This is a family saga. An extended family relationship. We go a long way back, Seven or eight hundred million years back
when multi-celled organisms first set off from our single celled ancestors on the tree
of life. Something interesting happened. We never left bacteria behind. We took them with us. It was a partnership from day zero. They've been living inside and on us for the
entire ride up the evolutionary tree. We depend upon them and they depend upon us. This wonderful cooperation where we both benefit. Yet for most of our history, we didn't know
they were there. The first evidence of microbes came in the
late 1600s. A Dutchman by the name of Van Leeuwenhoek. He built the first microscopes and described
the first microbes. An unbelievably great company of living animalcules…
very prettily a-moving through water. He was pretty enthralled with these microorganisms. But wonder gave way to fear. As scientists discovered that many of these
tiny creatures had been making us sick. These are bad organisms, truly horrible pathogens
that have plagued human existence which led us to believe that eliminating them
from our environment, from the water we drink and the food we eat, and from our bodies would
usher in a new era of public health, and it did. Hygienic practices lead to a spike in human
life span. New Antibiotics like penicillin became wonder
drugs, saving hundreds of millions of lives. It seemed the only good bacteria was a dead
bacteria, but our ideas about germs are changing. We are beginning to understand the very subtle
roles they play in regulating our own health. They help us digest our food and fight off
dangerous invaders. We don't know whether a human would be able
to live any meaningful existence in the absence of microbes. Inside every one of us is an entire ecosystem,
a microbiome. And scientists began noticing something else. What led to this extension of human life and
reduce human suffering and also may have brought with it their own set of problems. Many diseases are on the table obesity, heart disease chronic inflammatory diseases Things like Crohn's disease, diabetes, many
others, all on the rise. Our war on microbes may have caused unintended
collateral damage our own health, so getting back on good terms with our long-time fellow
travelers could mean the rebirth of a beautiful friendship. By the end of today's program you may have
a very different appreciation for the bugs in our environment, particularly bacteria,
which is what we're talking about today. The first thing you need to understand is
that they vastly outnumber us. Each one of us has about 30 trillion cells,
human cells that are uniquely ours, but did you know that living in and on us, are 39
trillion bacteria. Okay. Without further ado, let's introduce our participants. Our first participant is a professor of medicine,
microbiology, and immunology at Stanford. He's a pioneer in the study of the human microbiome. Please welcome David Relman. Our next participant is director of the Center
of the Microbiome Innovation at the University of California San Diego. He's the author of Follow Your Gut and Dirt
Is Good. Please welcome. Rob Knight. Our third participant is director of the Wisconsin
Institute for Discovery at the University of Wisconsin Madison. She was a science advisor to President Barack
Obama. Please welcome Jo Handelsman. In rounding out, this distinguished panel
is professor of medicine and microbiology at New York University School of Medicine,
and the author of Missing Microbes, will talk about that in a bit. Please welcome Martin Blaser. David, let's start with you. So we evolved with microbes from the very
beginning, but, and we just told everybody, we all have our own little world living in
and on us, but when do we acquire that, when do we get it? So the beginning is a little bit, a little
bit uncertain. We forget that our own individual histories
begin before birth, which means in this case that our own fetal development was influenced
by our mother's microbes and her microbiome. We have probably a little bit of direct encounter
with some of those microbes or parts of them before we're born, but then everything changes
at the time of birth, and it's that passage through, either the birth canal or out through
the abdominal wall that causes a sudden change in our relationship with the microbial world. And Rob you, you've had some interesting thoughts
about this and a personal experience. Tell us a little bit about your daughter,
correct? And what happened there? Yeah, sure. So after our daughter was born, as you know,
when you have kids, things don't always go according to plan. And that was true for us and we wound up having
to have an unplanned c-section for medical reasons. And straight after she was born, we coated
here with the microbes that she, she, she would have had had she come out of the regular
way. So you, you feel that strongly that that exposure
in the birth canal is- we, we, we felt that strongly as parents. Now the AAP recommends that you not do this
now, but this a lot of public interest in it until the research has done. So it's not something you should do from a
clinical perspective right now. Of course, as a parent, you're probably going
to have to do a lot of things that are not 100 percent based on evidence. That's right. That's true. I can tell you from experience, you know,
we saw in the, in the, in the brief piece on a whole bunch of diseases that rolled by. There seems to be some suggestion that there
is an autoimmune component. By that I mean that the microbiome somehow
interacts with our immune system. Martin, can you talk about that and just to
set the stage here, what, how might these interactions be happening? So mostly I talk about the microbes in the
gut and that's where a big part of the immune system is--in the wall of the intestine, and
it's pretty clear that there's interaction between the microbes and the immune system
and vice versa, and it's becoming more and more clear that the microbiome is training
the immune system, it's teaching the immune system what are, what are the good bugs, what
are the bad bugs, and if that training is off, if it's misaligned, then there's a risk
that the immune system won't develop in the proper manner. So that's, that's what we think are driving
some of the immunologic diseases. Two-way street there. Yes. Before we go any further, we need to sort
of set the stage for how a lot of the work in your area has done, and it's done with
mice. Joe, can you explain a little bit about how
you use the mice in this very unique way? Well, the mice have been particularly powerful
because they can be raised in a sterile environment so they can can be delivered by Cesarean section
and kept sterile in a bubble, and then they can be inoculated with any microbes you want,
and so it's the only system we have where we can do a very clean mammalian microbiome
or microbiome-free gut, and then add back one organism, a few organisms or the entire
microbiome from the mouse or even another organism like a human. And mice are, is this primarily the way most
of the work is done? Well, one of the powerful things in the microbiome
field is that it brings together many kinds of data. It's epidemiological data on humans looking
at large populations and correlations, and then experiments on humans in situations where
we can actually do the experiments with variables on humans, and then mice and other model systems
play a major role. Briefly back to humans though. When we're first born, we acquire our, the
beginnings of our microbiome. When does that stabilize? When do we say you've got it, this is you
and how long does that take? Rob. For the gut microbiome, it's about two to
