The Human Microbiome: A New Frontier in Health

The Human Microbiome: A New Frontier in Health

(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) (upbeat music)

99 thoughts on “The Human Microbiome: A New Frontier in Health

  1. Wow all these processed packaged foods are killing the diversity of bacteria in our gut. No wonder we have so many food allergies and sensitivities

  2. AMAZING and Mesmerizing !!!! I watched it once and should watch it few times more….Thanks for such valuable information and research ….

  3. An extraordinary lecture . The future of medicine starts from the gut .It must be placed left ,right and center. It is the only way to make sense of all systems in an evolutionary manner . Where we come from and where we are going

  4. We should really study people with “fibromyalgia” i.e. chronic widespread pain. I am certain it’s a condition caused by a disturbance in the gut microbiome. Curing these patients would get millions of people back to work, increase their QOL and save billions in healthcare spending.

  5. why? pope envoliving global village nwo may 23 your goal to cure, is opposed to their demonic mission to take all life into submission to the end goal of lucifer they hail.

  6. I am highly impressed ! Microbiome Science is in it's very beginning stage and has the enormous potential for application in treatment of ALL medical conditions. They are a true biomarkers of most deseases. I am full of admiration for Dr. Lynch for linking different ailments with different Microbiome diversity. These studies might be awarded with the Noble Price. It is already revolutionizing diagnostics.

  7. I am 20 minutes into the lecture and I have a major objection. The lecture compares the gut microbiome in the US to the gut microbiome of two "less developed countries (as a political scientist I have a major issue with this classification but I am gonna leave that aside for a moment). The key difference the study seems to find is that the gut microbiome in the" less developed" countries is inhabidated by bacteria that break down plant fibers whereas in the US it seems to be inhabidated by bacteria that breakdown simple sugars which is a clear proof of a so-called modern diet mostly made up by processed carbohydrates. But the lecture presents this difference as a difference between animal vs plant based diet. First of all, there is no evidence that the people in the lesser developed countries don't consume animal foods. It is quite possible to consume plant fiber in addition to animal foods as it is the case in most traditional diets. Second, where is the proof that the diet in the US is animal based (given the data in the lecture). It is clear that the key difference lies in a traditional diet made up by whole foods containing a good amount of plant fiber possibly in addition to animal foods as opposed to a modern diet composed of highly processed foods consisting of largely simple processed carbohydrates possibly with a good amount of probably highly processed animal foods. To sum up the key difference is between traditional and modern diets but not in plant based and animal based diets. And to me any country who managed to protect their original diets and food sources is more developed any other country no matter how economically and/or politically (militarily) powerful the later are.

  8. Simply fascinating! As a biomedical PhD student working on the Gut-Liver axis, the gut microbiome is extremely relevant for my research. I'm glad I convinced my PI to include a segment of experiments to check how the gut bacteria play a role in our models. Great things will come from microbiome research! It's still early days to come up with targeted therapies, but man, this is exciting research!

  9. Confirmation that the British gastroenterologist Andrew Wakefield was dead on when his small study suggested a correlation between the gut and autism.

  10. The asthma is coming from the vaccines. Dr. Thomas' data shows those kids vaccinated to the full schedule have the most asthma, those who are unvaccinated have very low incidence of asthma and those kids who use his modified vaccine schedule show up somewhere in between.

  11. 100 trillion good bacteria in gut IS 85% immune system
    Nowfoods 10 strain 50 billion probiotics powder
    Natural factors 12 strain probiotics

  12. Lord, desgusting, everyth but the right thing, vegan diet, so now yello soup!👎👎👎 whynot a wonderful calliflower color full incredible tasty dish wt or wtout lemon juice, wake up folks!! As for the scientists, take off yr bloody hands over the animals!!!!!! Monsters!

  13. Science is not this…I'd advise everyone to read, Science and Health, with Key to the Scriptures.
    The more one digests it, the healthier one grows.
    Erase THIS nonsense pseudoscience from consciousness, immediately.

