
But how do we test this?
We need to really think outside the box.
All we had was stool from these babies.
Nothing else.
And so what we thought is
we could take immune cells
from healthy adult donors
and we specifically
took the immune cells that
govern allergic response,
dendritic cell which
present antigen to T-cells
and educate the T-cells and
dictate what they will be
when they mature.
And so we purified these
specific populations of cells,
remember, from healthy adult donors,
and we co incubated the dendritic cells
with the cell free products
of the gut microbiome
of the high-risk NGM3 and
the low risk NGM1 babies.
So that we could prime
those dendritic cells.
We let them sit for a while
and then we cultured them
with the naive T-cells and we
were particularly interested
in what we would see with TH2 cells,
remember the ones that produce
inflammatory cytokines,
and T-reg cells, the ones
that dial down inflammation.
And what we found was that the
cells that were co incubated
with the NGM3 fecal water from that
one month-old gut microbiome
had far greater numbers of TH2,
allergic T-cells, they produced more IL-4
and those T-cells were
significantly less likely to be
regulatory T-cells.
So remember I told you the
cardinal immune features
of allergy and asthma at
the outset of the talk,
here we can recapitulate them
using the fecal products,
the gut microbiome products of a high-risk
one-month-old gut microbiome.
This is years before we
ever diagnosed the disease.
But we were really interested in asking
what are the products in
that kind of fecal milieu
that produce this immune dysfunction.
And we focused initially on this lipid
that I told you about 12,13 DiHOME.
Because it kept coming up
in all of our analyses.
No matter what way we carved out the data,
we kept coming back to this molecule.
And so we asked whether this
molecule could recapitulate
features of that immune
dysfunction I just showed you
that we produce with the fecal water.
And what we found was that
critically this one molecule,
as you increase the concentration of it,
you reduced those regulatory T-cells
and you reduce their capacity to produce
the anti-inflammatory molecule IL-10.
So now we have a molecule that
looks like it actually skews
a very critical part of the
immune response that we need
to dial down allergic inflammation.
So we wanted to test
that in a mouse model.
What we did is the same mouse model
as I introduced you to earlier on,
but here three hours before
we challenged the airways
with cockroach, we injected this one lipid
into the gut of a group of these mice
and asked whether it exacerbated
the allergic response
in the airways of these animals.
And what we found was a resounding yes.
Here are our controlled animals.
Nice, clean air spaces,
here the sensitized animals.
All these little black
spots are inflammatory cells
around the airspace.
As you can see they're constricted,
there's pink mucin there.
These are the animals
that got that one lipid
into their guts before we sensitized them.
Now we've absolutely
occluded their air spaces
with mucin and inflammatory cells.
Ad consistent with what
we've seen in a test tube,
these animals have significantly reduced
regulatory T-cells in their airways
and they have significantly increased IgE,
that antibody that we know is associated
with allergy and asthma
in their circulation.
So just by the simple
introduction of this one lipid
into these mice, we can exacerbate
their allergic inflammation
in their airways.
And it suggests to us that
elevated concentrations
of this lipid in the very
early life gut microbiome
could actually have the
same effect on that critical
population of immune
cells in these babies,
reducing their capacity to dial
down allergic inflammation.
But we wanted to dig a little bit deeper.
This molecule is the product
of metabolism of linoleic acid.
Linoleic acid is plentiful in breast milk,
it's plentiful in formula.
It's a key lipid in very
early life nutrition.
What we found in the
healthy babies is that
their fecal microbiomes
are highly enriched
for this other metabolite
DiHOMEgamalinoleic
which is a precursor to a whole range
of anti-inflammatory products.
The high-risk babies we had shown,
were highly enriched for this lipid.
So what we hypothesized is it's
actually the gut microbiome
of these babies has the capacity
to make 12,13 DiHOME from linoleic acid.
And we know that the final
step to make this product
is catalyzed by an epoxy
hydrolase, a special type of enzyme
that converts 12,13
EpHOME to 12,13 DiHOME.
So we went kind of dumpster
diving in the gut microbiome.
We went looking for microbial
epoxide hydrolase genes.
And we simply quantified them
in the gut microbiome babies
who went on to be healthy or
those who went on to be ectopic
or asthmatic years later in childhood.
And remember this is the
one-month old dot microbiome.
And we found that the babies
went on to develop disease
were significantly enriched
for bacterial genes
to make this lipid.
Not only that, they also had far more
of that lipid in their feces.