three years, and then for other sites, like with the skin on the mouth. That's a lot faster. So within a few months. And yeah, go ahead. I would just add, I agree, the vast majority
of what we see easily is established by about two or three years. I think we all would agree though, that there
have to be some other in really important but more subtle features that take a little
bit longer, well into later childhood, maybe even at the time of adolescence and beyond. and even even through old age. So the first three years is where you have
the most dramatic difference. So it's like your microbiomes going from,
from seawater to uh, to soil. It's that profound a change compared to different
physical environments, but then between the time when you're three and the time when you're
a 90, that's more like save the difference between one patch of farmland and another,
rather than being a completely different kind of environment. So the change is still important, but it's
subtle. And this is the timeframe when a lot of parents
who have little kids know that they get ear infections, and antibiotics are brought on
board. Is this a good thing, a bad thing? Well, I mean, it is what it is. Everything is a trade off. In this particular case, uh, antibiotics as
you've heard and seen, have had an amazingly important role in saving lives when they were
used for what turned out to be good purposes. But of course they have collateral damage
that they cause and everything is a, is a trade off. So when they're not used for a good reason,
those downsides are gonna outweigh. You. Have you have an opinion on this? I do. And so, so the, the, the point is as, as we
know, antibiotics are miraculous, uh, when they're used appropriately, but they are overused
tremendously. The CDC estimated 30 percent of the antibiotics
are overused. I think the actual number is higher. In Sweden they're only using 40 percent of
the antibiotics that we do. So it suggests that maybe 60 percent of the
antibiotics aren't necessary. And in the US, there's tremendous variation
between doctors, between regions, parts of the country that aren't explained by differences
in disease. They’re differences in practice and in culture. Some people and some doctors want to use antibiotics
more, others don't. There doesn't seem to be much difference in
outcome. So let's talk a little bit about the human
microbiome project. A lot of people are familiar with the little
petri dishes. That's what we think about when we talk about
studying bacteria, but there's a whole new way to study bacteria. Joe, can you sort of walk us through what
that is and how that intersects with human microbiome project? Well thirty years ago, uh, scientists began
to realize that we've been missing a vast amount of knowledge about the microbiome,
every microbiome, not just in humans but in soil and in oceans and on trees. And the reason that we've been missing that
information is a lot of microbes, the vast majority won't grow in culture. So those petri dishes that we all associate
with microbiology are only one little sliver of the story of microbiology. And so the, the effort became to study microbes
without necessarily culturing them and to circumvent culturing them we started extracting
DNA. And so that's the major way that we described
microbiomes today. And most of the work we'll talk about here
is based on DNA analysis. So it's not the old fashioned petri dish that's
gone. It's not gone at all. Some of it it still is. And when we want to study a particular organism
and it can be cultured, that's one of the most powerful tools we have. But if we want to look at the entire community,
including the half or in the case of other environments, besides the human system, as
many as 99 percent, that can't be cultured, then we need to go to the DNA methods. You've, you've done a lot of work with this. Tells us about it. And let's take a look at some of what you've
done, if you could describe it. Sure. So what you're seeing here is my daughter's
microbiome developing over the, over the first two and a half years of life, and what you
can see as she's starting off with these different regions, the gush in Brown, the mouth in blue,
the skin and sorry, the map, in green and blue, and she's moving more and more towards
the healthy adult stage as defined by about 15,000 healthy people in the American Gut
Project, which is our Citizen Science Initiative where essentially anyone can get their microbiome
sequenced. And so what's exciting about this is even
to a six year old, you can explain how she starting off in one place on this map. She's moving to another place and what the
regions are little defined by health and disease. So the different- explained again, the different
colors represent? The different colors are the microbiomes in
different parts of the body. Each dot is the whole microbiome, so potentially
a thousand microbial species from one individual, and we placed two dots on this map close together,
if they're more similar in terms of the evolution of the microbes that they have in them. We place them further apart, the more dissimilar
in terms of that evolution. How unique is each person's microbiome? um, every, every person’s, microbiome, every
time you sample it, is unique. So if you, if you sample yourself today, three
different times, and you sample yourself tomorrow, three different times, we can tell those apart
from each other. So it's all, it's all a matter of scale. It's about how different are you from yourself,
how different are you from other people and which of those differences are large, which
is small. And it's important to remember that you don't
have just one microbiome. The microbiome of your mouth, your gut, your
skin. They're all completely different from one
another. In fact, Rob's gut a lot more similar to my
gut than, uh, my gut is to my mouth, for example, Even within the human mouth, there's diversity. Is that correct? Absolutely. A very striking demonstration by Julie Segtr
at the NIH about the different habitats of the human skin, and how they're as different
as Rob was saying, as, as grasslands are from forest are to deserts. So let's talk about what we've been doing
in the last 40, 50 years. How long has the- 70 years? Seventy years. That's what. That's when antibiotics first came on about
70 years ago, and this is an area of intense interest to you, Martin. In fact, he wrote a book that's been a compared
to Silent Spring in its importance in terms of understanding exactly the impact we're
having on our own ecology, if you will, called “Missing Microbes”. Tell us a little bit about that book, your
thesis and sort of what you think about the future. Yeah, so it it the. The idea begins with many of the things that
we've discussed before. The idea that the microbes that we have in
the human body are ancient, that we've inherited them from our ancestors, that they're formed. The structure of our microbiome occurs early
in life. That they have benefits to us, they're doing
all kinds of good things, and and now there's more and more evidence that our microbiome
is changing, that we have lost diversity, that we have lost important ancestral microbes. And I hypothesized that this has consequence,
and and there's more and more evidence that the consequences are related to the diseases
that are now becoming epidemic since World War II. We've had rises in asthma, in obesity and
diabetes, in juvenile diabetes and inflammatory bowel disease, and there is an increasing
body of evidence for all of these that the change in the microbiome is playing some role
in the story. You and I were talking beforehand, and you
likened it to other sort of human intervention impacts like climate change? Yeah, so climate change is how humans are