  14. Will any OTC probiotics restore a healthy intestinal microbiota ? Some products have 5 or10 strains , some 20 and one has 31 strains . Are they just "snake oil" ??? Would OTC probiotics work better if administered via enema ?

  15. Macroevolution is a joke. Why are there still monkeys if we evolved from monkeys?

    I believe in microevolution cuz we can adapt to our environment and so on. But macroevolution is false.

  16. Fantastic: I''ve had three exposures to Lyme disease and the structure that
    conceptualized it coherently were as a 'Biofilm'. Googling "biofilm disrupters"
    or just biofilm certainly will give more understanding to and put this in a perspective
    that will mean a very positive move forward!!

  17. One thing I'm disappointed in is that they ignored the Round Up widespread in the food supply, which destroys soil bacteria, and our food normally picks up soil microbes and that's how we normally inoculate our guts, from the food.

  18. The Lion Diet

    The Lion Diet is a carnivorous diet that consists solely of ruminant meat (beef, lamb, goat, etc.), salt, and water. It’s the ultimate elimination diet, as it eliminates practically all other dietary variables, while still sustaining your body’s nutritional needs. Thousands of people have followed this way of eating for years, reporting complete remissions of autoimmune, psychological and digestive illnesses, as well as significant improvements to cognitive, emotional and physical functions.

  19. Besides the microbiome we should also be looking at the state of the gut. Modern western diet is wreaking havoc on the gut environment through the constant putrefaction and deterioration of the stuff we call food nowadays. Proper diet has never been so important.

  20. Thank you, your lecture is very well presented and enjoyable…..
    Whole plant based foods on Instagram to develop and support the microbiome == mikewakethefoodup

  21. The tools for understanding are also the tools for misunderstanding. Natural systems are complex super dynamic interdependent scenarios, a bit beyond our comprehension, but not our facilitation and participation, so long as we can curb our misunderstandings. Thanks for the excellent information!

  22. Fascinating and well presented. It would be great to see some controlled studies on the health effects of fasting and time-restricted eating, both of which eliminated my chronic atopic dermatitis. No doctor had helped me before that, or suggested a link between my gut and my skin. Of course, fasting and eating fewer meals are free, so probably a hard sell.

  23. Big challenge understanding microbes. Very complex. They’re very clever. Were fortunate they didn’t evolve over the past billion years.

  24. 🧫🔬🦠 how is soil microbiology / healthy plants so different 🤔
    🥦 More people should grow more fresh veggies the their backyard 👍👨🏻‍🌾

  25. Some of those critters can be very harmful in the body. Some like a acid environment and some a alkaline environment.within the body. If the body PH is not balanced they have you for breakfast lunch and dinner and cause disease areas in the body . There is a therapy outside the box that’s balancing the PH and kill off the virus, bacteria, fungus and parasites that are harming the body. Dr Isaac Goiz cured Aids in 1988 and was prevented by the Mexican authority to continue his clinic was burnt, he was also banned by a reputable health Big wigs as it will affect the profits of big pharma. It’s now taught worldwide and at the university in Mexico there are over 25 thousand doctors and lay persons changing peoples life. Watch interview Maria Valdivia. Cures of forth stage cancer, It’s call medical biomagnetism pair.

  26. It could have been solely 'these nations' instead of continually repeating 'less developed.' Group based hierarchical connotations imply the literal definition of racism, in context of a cognitive heuristic equivocating actual group capability (from an elitist Western culture appraisal of group results) with the value of social groups based on their subjectively appraised results. Something also feels ethically careless about the choice use of the word 'segregated' when 'isolated' or 'separated' would've had adequate equivalency without the disconcerting prominent racial connotation of her choice of word. These seemingly minor slights can have a significant impact on whether or not members of certain social groups feel welcomed and as if they belong in these spaces.

  27. All good info but all going down the wrong road to heal anybody of anything by itself. The real solution is the gut and autoimmune issues we are all dealing with and do not realize it ! BINGO, now go heal yourself ! Most supposed doctors today are delusional and not healing anybody because they are looking in the wrong places and totally consumed in their own ignorance. Most have become simply no more than pharma sales people. It is all much simpler than most of us realize.