And we went on to functionally
test these bacterial genes
and found that three of
them could specifically
make 12,13 DiHOME, this lipid
that seems to be so critical
in promoting allergic inflammation
as we've seen in our studies.
And these are species that every baby has.
They have them in their
meconium microbiome.
Every baby has an Enterococcus faecalis,
every baby has a befitted
bacterium bifidam.
But we think the difference
between health and disease,
is that the babies who have these species
with these bacterial genes
are the ones that go on
to develop allergies and asthma.
And we show this is true
using two birth cohorts.
So we showed that for every
doubling of the number
of epoxide hydrolase
genes in the one-month-old
gut microbiome, there's a
significant increased risk
of developing allergies and
asthma years later in childhood.
And that's also true for
every nanogram increase
of that lipid 12,13 DiHOME
in the feces of these babies.
And that's consistent when we
look at a completely different
cohort of babies based here
at San Francisco at UCSF.
So what this tells us is we've
gone from a gut microbiome
perturbation to identifying
what we're thinking
of microbial risk genes.
These genes confer
increased risk of developing
allergies and asthma
years later in childhood.
And because of these
genes and their products
we're beginning to understand
why these babies develop disease.
These microbial products
really skew immune function
and reduce the key immune cells necessary
to dial down allergic inflammation.
So we've got a new model for a pathway
by which allergy and asthma may develop.
It's one in which babies inherit
microbes from their mothers
and they begin to develop
their gut microbiome.
And those have a specific
type of gut microbiome
that is enriched for
microbial capacity to produce
this lipid 12,13 DiHOME,
they have reduced T-regs,
these key immune cells to
dial down inflammation.
We know from our mouse studies
that this lipid escapes
the gut and actually
enters the circulation
and goes to the airways.
And we think it exerts
the same effect there,
reducing these key immune
cells in the airways.
And what that gives rise
to is a lack of capacity
to respond to pathogenic microbes
we encounter with every breath.
And those babies build up a
pathogenic airway microbiome
over time and that's what
gives rise to the diagnosis
of asthma in these children later in life.
We know that this starter
distinct perturbed gut microbiome
gives rise to a different
trajectory of microbiome
development in the gut of these babies.
So what can we do?
Well, we've rationally
designed a synthetic cocktail
of microbes to be introduced
in very early life,
day one, day of delivery, to
babies at high risk of asthma.
These microbes encode all of
the functions that these babies
are missing in their starter microbiome.
And the idea is that these
microbes shape the immune milieu
around them and that that
governs the trajectory of
microbiome development and
will allow for appropriate
microbiome development in early life
and also will change the metabolic output.
We will re-engineer the
microbiome in these babies
to change the metabolic output,
change the interaction
with the immune response
and prevent asthma and this
product is currently in
clinical safety trials first
before we use it as a treatment
but it's not just about
allergy and asthma.
We also are performing
studies on the very early life
gut microbiome and obesity.
Another plague on our nation.
And we're finding very exciting
and somewhat familiar findings.
Here again, we find three
distinct gut microbiomes
in a much larger cohort of babies.
Over 400.
One of them confers a
significantly higher risk
of developing overweight and obesity
phenotypes in childhood.
Those babies are more
likely to be formula-fed.
And what we found is
that the products of that
gut microbiome change how
the cells lining the gut
take up and release lipids.
In fact it accelerates that process
and so that we think
that that excess lipid
is entering the circulation
and if it's not used up
it's laid down as adipose
and this could be a mechanism
by which these children
ultimately develop obesity
and overweight phenotypes
later in childhood.
Also offering the opportunity
that perhaps again,
early intervention in these
high-risk babies could change
the course of their microbiome development
and metabolic output of those communities
and change their course of health.
And again, it's not just obesity.
Tiffany Scharschmidt who's
an incredible faculty member
here at UCSF is showing that this happens
on the skin as well.
The first microbes that
colonize the hair follicle
change or influence the immune
milieu in that hair follicle
and dictate which other organisms
get to come to the party
and co-colonize in that niche.
And this is offering
opportunities for again,
changing the microbial host interaction
to change the course
of disease development.
We've also been looking at this
in terms of the upper airway
microbiome development and
again have shown that babies
with different trajectories
of microbiome development
in the upper airways are
at higher risk of asthma
and there's specific colonization patterns
that we've identified in the upper airways
that not only increase the risk of asthma,
they also increase the
risk of the exacerbation
in those children.
So again, thinking very
differently about this,
thinking about early life as
an opportunity to re-engineer
the microbiome in a manner
that changes the physiology
of the host and alters the
trajectory of disease development
in these individuals.