affecting the macroecology through modernization, through all the things we did. When Henry Ford or Benz developed the internal
combustion engine, they didn't anticipate that the, every time you turn the ignition,
that the ice cap in Greenland is going to melt a little. But we think that that's true, and and in
a sense, I think that that's what's happening in our human bodies. Every time we take an antibiotic, perhaps
a few organisms become extinct. And. Exactly. Yeah. That's kind of change in our micro ecology
is paralleling what we’re doing in our macro ecology. You also said you think what's happening to
our microbiome is happening much, much faster. Yeah. Well, we're 70 years into the antibiotic era
and antibiotics are not the only factor. C-section. There are many other factors involved, but
maybe it's, it’s the most important. And so it's a difficult problem. Antibiotics are miraculous. They save lives, but we're overusing them,
so we have to, we have to dial it back and we have to understand what we're doing, and
then how we can restore what we've lost. Dirt is good, right? Title of your book. Tell us why dirt’s good. It's good because exposures of a lot of natural
microbes in the environment, whether it's from dirt or whether it's from animals in
farms, or healthy, healthy water, healthy soil and so forth has surprising number of
beneficial effects, and it can give the microbial diversity that we need to reduce the, reduce
the frequency of some of these conditions. Although it's an open question, how much we
can restore, like I think much more direct analogy with antibiotics is DDT where it saved
millions of lives and yet you have this hugely deleterious effect on the ecosystem and then
afterwards just introducing a few rats and pigeons isn't really going to cut it for improving
biodiversity again. Right? So understanding what we're changing and what
we need to do to restore is really key scientific challenge at the moment. In the meantime, if you're a parent and the
pacifier hits the sidewalk, do you boil it? Do you call in the Hazmat team? Yeah. Well it depends a bit where the sidewalk is. Like if you, if you think there is a lot of
lead, maybe you shouldn't, maybe you should worry about, but it's more a more chemical
than a microbiological segment you should worry about. So if it drops on a hospital floor, you probably
want to wash that off, but if it's your floor at home or if you don't have any reason to
believe that there’s anything bad there, probably the positive effect outweighs the
negative. Any, any opinions here on the six second rule? For some reason the NIH hasn’t funded a
lot of research. I'm, Interesting, big problems. We, um, let's talk about some of the specific
diseases that we, we've been alluding to. The first is asthma. Asthma is a major public health issue. If you're in New York City, there are certain
neighborhoods in New York City that are truly plagued with asthma. Overall eight percent of Americans have asthma,
but we've looked at these sort of ecological studies, and the stories actually vary kind
of stark when you look at very particular communities. Two of the communities in a recent article
in the New England Journal of Medicine looked at the Amish and the Hutterites. Why those communities and what did we learn
from them? Yeah, so this was what from Jack Gilbert and
Erika von Mutius have found in a certain number of their collaborations, and what's amazing
is that the Amish and the Hutterites both live what we would consider relatively traditional
lifestyles, very fun based, but they have completely different rates of asthma where
the Amish have essentially no asthma and the Hutterites have a lot. And what's different is that the Amish will
take their kids on the farms to interact with the animals, whereas the Hutterites have a
very, have a very tight distinction between farm life and home life, and they make sure
that they change their clothes and take their kids out of the farm and so on. And the exposure to particular kinds of microbes
including some kinds of lactobacillus seems to be really important for the difference
in health between the two communities. The Amish were six times less likely to have
asthma and allergies than the hutterites, and the Hutterites have asthma rates that
are consistent with the rest of the country. Does this, does this go towards what they
call the hygiene hypothesis for the development of diseases? Can anyone? That's right. So, so the, the first iteration of the hygiene
hypothesis was the idea that exposure to childhood pathogens was good, and there hasn't been
a lot of evidence in favor of that. What we're thinking now is much more along
the lines of it’s exposure to those diverse array of beneficial microbes from the environment,
that’s good. But by trying too, trying too hard to keep
yourself away from the pathogens, you may also be walling yourself off from those beneficial
microbes. David, did you want to add to that? No, I think I mean a lot of this, as Martin
was saying, it's just a function of what we have been doing both to ourselves and to our
environment. It's a function in part of the built-in environment
now we have segregated ourselves from the environments we used to, to be born and raised
in And it's striking that kids traditionally
have liked to eat soil, and a lot of animals eat soil. In fact, when they're sick, some animals self
medicate with soil, so it seems like there's some natural process of ingesting soil, and,
and maybe we're learning why that, that was an impulse for so many kids. In some ways when you look at those kids,
what they do and what we all do, it's really also about continuing to sample the, our environment
in order to find those missing microbes, right? That, that, that can fill in the niches that,
and habitats that had been emptied. And so in some ways that natural behavior
is a really a very adaptive one. I know you guys are working on some additional
information about this? Yeah. We're working on a new study with Erica in
Bavaria where, uh, where you have, you can go down a street and you'll have houses that
have cows where they bring the cow into the barn versus houses that don't have cows. And even on that level, one house to the next
on the street, if you have a cow, you're much less likely to have asthma than if you don't
have a cow. Now obviously in New York, recommending that
every parent get a cow for their kid is not particularly helpful. So, so this is an ongoing going study that. Okay. All right, so we, so that's asthma, but I
think even more interesting than asthma is obesity and um, you know, we all know that
obesity is an epidemic in this country. This is not news, but Martin you have looked
at, we've overlapped some information and what you're talking about in terms of the
obesity epidemic and some of the So, so there are many things to say but I,
I don't want to take up the whole time, but you know one, one of the most important observations, These are the rising of the obesity rates. These are data from the CDC and the darker
the color, the more, the higher the percentage of obesity. So you can see the difference between 1989
and 1999 and 2010. So this is only 21 years, something very important
has happened. It's happened all over the country and about
2012 we made the connection. I think it's in the next slide that if you
look at the, if you look at the obesity map and the regional variation in antibiotic use,
there's a lot of similarity. There was a lot of overlap, so that's it. That's kind of interesting. It doesn't prove anything because it's observational,
but 70 years ago farmers found that if they gave antibiotics to their farm animals, it
would change their growth. They would grow bigger, they'd grow faster,