  28. Thank you for the video.
    Clear and comprehensible presentation .
    I hope people stop using toxic pharmaceuticals and return to using phagocytes . Nurses in Georgia, USSR did a lot of work in this field. They drink deeply from the Pierian Spring.

  29. I have watched to 40 minute mark and no mention of how huge amount of childhood vaccinations might impact the gut microbiome. If allergic asthma is happening disproportionately to children, then why not examine the main pharma introductions to children? Vaccines and antibiotics….

  30. What?!? No! Do your research! Don’t make sweeping statements about the efficacy of fecal transplants for crohn’s disease and it’s implications across the board: that we should be stepping back from this lifesaving treatment without doing proper research. This is just irresponsible! Take this video down.

  31. this needs to be on the news not shite stirring politicians . funny how 90% of autistic cases have extreme gut dysbiosis tot he point an xray of the stomach looks like someone took a pellet gun to them. symptoms vs root issues. bravo wonderful information absolutely awesome and appreciated

  32. Go to the videos by Dr Natasha Campbell Mcbride. You will know more about microbiome. She is years ahead in gut science.

  33. i suffer from multiple food allergies, eczema, IBS, insomnia, ME/CFS… there must be something wrong with my microbiome..
    29:03 i believe microbial transplant should work for Crohn's disease.

  34. Ohh man I’m so glad I came across this post .
    I have some sort of circulatory inflammatory problem I’m hoping this can help

  35. Would be awesome to see if this type of research could help to eliminate autoimmune disease like – Hashimoto's because I wish I had never gotten this disease and I wonder how I managed to develop it.

  36. So we have to avoid contacts with obese people? They can transmit their disease to us?

    I started to get more weight when I had contacts with obese people and was eating at the same table.

    I suspect the worse.

  37. Poor mice, and other animals for that matter. We just use and do whatever we want with them. It’s so horrible. I understand that it saves human lives. It makes me feel horribly guilty and I don’t even work in any kind of research area. Poor helpless unsuspecting animals. Yes, it saves humans but honestly it would be a much better Earth if humans went extinct.

  38. This is a little long but I think it’s kind of interesting. I was a 4oyr old nurse that had naturally been thin all my life. I could eat all I wanted and did. I was a formula feed baby. I was brought up an a meat and potatoes diet. We always has a meat (beef, pork mostly, and sometimes chichen, NO fish or NO seafood) so we always had a meat, a starch whether it was potatoes or rice, and a vegetable. I don’t remember there being any fruit in my house when I was a child. I even had a set of triplets and all the weight I had gained came right off at age 33.

    However, everything changed when I was 37. I have breast cancer and needed surgery and 3 different chemo medications over 4 months. I pretty much made it through okay. But come about 1 1/2 – 2 years later I started to blow up like a balloon. I was gaining weigh so fast that sometimes my abdomen ached. I couldn’t stop it. I couldn’t eat as much as a used to eat and I started eating very little but still the weigh kept coming. It hit my belly first convincing everyone around me that I was pregnant. I was not. My doctor looked for tumors or cysts like on an ovary and there was none. Just fat. I know had a fatty liver and I don’t drink. The weight still kept coming. I went from weighing 125 lbs to 200 lbs over a few years. I have been at 200 lbs for probably 4 years now. I’m currently 50. But my weight still creeps up. I will look at the scale and I will be 210 lbs and then I have to starve to death to try to get back down to 200. I have tried dieting but I get sick when I down eat. Meaning my stomach hurts, I get a headache, and I’m nauseous. So instead a try eating just a small portion of food but that only holds me at this weight,

    Here’s the interesting part and this is all guess work on my part. This is all so new my doctors think I crazy. Remember that I am a nurse. My specialty is working with diabetics. Almost of of them are type II which is the one associated with obesity. My glucose level has been steadily raising and I now had pre-diabetes. No doubt to become full on type ii diabetes. I had 21 patiences a day and I worked a lot of hours. If you’re thinking many diabetic nurses are thin you are probably right but there are a lot of fat ones too. Here’s what’s different in my case. I had my gut biome completely destroyed by chemo therapy. One week before I started chemo I had some kind of skin infection so the doctor gave me everything under the sun that would kill whatever was affecting my skin. I had strong full spectrum antibiotics, anti-virus medicates and I don’t remember what else. So for the week prior to starting chemotherapy I had already given my gut biome a good killing. Then for four straight months, death to my gut biome.