So what have we learned from this lecture?
We know that very early
life is a critical period
in which we build our microbiomes.
Not just in the gut also in the airway
and at other sites across the body.
And that the types and more
importantly the genetic capacity
of those microbial
communities is really critical
to promotion of health in humans.
We know that there's
distinct founder-populations
of gut microbes in very early
life that strongly shape
immune function and that relate to
childhood disease outcomes.
So we believe again, we've got
this canary in the coalmine,
we've got this very early
perturbation that gives rise
to a downstream disease development
years later in childhood.
And part of that is that
the microbes that are there
are producing specific small molecules
that are skewing immune function.
And we believe that this is
occurring in the earliest stages
of postnatal life and then
that skewed immune function,
that inflammatory milieu in
the gut, is really strongly
selecting the types of
microbes that are permitted
to occupy the niche in the
gut and that's why we see
a lower diversification
of those gut microbiomes
over time in these babies.
And we're really excited
because we really believe
that this is a new field
that is changing the face
of human biology and we are
delighted to just this year,
launched the Benioff Center
for microbiome medicine here at UCSF.
We're excited for what this field can do
and I've just really shown you
a snippet of the background
and some of the exciting work
that's going on in the field.
Within the center, we're
leveraging for example,
healthy periodontal microbiome
to find new microbes
and molecules to tackle
periodontal disease.
We're looking at how the gut microbiome
relates to multiple sclerosis.
Sergio Bernzini and neurology
has really strong data linking
this disease with the gut microbiome
and he's now actually engaged
in a fecal microbial transplant
study of this population
asking whether that can improve
symptomology in his patients.
Katey Pollard who's here at
UCSF is a computational whiz
and she's the one that that's
allowing us to look past
who's there and look at specific genes
that are the differentiator between health
and disease development in our microbiomes
and in our patient populations.
And then finally we're
delving deeper into our
trials of fecal microbial
transplant to understand
how does it work, which microbes matter
and which molecules matter so
we can build bespoke synthetic
microbial communities that are
tailored to specific patient
subsets and not just necessarily
go in with the blunderbuss
fecal microbial transplant approach.
And we believe with this we can actually
enhance efficacy in this population.
There's other things we're doing.
We're leveraging microbes
to combat microbes.
Because that's what microbes do naturally
in their ecosystems.
they antagonize one another
and we're leveraging this knowledge.
We're using phagers
Phagers like viruses that bacteria have
and they are very specific
in what they target
and we're asking whether
we could use phage therapy
instead of antimicrobial therapy.
Can we be really specific
and go after key pathogenic
organisms that we believe are driving
the pathology in our patients.
In our upper airway studies for example,
we've got a couple of
very key target organisms,
Moraxella catarrhalis.
we've seen a crop up across
multiple different studies
and we're now gonna target
it with phage therapy
to ask whether we can specifically
take out that organism
and re-engineer the
microbiome of individuals
that have these colonization patterns
associated with their disease.
There are efforts, not
necessarily at UCSF,
but at other sites to leverage microbes
to express specific cargo in the gut
to produce the IL-10
molecule, for example,
that dials down inflammation.
We're working very hard
at UCSF to understand diet
and the microbiome.
I showed you a snippet of
work from the Turnbull lab.
We're using diet in a pilot study
in ulcerative colitis
patients to ask whether
we can change the
microbiome of those patients
and induce remission by diet.
We're also as I mentioned,
developing bespoke synthetic
microbial cocktails and
ultimately I believe that is the
combination of diet and
microbiome or specific substrates
and microbiome symbiotics
that I think will be most
efficacious in our patient populations.
And ultimately our goal at the center is
to focus on the early life
microbiome as an opportunity
to intervene early to prevent
disease and to develop novel
therapeutics to treat
the variety of diseases
that our patients suffer from.
And with that I am very
happy to take any questions.
(applause)
- Yeah, the question is
about probiotics in food
and probiotics themselves
over-the-counter products.
It's not an FDA regulated area.
Although they have been trying
to really hone in on claims
being made by companies
about what probiotic
supplements can actually do.
I'll also say that not
all probiotics are equal.
There are differences in
A, the types of microbes
that are in probiotic supplements
and in B, the quantities
of microbes, of viable live
organisms in those products.
And that vary very tremendously
across products on the market.
I think what's really key
is two papers that came out
last year that I think
were really critical in our
understanding of how probiotics may work
and these were studies
looking at the gut microbiome
of healthy volunteers who
consumed a probiotic product.