it changed their metabolism, and they found that the younger they gave the antibiotics,
the more profound the effect, so we thought that maybe that's one of the things that’s
filling, and we began to do experiments in mice as with others in which we could give
antibiotics to mice as the only variable and that increased their obesity. Jo, you've done work on that. Can you take us through what these mouse experiments
where Yeah, this isn't my own work, but other people
have done obesity experiments where they transfer the microbes from obese humans into mice and
they see the mice are gaining weight quite dramatically. I think this was one of the turning points
in the microbiome research field because we began to see cause and effect, as Martin said,
the those maps show you great epidemiological similarities and correlations, but this was
a direct effect by transferring microbes. It's, it's amazing. I mean, how, how could this work? Is anyone working on what is the mechanism,
the elixir, the, the genetic turn that happens here? we and others are working on. It's not genetic, it's environmental. It's, because the obesity epidemic is too
fast to be a genetic problem. It's not taking multiple generations. It's happening in years. And again, it goes back to the early years
of life when the microbiome is forming. It's educating our immune system. It's educating metabolism. It’s educating the liver and the fat cells
on how, how big to be and how much, how much energy to store and how much to save. And it's very, it's, it's very conserved because
the farmers found that it works in cows, but also works in chickens. And that's a big, big swath in vertebrate
evolution. Is there a, is there any, um, knowledge about
exactly what the microbes are doing that lead to? There are many things that are going on at
the same time. It's, it's changing how the microbes use energy. It's also changing how the microbes are signaling
human cells at this critical early time of development. And that's also a strong correlation between
the inflammatory response and many chronic diseases and so the bacteria are in direct
contact with our gut and they can incite an immune response or inflammatory response,
and there's some evidence that reducing that inflammatory response with food or other additives
to the Diet, including microbes may be one of the ways we could treat obesity. I would, I would just add a note of, in my
view as as slight caution, but actually I think it's incredibly exciting. The idea that these communities, like any
of the communities, are amazingly adaptable, so they will recognize conditions those members
and and interacting parts of the community that are favored will flourish and the others
not. So essentially these communities remodel themselves
under whatever condition they are presented. In this way, they become almost a reinforcing
factor for whatever the host or human disease or health state might be, and I think in part
that may be why the transfer of a gut community that's now adapted to a state of obesity will
bring with it the metabolism and the and the biology that it took for them to adapt. They bring it to that new host, but it's just. It's a piece of the story and it's a caution
in the sense that the microbial community is not the whole story. It could be a reflection of, as well as a
driver of, or a reinforcer of whatever the host problem might be. And especially with human obesity. There's a lot of complex moving parts there. Even in mice, though, one thing we haven't
heard yet about is behavior, and for example in the toll-like receptor 5 knockout mice
that we studied with Andrew T. Gewirtz and Ruth Ley, what was amazing they are is that
you have a genetic change in the mouse that causes, that causes microbial change. But you can transmit from one mouse to another,
transmit obesity, and what was going on there was it was almost all behavioral. So the ultimate microbes made the mice eat
more. That's why they became obese. You can make them lean again by just cutting
off their food supply to what a normal mouse would eat. And so these connections between the gut and
the brain are really exciting, even in the context of things we might think of as more
physical, like obesity. Marty, you said it's not genetic, right? That it, that this phenomenon that we're seeing
is not genetic. And yet you have also said that certain conditions
like inflammatory bowel disease may actually be transmissible to the next generation. So how does that work if it's not genetic? Well, um, you know, when we classically say
genetics, we're talking about our human genes passed from generation to generation. But of course we're also passing our microbial
genes from generation to generation when, when, when we're born, it's, it's not quite
as precise as the humans, but there's still a lot of inheritance of the microbial genes. And we've, we've done experiments to look
at this particular question. You've done experiments in mice and this should,
what are we looking at here? Yeah. So, so we're looking at the colon of two mice,
uh, on the left side are, we'll call that the normal, right as the perturbed. So did the experiment we did here is that
we took poop essentially from mice that were either normal or had received antibiotics. So we had a perturbed poop and a normal poop. And we gave that to germ-free mice, mice that
had no flora who happened to be pregnant, and who also were immune-deficient, they were
IL-10 deficient mice. These are mice that spontaneously develop
colitis. And so now we gave the poop to the, to the
moms either the normal, the perturbed. Then we asked would the mom transfer the microbes
to the, to her pups. She did, we followed the pups till they were
middle aged. And then when we sacrificed them, we looked
at their colon. And what we found is that the mice whose mothers
got the perturbed poop, they had much worse inflammation. That's the panel on the right. Had much worse inflammation in their colon
than the than the other, so there was a huge difference. And the point here is that those pups never
saw an antibiotic. Their mother never saw an antibiotic. All they saw was a perturbed poop. So this was evidence that the signal, that
the disease signal is being transferred by the microbiome, and it also is evidence that
the inheritance is also involving microbiome, involving microbial genes, not host genes, Right? So not host genes, microbial genes. What are the implications of something like
this? One implication is that many of the diseases
that we think are genetic, it may be more than human genetics, for example, inflammatory
bowel disease. If you take all of the genetic low side that
have been found to be associated with inflammatory bowel disease, that explains 10 percent of
the risk. The other 90 percent was unexplained. I think this is part of it. It also has kind of profound social implications
because it means that we can pass our experience onto our children. You know, Lamarck was sort of debunked a long
time ago. The concept that we acquire traits during
our lifetime and then pass them on. In other words, if you lift weights a lot,
your kids will get big muscles. Exactly right. And, and you know, we, we don't believe that,
that sounds silly, but on the other hand, if we're passing on our microbes and they
are a product of our existence and during our lifetime and not just our own genes, then
it really has almost a, uh, and I, I think almost anti democratic quality to it, that
it says that the old adage of pulling ourselves up by our bootstraps and creating our own
lives and every life is a new life and has the fresh start with all the opportunities
just simply isn't true. We are literally inheriting our parents' experience. Wow. This brings us, this is good point to talk