    Going back to my job. I always eat the same foods that these people eat because I never brought my lunch so i would just steal the extra trays of food. I was very up close and physical with all these patients while taking care of there missing limbs, wounds that wouldn’t heal, and all kind of diabetes ii problems they had. At times I would have to use the main bathroom where many patients also used although they were supposed to use their bathrooms in their room. I know my microbiome was pretty much wiped out. The chemo also wipes out and reeks havoc with your immune system. I think as my biome was replacing itself it did it just like when you are a child. It got it from my environment and that happen to be a diabetes ward with a bunch of obese patients and their families.

    I think a fecal transplant but there’s not a lot doing obesity. Most are already full. And beside I live on the gulf side of Florida. And the weigh transplants aren’t near me. Another problem is that nobody takes me seriously. My story could be a possibility. It’s not impossible that it happened sort of like this. One good thing came out of chemo. Before chemo I had restless leg syndrome so bad most nights that I would cry because i was frustrated and it hurts. It would go on so long that eventually I would be so exhausted I would fall asleep for a little while. Well, guess what’s gone for almost a decade and a half? Yep, RLS completely gone. I think that is due to the destruction that chemo therapy does to your nerve or maybe it’s an unknown virus. I have no idea but I am so glad it’s gone. I wish I could tell this to a chief researcher of RLS. It might just be a fluke or maybe it could give them a clue.

  39. As long as we are forced to ingest toxic antibiotic poisons like Flagyl, the natural complex human microbiome will never survive intact.

  40. So what are people's take aways to help ones own health. Less processed food to start? With the micro biomedical developed at age 3 is there much more we can do after that age. And what can we do for kids under that age? Tks

  41. Our bodies are being destroyed from the time we're in the womb by the SAD diet and big pharma. Then from the womb on we consume nothing less than garbage for a diet when we are eating processed foods which cause us to become sick then run to the dr and get some poison to fix it. Its no wonder we're so sick. Not to mention all the chemicals that our food is grown in. Eat as clean as you can. Avoid all processed foods. Fast frequently and listen to Dr Eric Berg and Dr. sten Eckberg and many others and you will heal. I'm speaking from experience. I've suffered from fibromyalgia for 20 years. I have heart disease and conjestive heart failure. I have suffered from fatty liver and disseminated histoplasmosis and hbp plus pre diabetic. Today after just 8 months of clean diet which includes no sugar or any grains and IF I am no longer a sick person with one foot in the grave! I'm 51 and feel better than I did in my 30's! Im thankful to God for leading me to information so I could heal and I'm thankful that although our bodies are so complex and one could study a lifetime and still not know everything, one doesn't have to be a genius to know how to treat the body so that it will give us the best life before it expires.

  42. Not sure what my problem is but I will go into a unprovoked rage then i have gut discomfort and then poop out sludge and I'll be back to normal after that.

  43. so what would u recommend for morbus crohn ? u said stuhl transformation is not workin right? i wish somebody could answer my question

  44. What is quite extraordinary is that there is no mention of antibiotics, and the long term dangers of their use on human microbiome… Their impact is hugely destructive on the ecology of the gut…. By now, everyone knows that…. I wonder when our medical scientists will awaken to this fact and begin to correct the devastation of the prolific us of antibiotics….

  45. I'm a formula fed 70's child FUT2 non excretor. Suffered ADHD, numerous illnesses, addiction issues etc.. I'm finding health through organically growing my own vegetables with which to support my microbiome. Prolonged fasting has massively helped too as has cutting out alcohol, bread and vegetable fats. I make my own ferments and herbal extractions for digestive tonics. I fully subscribe to modulating your microbiome to help the physiology reach homeostasis.