And what they showed
was whether this species
in the probiotic were
basically allowed to engraft
or were capable of engrafting in the gut
was entirely dependent on the microbes
that were there already.
And again, this gets at
this idea that the microbes,
the first-come-first-served.
The microbes that are there already
dictate who gets to come into the party
and that was shown very clearly.
And that may explain why
individuals may respond
very differently to
microbial introduction.
Be it by probiotics, be it via microbes
that are on the food we consume.
Our microbial encounters and
which microbes get to engraft
anywhere in our system seem
to be strongly influenced
by the pre-existing microbiome
that is there already.
So I think we can do better.
I think there's some nice
proof of principle out there
and in fact some products
have shown efficacy
in controlled clinical trials
but I think there's a broad
variety of products out there.
They're really not equal.
And in fact there's been
some studies that have shown
that in some cases some
of the products, A,
don't contain the species that
they're supposed to contain
and actually contain a different species
that could be detrimental to the consumer.
So the question is you
know how do you explain
meconium microbiome?
Does it come from the mother,
where does it come from.
And if you're gonna
treat, why treat at birth
and why not treat the mother.
So a few things:
meconium is swallowed amniotic fluid.
It is by definition formed in utero.
In a study I didn't show
you that we are preparing
for publication is one in
which we've actually asked
when are microbial encounters occur
in the human fetal intestine.
There's a lot of controversy
around whether there's
a microbiome associated with the placenta.
The kind of jury's out on that.
But we actually asked what's happening
in the intestine of the fetus.
Because there we know
through previous studies,
not from our group but by other groups,
that the immune system has already started
to evolve and develop.
And by 13 weeks gestation
in humans, has the capacity
to sense and respond to microbes.
So we looked at mid gestation
and found that there
was a very sparse microbial
signal in human fetal meconium
but that we could find microbes there.
They're in these tiny little pockets,
they're kind of tightly
densely packed together.
They're embedded in the mucin
so this is not contamination
and they're in a subset of
the samples we examined.
We found an organism whose
presence was correlated
with a specific type of
immune cell response.
We weren't able to isolate that organism
from the fetal meconium using
media that traditionally
selects for that type of organism.
We had to add pregnancy hormones
and an immune cell population
into the selection media
to be able to isolate that organism.
We've sequenced its genome.
It looks like other organisms
that are phylogeneticly related
but it has unique genomic
features that we've not
seen in other species,
even those that are highly related.
Suggesting that it may be highly evolved
to be in fetal intestine in utero.
We think that that process
probably ramps up later
in pregnancy because the this communities
that we detect in and postnatal meconium,
the first bowel movement after birth,
they're simple but they're more complex
than the really really simple
communities that we saw
in the fetal intestine.
Why not treat the mother?
We don't know enough.
It's what I would say.
Our studies have shown us that,
other studies have shown
that there's a difference
in the three-month-old
got microbiome related
to allergy and asthma,
our studies have shown that
through at one month of age
and in meconium and
that's what's driven us
into the fetal intestine to
ask whether microbes are there
but we know virtually
nothing about the maternal
microbiome during pregnancy.
There's a sparsity of papers out there.
We know it changes with
advancing pregnancy.
We don't know why that happens.
We don't know what the
implications of that are
on downstream health
outcomes of the babies.
And I guess the reason for intervening
at early postnatal life is
that's the inflection point
in microbial development.
That's when these communities
are at their simplest
and when we believe there
is greatest real estate
open in the gut for colonization.
And rather than we will
perhaps ultimately intervene
in pregnancy but until we
know a lot more in that field,
that's not something that
we are comfortable doing.
We do know and we have
lots of different studies
telling us what high risk
for asthma babies are missing
in terms of microbial
capacity from the get-go,
from the day they arrive out
through the first year of life.
And for me that's a safer approach to take
rather than playing with
what's happening in utero
when we have no idea the
implications of what we may do.
Yeah I mean I have to say
I would preface the overuse
of antimicrobials and its
effect on the microbiome.
I think there's a number of things
that have gotten us to this
place where we've extinguished
a number of microbes that we
think are probably critical
for human function and health.
One of them is plausibly antimicrobial use
but there's many other things.
Diet for example has dramatically changed.
We know that antimicrobial
administration causes an acute
and sometimes pervasive
drop in the diversity
of microbes in the gut but
your response to antimicrobial
treatment again is
predicated on which microbes
you have in your microbiome.
Antimicrobials have saved lives.
We have to first and foremost remember
what we've used them for but
in doing so we may have created
a bigger issue with chronic
inflammatory diseases
is the thinking.