about antibiotic, antibiotic resistance. Before we, before we get to that, we want
to talk about the bad boy of anti-resistant bugs, one of the baddest boys, and that is
C. difficile, which causes untold miserable outcomes in many, many people. And the CDC has turned this a very urgent
situation, but there is a very wholesome potential treatment for this and we're going to talk
about it in this video. I was seeing urologist for chronic pelvic
pain. They would just prescribe me an antibiotic
after antibiotic. The antibiotics cleared up the infection causing
his pain, but then Ryan began to get different symptoms. I finally found out that I had C. diff. C. diff or C. difficile is an opportunistic
microbe that often afflicts those whose microbiomes have been compromised by antibiotics. It's notoriously difficult to treat and makes
day-to-day life miserable. C. diff can be life threatening. People can die of this. None of the medications help with my symptoms. It’s just been really draining having this
disease for so long. I have a disease I know is due to biome disruption. Let's fix the biome. Easy to say, challenging to do. The treatment. It's called a fecal transplant. The check there was FMT, fecal microbiota
transplantation. It's exactly what it sounds like. Someone with a healthy microbiome has donated
his stool to be placed in Ryan's colon. We drive our camera to the top of the colon. We squeezed in some biome, scored it in with
a syringe. That's exactly how elegant it or not elegant
that is. Inside of the stool, there are trillions of
bacteria that when transplanted actually outcompete the seeded bacteria. And that repopulates you. Soon after the procedure, Ryan was free from
C. diff. How does that work? Did you. Is this more than you bargained for? Is everybody okay? Well, I mean the good news is that it's been
almost a miracle for people like this patient here and many others. It's remarkable in fact that it, that it works
at least in this circumstance. And the ideas that in the wake of this very
inflammatory, destructive infection caused by C. difficile and its toxins, the habitat
is damaged and yet in some ways unstable and receptive for a new community to replace what
is now sort of the ravaged remains of what might be there, and in that particular setting,
the, the provision of a new community, it's really restoration ecology allows the habitat
to now be filled by a community type that really was destined, in some ways, to be in
that environment when the inflammation has subsided. So it's a very particular circumstance, and
I think a very important lesson about what we ought to be working towards. Not necessarily, you know, poop as is, but
next generation. Restoration. Well the good news is you can get the poop
in a pill. Well you can get poop anywhere actually it
looks like. I found that to be true here in New York. So true. It's so true, but so. Well, I mean it should we be, should we all
be seeking these, this type of treatment? I mean, can I reverse obesity this way? What? What is, what are the limits of this right
now? Well, the first thing to say is is the C.
difficile infection are very specific diseases. We know what causes it. It's acute and onset. The treatment is is really it has now become
the standard of care because it's so good and it's the proof of principle, but that
doesn't mean that other conditions, conditions that have been going on for decades, conditions
that we don't know the cause of will be affected. Those are the kinds of questions that have
to be addressed in clinical trials. Trials where just like, we've made enormous
progress in treatment of many cancers, in the treatment of HIV. That's all come from clinical trials where
they've compared one medication to another, one approach to the other, and gradually we've
ramped up our approaches to these diseases and that's what has to be done in the microbiome
field too. They, they are trying it with certain diseases,
aren't they? What is the status of that? That work? Lots of ongoing trials now for everything
from Crohn's disease, ulcerative colitis to obesity and any of these conditions that we've
been talking about. There are trials underway. I think my own view is that it's going to
be a bit tougher and less likely to work easily for the reason that Marty suggested. We don't know the the instigating cause or
something that is easy enough to knock down temporarily the way we can knock down C. difficile
temporarily in order to open up that niche space for the new community. A lot of these diseases as like the health
are associated with intense resilience. The system, whether it be harmful or beneficial,
is really stuck in a, in a deep valley that's hard to dislodge and we're going to have to
figure out, I think ancillary approaches along with the restoration community in order to
dislodge, say, a harmful community state and replace it with beneficial one. I know one of the things about the fecal transplant
studies that is kind of frustrating is that they work so well with C. diff that patients
don't want to stay in the studies. They just get better. They go out of the hospital after 48 hours
and they're done, and so we don't have a good enough understanding of why it works, even
in the most extreme case that we, we can't really transfer that knowledge to the all
the other much more complicated conditions that you're talking about. Well it's important to point out that C. diff
is a disease that is acquired by physicians who give patients lots and lots of antibiotic,
kill their natural microbiome, and the C. diff takes over. I mean, so they're very different than some
of these chronic diseases. It can happen even with one course of antibiotics. It can happen even with one. It doesn’t have to be lots of But, but it's uh, but it's an insult that
we know that happens and that's unlike Parkinson's and some of the other diseases are diseases
that are going on for years, for decades. Those are diseases that are going on for years
or decades, right? And that's the problem. But you know, one of the problems is that
all of these diseases are heterogeneous. There may be many different subsets in there. And if, if for example, the fecal transplant
worked for 10 percent of the people, right now, we can't really tell who's that 10 percent,
and we need much better tools to understand. And for example, back in the old days, breast
cancer was considered one disease and now we know that there are at least three major
pathways. If we tried to treat everybody with one treatment,
we would be undertreating some women and over treating others and it's kind of a way that's
where we are on the fecal transplant for many of these other conditions. And even for C. diff, there is a large proportion
of patients that respond even to their own fecal transplant being transplanted back. And that doesn't really make sense given the
mechanism we think it's acting by. So we don't even
understand it with, with that disease. Early days. Yes. The heterogeneity is even not just with the
disease and disease states and individuals and host, but also in the therapies. So what is, you know, one person's fecal miracle
is another person's fecal dud. And because they're just not well characterized,
what we need to be working towards is a much more precise blend of organisms and nutrients
for those organisms in a particular host matched in the right way that it, that it makes sense. Yeah. And the American Gastroenterological Association
has, um, has set up a new national fecal transplant registry to try to track all this and get
the, get the evidence that we need to figure out when it's going to work, what formulation
you should use, whose poop is right for you, all that kind of stuff. Let's, let's, let's, let's move past the colon