  46. I make my own bacteria to make smoothies. That is all I eat until night. I live on kefir that I make with different things. I like to take medical drinks like ensure loaded with sugar to feed them. I get the nutrition without the sugar that caused me a candida problem.

  47. Funny how some people just assume everyone believes in evolution and that everyone believes it as fact and not a theory. Theres a huge difference between macro evolution and micro evolution. One has been observed, while the other has not. Science is always observable. Theory is not.

  48. We are finally recognizing that aliens have always been here,living inside of us.. They want to be our friends. There are many mansions in my Father's house.

  49. And no one is looking at vaccines and the adjuvants causing asthma. I think they are causing ASIA syndrome as well as metal implants.

  50. ◼️All creatures were, Human Beings, in a Dream before this.
    ◼️Be careful about what you Think 'Selfishly', in this Dream.
    ◼️And you may Evolve as a creature (Fungus to Beast), with the consciousness of a human being, in the next dream.

  51. Yeah, and how vaccinations with their thimerisol and the rest of their chemical soup destroy the gut's microbiome and cause autism.

  52. How about educating the population on the consumption of 'real food' and on the dangers of 'junk food'? A simpler, safer approach? Type 2 diabetes can be reversed by diet strategies, elimination of sugars and fasting. The obesity/diabetes epidemic is directly related to the spread of the Western SAD diet.

  53. Sulfite intake is directly linked to asthma symptoms and urticaria. Sulfites are ubiquitous, as they are used as a fumigant, antimicrobial agent and bleaching agent in the manufacturing/processing of foodstuffs. In the U.S. ingredients of ingredients are not required to be listed on food labels. So you won’t see sulfites listed when they are used in the processing of food raw materials. The worst offender is high fructose corn syrup (HFCS). Sulfites are used as antimicrobial “preservatives” in high fructose corn syrup at 1000 times the level permitted by the FDA as an additive, but as an ingredient of an ingredient, it need not be disclosed. Compounding this problem is the fact that many pediatricians tell parents of asthmatic children to replace milk with juice – often containing high fructose corn syrup, thus heavily laden with sulfites.

    Sulfites are also used as a bleaching agent in regular sugar, flour and salt. So condiments and gravy and other flour products can be a problem. Sulfites are also used in the manufacturing process of all alcoholic beverages and all sugared beverages.
    Additionally, sulfites are found in all frozen seafood, to prevent black spots.

    The food technology industry has been allowed to become insidious in renaming high fructose corn syrup and even changing the manufacturing process, making it more potent and requiring more sulfites.

    There is information available on the internet regarding the tested content of sulfites in foodstuffs and the renaming of HFCS. If you, or someone you know suffer from asthma it’s worth the effort to research.

    Most of this information regarding sulfites became known because previously, restaurants were allowed to sprinkle metabisulfite on salad bar foods, e.g., greens, veggies, fruit, etc., resulting in more than a few asthmatics having immediate lethal asthma attacks.


  54. This is well known that in plant species bacteria can cause mutation and also cause modified cell division called gall. Since I started to do this, I have believed that in humans microbiome mutation is causing cancers etc. This mutation happens in plants and can be induced through harmonal analouges of the benzene ring. In humans microbiomes may be mutating causing hormonal mis secretion causing cancer. Please use hormone analouge and check it out.

  55. EcN 1917, dr. Nissle had extracted non pathogenic Ecoli 103 years ago to treat IBS and dysentry, its much broader now to take FMT fecal microbiota transplantation, as its a whole microcosm not just one, FMT now treat Cdifficile colitis, IBD and IBS

  56. WHY YOUR SICK Read The Book Population Control Through Nuclear Pollution Read The Book POPULATION CONTROL THROUGH NUCLEAR POLLUTION A Dr Phd Of Truth

  57. Looking at her cheeks she has inflammation in her body. Probably he digestion. How ironic. Not to mention she's a tofi… or at least skinny fat.

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