But I will say that I still
think they have great utility.
In our fecal microbial transplant studies
with ulcerative colitis patients
when we simply did a single
colonoscopic delivery
of the fecal microbial transplant,
no one responded to the treatment.
When we pre-treated the
patients with antimicrobials
and then gave the colonoscopic delivery
followed by a month of treatment,
that's when we got to 40% efficacy.
So I guess it proves principle
that it clears the decks
for colonization and there is utility.
And I think there's been a lot of effort
for improved antimicrobial stewardship.
I know I've gone recently with
my child who had an earache
and we were given a prescription
but told to wait 24 hours
and we never filled the prescription.
And I think that there's
a lot more awareness.
We didn't know about
this field 15 years ago.
We didn't know the impact or the,
we really thought about
antimicrobials in terms
of antimicrobial resistance.
We didn't consider what we
are doing to the microbiome
with their administration.
So I think if anything been
beneficial and prompting
greater antimicrobial stewardship
across the health based system.
There's one great paper out of
Israel a couple of years ago
where they studied just that.
They studied Aspartame which
is an artificial sweetener
and they showed that A,
it impacts the microbiome
and B, that the glucose spikes
that they found in patients,
participants who consumed
the artificial sweetener,
were actually higher than
that of a glucose hit.
So it it yeah, yes, yes and yes.
It affects the microbiome
and it is really changing
the kind of metabolism of the system
which we believe is really
what's driving the physiology
of cells in the human super organism.
So limited information on it
but what has been out there
has been pretty interesting.
They may not be doing what
we think they're doing.
So just to be,
the question is we've
talked about introduction
of fecal material in children.
I haven't, I'm talking about
introduction of very specific
microbes into babies not feces.
What about adults?
Great great question.
Yeah, I mean we believe
that you can manipulate
and re-engineer the microbiome.
I think it's a higher bar in
established chronic disease
and I think we're beginning
to understand why.
We're starting to look at
whether these microbial molecules
actually don't just change
what the cells of the host
are producing but also
maybe hardwire the genome
of those cells and we've evidence
that that actually occurs.
So you're really undoing several layers
of selective pressure on the
microbiome from the host side.
So I think that that's why you
require a month of treatment
in the case of autism
spectrum disorder children
to see a significant
reduction in symptomology
in those children.
And I would argue that
perhaps for those with
chronic inflammatory diseases,
it may be even more long term
treatment to manage their
disease symptomology.
In some severe cases, the
jury's out whether we can
ultimately bring back that
system to one of a healthy system
but we'll certainly try.
So the question is
whether there are studies
that have examined the microbiome
in adults with obesity.
There's a large body of literature on that
and I would say that there are
some of the seminal studies
in the microbiome field.
The very earliest studies showed
that the obese gut microbiome
is significantly different
from that of the lean microbiome.
And even in the simplest
terms, just the relative ratios
of the key groups of microbes in the gut
are kind of firmicutes and Bacteroides
or a ratio of three is to
one in lean individuals
and it's more like 30 to
one in obese individuals.
And that's what prompted those studies
asking whether you could
transfer an obese phenotype
by just simply transferring
the gut microbiome
to those germ-free mice.
Whether there are approaches to manipulate
the gut microbiome to try and undo that,
in one of those early
studies they did show that
an intervention that comprised
of calorie controlled diet
and exercise regime led to
weight loss and to the return
of the gut microbiome
back to that 3:1 ratio
compared to the obese microbiome.
It was a year of intervention.
And this is the thing,
thinking about what it takes
to get to those and the severity
of those chronic conditions
I think it's going to be
a long-term intervention
to really bring that system
back towards something
that resembles a healthy microbiome.
The question being about H.
pylori being a carcinogen.
I think what's really
important to think about here
is how these organisms
behave is entirely related
to their microbial peers
and their local ecosystem conditions.
And thinking about Helicobacter
as a single thing to target,
I'm I'm not sure that
that's the right way to go.
Marty blazer would counter that
loss of Helicobacter Pylori
is associated with increased
allergy and asthma development
and western worlds.
So I think we have to think
a little bit more critically
about what these organisms are doing,
how they're functioning and
really targeting the function
rather than the organism.
Because, most of us have
Helicalbacter Pylori
but it's controlled in healthy conditions
both by the conditions in the stomach
and by the organisms
around that Helicobacter.
So I think as we dig deeper
into understanding specific
mechanisms by which specific microbes
drive disease processes,
we become more precise
in how we target those disease
processes via microbes.
Okay, thank you so much.
(applause)
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