and up to the brain. For a long time, we thought that these systems
had nothing to do with each other. They didn't communicate in any way. Um, but we're beginning to understand that
there is a real connection between the brain and the gut. And one of those connections is through neurotransmitters. Things that we, if you familiar with them
at all, you know, you think of them only in terms of the brain. But that's, that's not the case. There is a there, there's way more of a connection
there than we, we've, thought about in the past? Jo, can you? Well, you know, we knew things that we ignored
and one, one of the statistics it's so interesting is that serotonin is one of the most important
hormones for our brain activity and for happiness and we know we've known for a long time at
90 percent of the serotonin receptors are in the gut, but what are they doing there? Yeah, we should have been asking this a long
time ago because that discovery alone should hint that it's not just about the brain and
so for a long time we've thought of the gut as the second brain and that probably is a
pretty accurate description and what they're interacting with, we don't know, but we can
imagine they're interacting with microbes and the chemical products of microbes that
may mimic neurotransmitters or may produce serotonin itself or we don't know what else. We know that depression is a tremendous problem
worldwide. It's, I think the World Health Organization
listed as the number one health threat in the world. How can, there is some work on how we can
use this understanding about the microbiome and its effect on, on depression to the, to
help patients. Again, like many of the things we've talked
about, it's a little bit too soon for treatment, but there's clear evidence that the microbiome
in depressed people is different from the microbiome on average in not depressed people. And so we need to be asking whether we can
do fecal transplants, whether we can change diet, whether we can take probiotics or other
chemicals that would change the microbiome in important ways. Um, there was a fascinating mouse experiment
where they took the microbiome from depressed people and introduced it into a sterile mice,
germ free mice, and they found that the mice from, that received the depressed people microbiome
became depressed. Want to hear about depressed mice. How do you know a mouse is depressed. We had a great picture of a depressed mice. It's going to come up there. Poor little guy. We'll come back to that, to that fella in
one second. But we know we learned about the blood-brain
barrier in medical school that nothing gets past the blood-brain barrier. It's a very, very tight system, but that's
not necessarily true where the gut is concerned. They're actually connected in a way. How. How does that work? Well, there are a lot of connections. They're just very precise. It's not an easy flow. Um one of the easiest connections is electronic,
so the flow of neural signals from the gut to the brain through the vagus nerve is an
enormous route for information to flow. So you could imagine that's an image of the
vagus nerve. You could imagine microbe stimulating the
vagus nerve in the gut, and that having an effect in the brain. Another way that microbes could be affecting
the brain is we know that the composition of the microbiome in terms of which organisms
are there, changes the composition of chemicals in the blood, and blood certainly can deliver
chemicals to the brain. Blood certainly crosses that barrier, so there's
no question that there are ways for information flow from the gut to the brain. And in the figure that was just up with the
vagus nerve. We are hardwired with signals going down from
the brain and coming up from the gut. Is that, is that something that is being studied
in humans? Could it work in humans? We talked a little bit about it, but- That work is just beginning. And of course we have to remember mice aren't
humans and mouse depression is not identical to human depression, but some of the symptoms
are remarkably similar. So one of the tests they use is the swim test
and it turns out that mice will swim for quite a while to try to survive, but if they're
depressed they quit and they just flop over and give up. And so there's the helplessness syndrome,
which is one of the symptoms of, of human depression as well. They also become less adventuresome, and so
if you put a mouse on a little island, it will dip its toe in the water like a cat will. But if it's depressed, it will just sit there
and hold back. So there are all these symptoms that have
corollaries, but of course we're human. We're, we're making a lot of inferences there
and imagining what the mouse is feeling. So of course all of this needs to be transferred
to humans and they called this study “transferring
the blues”, which is- Again, you know the incredibly promising if
it can be used to design a useful intervention. The complications of course, are that depressed
people eat differently, their activities are different, the degrees and ways in which they
interact with other humans are different. They take medications, and so all of those
things we know can independently affect a microbiome. That microbiome in turn may now turn into
a reflection of all of those factors given to a mouse may not be so surprising to induce
changes that we read as similar, but again, the actual causation and multiple contributions
of many factors make this much more complicated, much harder to solve unfortunately then that
might suggests. Than in the mice. Yeah, so David is emphasizing a very important
note of caution. I think we're all here because we're enthusiasts
about the microbiome. We recognize that it is a scientific frontier
just like many scientific frontiers that's going to bear a lot of fruit one day, but
maybe not tomorrow because it's going to take time to translate, and to understand all these
new findings, and to convert them into new approaches to health and treatment. It's not. It's not coming tomorrow, except for C. diff. Sometimes it takes only one study to take
a gigantic step forward. I thought that the brain science that that
people are doing now with the microbiome would take forever to begin to sort out what's really
going on in those mouse brains and then just last month the paper came out that showed
anatomical changes in the amygdala, which is the part of the brain that controls feeling
and depression to some degree, and if you changed the microbiome in a mouse, you changed
the structure of the Amygdala. Now that's starting to get to a structural
level and I think ultimately it will be a biochemical level where we can really dissect
it. So sometimes it just takes a very innovative
study to take that giant next step and get down to the mechanism of what's going on. It’s early times, but would you agree that
there are hints that there is a strong strong association between what's happening in the
gut and behavior? Rob, I think you've done some work in PTSD
or you're familiar with this? Yeah, well, well again, again, muscles mostly
in mouse models, but with Chris Larry at Boulder and a number of others, we were able to show
that if you expose mice to the right kinds of soil bacteria, an organism called Mycobacterium
vaccae, then you can put it into social stress conditions. So basically you either put it in with a huge
dominant male mouse that would beat it up or you just let it watch it. Watch that through glass, which also upsets
them, right? And say normally they'll hover in the corner
of the cage, they won't eat, their hair falls out, but if you inoculate them with these
soil bacteria, they're very resilient against that stress. And we also did another study looking at looking
at children with PTSD where there were some microbiome differences between those with
and without p, uh, PTSD. But again, we don't have causality in that. We just have association. So, so, so the, so the concept that you can
modify the mouse’s behavior in response to the social stress by, by adding a microbe. That's very exciting, but it takes a long
time to translate that to something that you could do in humans. And, and you've even looked at mice with autism. Is this correct and? We haven't, but Sarkis Mazmanian at Caltech
has done that and so what's, What is this we are seeing here? That's the marble burying test. So one of the hallmarks of autism as compulsive
behavior and that's a mouse that can't help burying marbles. And the reason that- A mouse that likes to bury marbles? Correct. So the number of marbles that there is in
a fixed amount of time, it is a measure of how much compulsive behavior there is- Is this repetitive behavior? Exactly like, like the mouse version of OCD. Interesting. Okay. So- And so, so what happens is when you, when
you inject the pregnant female mice with a double stranded RNA, so you simulate a viral
attack, and then the pups do that. They have communications deficits, they have
cognitive deficits, and they have problems with their GI tract, all of which resemble
human autism. And so what, what Sarkis showed was that this
molecule called 4-ethylphenyl sulfate that’s overproduced in the microbiomes of those pups,
that if you inject a normal pup worth it, it'll do many of the same things. You can also use the natural microbiota of
the human gut as a probiotic to reverse some of those effects. So, so again, this is all pretty clinical. There was another consortium of three groups
in ours that I know did a really exciting clinical trial that was published a little
over a year ago with a small number of kids doing fecal transplantation for autism. And so they saw some benefits both in GI dysfunction
and also in cognitive function in those children. But it's still very early days, right? It's a small open label trial and before you
believe that it's going to be the next thing, likeC. diff that can be addressed with fecal transplant,
you really want to see a lot more research? But it's very encouraging. Has anyone looked at populations that have
not used intensive antibiotics the way we have in developed countries, and what their
microbiomes are like compared to an American's microbiome? So Rob and I have been involved in several
studies that have looked at that very question and the people living out in the jungles,
in the bush, who have not had much modernization, their microbiomes are much richer than ours. They're much more diverse, and that these
are people who live in Africa and South America and New Guinea. They're genetically different. They're on all different diets, but what they
share in common is that they have very rich microbiota, and the people who live in Italy,
Australia, US, different continents, different ethnicities, et Cetera, Japan, but we, we
share modernization and industrialization. Our microbiota are less rich. does that have an implication on their health? Are they, are they in terms of the chronic
diseases we've talked about today, asthma, obesity, some of the- Those comparisons are different, are difficult
because we are different from the people living in the jungles in many different ways, but
in general, they have less asthma, and they have less obesity but that it's hard to prove
things from that, but what we can say is that they have a much richer microbiota and it
suggests that theirs is more typical, is more similar to our ancestral microbiota and that
we have lost diversity. So if I understand this correctly, you're
saying that it's possible we cannot recapture that diversity that we most likely started
with some of the. I don't think we want to say. We certainly don't want
to believe that. We need first of course, to understand what
parts of that ancestral diversity, if you will, are important to us today. In some ways. Of course you don't want the Hadza’s microbiome
in order to be able to survive in New York today. The who? The Hadza was, the one of the ancestral, the
hunter gatherer populations. That would not be well suited to modern day
life. But in turn, we ought to be thinking about
what elements of it should we attempt to restore? What functional aspects can we restore? Can we restore and should we restore in order
to improve long, long-term outcomes and avoid some of the calamities of modern life, if
that's Rob and I are involved in a new foundation
that my wife, Maria Gloria Dominguez, uh, is establishing to create a microbiome vault
similar to the seed vault that is in Norway to preserve all the seeds of humankind. You guys familiar with the seed vault? So the same idea is to archive those ancestral
microbiota now before they're lost, so that at least we have the resource so that if there
will be, if the restoration will be feasible, we will have the materials for the restoration. We don't know yet whether it will be feasible
or how, uh, I'm optimistic, but it may, it may take some time to figure out what are
the rules, what are the ground rules? Is, is, is the restoration of my children
going to be the same as the restoration for your children? I think for us, maybe we're. It's a little late. It's a little late. It's not so much the crop trust was the crap
trust, if you will. But we really need to preserve this material
now when we have the opportunity, Right? Well, we've spent a lot of time sort of talking
about the ways that we've hurt ourselves and our own microbiome over the last decades,
if you will, with antibiotics and other things. Let's try to end on a positive note. Let's talk about ways we can enhance or improve
or change things going forward. How can we keep our microbiome happy? What should we be doing? Rob, you talk about getting outside. Tell us a little bit about that. Give us some advice. How can we be, um, moving forward for ourselves
and our kids and maybe maybe turn things around a little bit here. Sure. Well, the most important thing you can do
for your gut microbiome based on what we see in the, in the American Gut Project is eating
a wide range of different plants. So that seems to matter a lot more than if
you sit down to a huge plate of kale or if you sometimes eat meat, but that diversity
in plants also seems to be really important. So, so okay. Also, when it comes to particular foods, what
types of foods should we be eating Well, so at sort of general level, you should
avoid sweet and salty snacks, but I think you knew that already. One of the things that's coming out in the
microbiome, is this amazing individual variability that explains why different people respond
so differently to changes in diet, so the science isn't quite there yet to give personalized
recommendations, but it's getting pretty close and in the context of individual research
studies, that's working pretty well now. But don't we know that insoluble fiber, for
example, increases butyrate-producing bacteria, and butyrate is a pretty important part of
gut health? Absolutely. That's really good for most people, but if
you have IBD, it's a significant problem, and eating fiber it's really bad, so that's
why it's always challenging to give generalized recommendations that work for everyone, but
there was one Israeli. There was one Israeli study in particular
from Eran Segal and Eran Elinav at Weizmann Institute a couple of years ago where when
they look to their population, they found for a fairly sizable fraction of people, it
was actually better for their blood sugar to eat ice cream than it was to eat rice,
and they never expected that rational. When you find that out, you might wonder is
there a test I can do to find out if I'm in the ice cream or the rice category, and the
answer is yes, but so far it only really works in Israel, if you're eating the Israeli diet,
but then the more interesting question is, you know, suppose I’m in the category of
people who should eat rice and I want to be in the category of people who should eat ice
cream, can I change my microbiome to get there? And that's the kind of thing we don't know
yet, but it's plausible based on what we can do in mice. Will we one day be able to match the things
that we need to be doing to our microbiome, sort of the way we might other things? In other words, use information about our
microbiome to inform what what medicines might work best for us? That that's very plausible and again, in the
context of research studies, figuring out if a particular drug, whether it's a painkiller
or whether it's a heart drug, whether it's a checkpoint inhibitor for cancer, we'll work
on that based on the microbiome. That works really nicely at a research level. It's not yet ready for clinical use because
it has to get through FDA approval and so on, but that's probably coming pretty soon. That's a huge frontier because with every
medicine that we use, we know that there's tremendous variation in how well it works. What's the level of toxicity? And there's more and more evidence that your
microbiome is one of the controlling factors. So if we could understand that, we could make
drugs work better and less toxic, more effective. Or choose the right drug for the right person. Billions of dollars have been spent looking
for those answers in the human genome, but there are probably not nearly as much there
as there are in the microbiome. And the other thing is that you can't change
your human genome right? To change it from being a non responder to
a responder, but you may be able to change your microbiome. In just the same way that, uh, that variable
response to drugs is so individualized and potentially related to the microbiome, so
is the individual response to environmental chemicals, heavy metals in the environment. Look at lead, look at arsenic. There are huge populations at risk and yet
within a population of identical exposure, there's a lot of variability in outcome. And that's where I think we could have a huge
impact in public health on both predicting who is more or less likely to suffer the ill
effects of let's say lead because there are genes in our gut microbiome that manage these
metals. They've seen them for eons. And if we can predict that, that would be
great and if we could do something about it, it'd be even better. You mentioned response to different medications
and there is some work in antidepressants. Is that correct? That there's- My lab is actually starting that work with
some collaborators at Wisconsin, so we don't have anything to tell you yet. What's the goal there though? The goal is- because we all know that it's, for people
who are depressed, it might take several trials to find a drug that works for them. There's no one pill that works for everybody
all the time. No. And in fact, the efficacy of antidepressants
for any given antidepressant working in any given person is the lowest of any drug group. So it's about a 20 percent response rate. So typically people have to go through four
or five drugs to find one that works, and that's a very long and painful and depressing
a process. And so if we could upfront decide just by
a microbiome sample, which person is likely to respond to which drug, it's a very quick,
uh, and I think short term use of microbiome data because we don't even have to understand
the mechanism if, we hope to, but if we find such a connection, it would just be a predictor
that could save physicians and patients a lot of time. A lot of time. We already know, for example, that tylenol
response is microbiome driven, so there are differences in the human population. That's been known for years and there are
several other drugs coming along that look like their efficacy is driven or in some cases
toxicity is driven by the microbiome. Likewise, anticancer drugs, the big recent
wave and the use of checkpoint inhibitors now is clearly related to the presence of
certain kinds of microbes in your gut that either make them more or less effective. It's incredible. We must discuss probiotics. We've only got three minutes, 40 seconds left,
yes or no. Marty. The future is great for probiotics. We're all thinking that there will be probiotics
that people can use. Most of the materials out there for sale in
the health food store, grocery store pharmacy, very variable, almost completely untested. So caution on the probiotic thing. It's, it's hot right now. It’s really hot. It's really millions of people take it every
day. Yep. Astonishingly little data. Astonishing little data. Okay. But there are some really good studies that
show effects of, of probiotics. Some of the lactobacillus in particular, lactobacillus
reuteri, which seems to be throughout the Mammalian world, which suggests that maybe
there's some coevolution of mammals with that, that bug that seems to have a reproducible
effects in people. There is even- What do you mean by reproducible effects? Well, in one case it had effects on the immune
system and um, it, it reduced inflammation. And then there's another study that shows
a lactobacillus that reduces depression. That was this one study from England that
hasn't been reproduced. So I think there are several things coming
along that we will have data, but we just don't have enough now. But save your money for the moment. What about you Rob? Yes. So just like with drugs, there are, there
are studies that particular probiotics work for particular clinical indications, but that
doesn't mean that you should just take a whole lot of probiotics all the time, even if you're
not sick any more than you should take a whole lot of drugs all the time, even when you're
not sick. Okay. There's enough to say that the future is bright. The present is a little bit murky. David Mills at UC Davis did a study and showed
that about half of the things that he could buy in a health food store when sequenced
in his lab, were not even the organism that the label said they were, and we know that
this, not just the species, but the strain matters. So I think we're just working with really
imperfect material and we can't know yet. The probiotic manufacturing industry is the
wild west. The wild west. Okay. Caveat emptor. Buyer beware. Okay. Marty, I just wanted to end. You have a particular vision for what the
future might look like when we've understood the role of the microbiome in our own health. You say that particularly pediatricians are
gonna have a very different way to examine patients. What's that gonna look like? And. Well, certainly we're going to live happily
ever after. Okay. But beyond that, I, I think, uh, I, I envisioned
that the doctor of the future isn't gonna examine babies and they're gonna examine babies
diapers, and they're going to analyze those debt, those diapers with the knowledge that
is being created in laboratories all over the world, and try to use that information
to optimize health. And if there are particular microbes that
are missing in that baby that every baby should have, I believe that the doctors of the future
will be giving those microbes back and that there may be specific microbes that, that
baby is missing that they need, that will become part of the medical care of the future. Not Tomorrow, maybe 20 years from now. I'm not sure. Stay tuned. Right. Well, we'll get back to you on that. Right. I want to thank the panel here today, David. Rob, Jo, Marty. Thank you so much for this incredible discussion.
