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The Gut Microbiome in Health and Disease | Susan Tuddenham, M.D., M.P.H.

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All right, our next speaker,
well, first, we're changing
the topic altogether. We're going from
the basics of immunology, and a little bit
of immunotherapy, now to the gut and
the immune system, as promised. And our first speaker in
the series, Susan Tuddenham, has a longstanding interest in
the interplay between sexually transmitted disease and
the urogenital microbiome. And she'll tell us a bit
about her work today, thank you very much. >> Okay. Okay, thank you, okay,
can you hear me okay? So my name is Susan Tuddenham,
I'm an Assistant Professor in the Division of Infectious
Diseases at Johns Hopkins. And today I'm not
going into bugs or organisms that live on us. So we've known for a long
time that we are colonized by many different organisms. But new technologies developed
in the last 10 to 15 years have enabled us to understand
that there are literally trillions of bacteria and other
organisms living on our bodies.

They colonize our skin, they
inhabit our gut, our intestines, and really, are living on nearly
every crevice of our bodies. Amazingly, we've also started
to realize that these organisms can harm us, but may also be
critical for our health, and that many of those
beneficial effects for our health may be mediated
through the immune system. So this very interesting finding
that these organisms may be beneficial to our health
at the same time as they can harm us has caught the attention
not only of scientists and physicians, but also the public, as you can see
from these slides.

I particularly like this
one with the impending cloud of organisms
descending on this newborn. So there are technical
differences between the term microbiota and
microbiome, but for the purposes of this talk,
I'll use them interchangeably. So the microbiota, or
microbiome, then is defined as all of the microbes that
we share our bodies with. And that's mostly bacteria, which has been the focus of most
of microbiome research, but also other organisms,
like viruses and fungi. Amazingly, there are actually
more bacterial cells on our bodies than human cells, so
we're at least as much bacteria as we are human,
pretty incredible concept. So what about the makeup
of the human microbiota? Well, the first interesting
thing is that we each differ, so the microbiota living on
my body is very distinct to the one living on yours. So we're each very different
in our microbiota. And then secondly, amazingly, there are huge differences
in the microbiota, not only in between individuals,
but within the same individual.

So you can see from
this plot here, this is a plot that basically
shows samples taken from a bunch of different patients. And it's color-coded by where on
the patient's body this sample was taken. And so you can see that here
in the orange, the bacterial communities inhabiting the mouth
are very different from those inhabiting the skin, which are
shown in green here, which in turn, are very different from
those inhabiting the gut, or GI tract,
which are shown in blue. So the first key concept is
that we each differ in our microbiota. And the second key concept is
that there are very different microbial communities inhabiting
different parts of our bodies. They're really specialized
to optimize the tissue in that environment, or niche. So the gut microbiome, which is really what we're going
to talk about today, is, by far, the most diverse of any of
the microbial sites on the body. And there are over 1,000 species that have been found
inhabiting the gut.

So gut microbiome
research actually goes back a little bit further
than you might realize. So a germ-free animal is
a special animal, in this case, mice, which has been raised
in special conditions. So it's isolated from
the environment, and is not colonized
with any bacteria. So the first germ-free mice
were developed in the 1930s. And actually, long ago, people
noticed that germ-free mice could eat about 30% more
calories than a regular mouse, but not gain weight. That's pretty fascinating, why
can a germ-free mouse eat 30% more calories, but
not gain weight? I kinda wish I could do that. However, when you actually
transplant the gut microbiota, so the bacteria
living in the gut, from a normal mouse into
that germ-free mouse, the germ-free mouse
gains weight rapidly.

So we've suspected for a long
time that the gut microbiota probably plays an important
role in nutrition and how we get nutrients
out of our food. Another interesting study you
may have heard about sort of extended these findings, and
took stool from paired twins. So these were human twins, one
twin was obese and one was lean, and they put stool from those
twins into germ-free mice. And very interestingly, they
found that the mouse that got stool from the obese twin gained
much more weight than the mouse that got stool from the lean
twin, so very interesting. This is just showing how much
change in fat mass they had, and you can see there's much more
with the mice that got stool from the obese twin. So very interesting, and suggesting that obesity can be a
microbiota-transmissible trait, at least,
between humans and mice. So this brings us to what do we
know about the gut microbiota and health, and there are a few
sort of key concepts.

So the first, based on that
information I told you about, the mouse studies, and certainly
other studies as well, is that we think the gut microbiome
helps us to digest food. Basically, we think these
organisms help us to break down our food, such as dietary fats,
proteins, carbohydrates, and help us absorb those
important nutrients. And there's another key concept,
which is that the gut microbiome basically is a community of
bacteria that flourish and help keep out bad bacteria,
pathogenic bacteria, from coming in and colonizing, and
overgrowing, and making us sick.

So that's another key concept. And thirdly,
really relevant to today, we think that the gut microbiome
is probably very important for the functioning of
the normal immune system. So first of all, we've observed
that germ-free mice have a lot of immune system abnormalities. So they don't have the proper
number of immune cells, they're not normal in that way,
and there are some other interesting studies that
suggest this connection, too. So one of them I'll highlight
is a study where they basically looked at germ-free mice and
gave them a flu vaccine, so the regular flu
vaccine that you all get. And they found that germ free
mice just really don't make antibodies very well to that
flu vaccine, at least early on. Then when they actually gave
normal bacteria back to those mice, they found that they had
an enhanced immune response. So they made antibodies much
better to that flu vaccine, so a really interesting
finding there.

What about the gut
microbiota in disease? So I just wanted to highlight
some really exciting work by my mentor, Cindy Sears, and
her lab at Johns Hopkins, who found that there
may be a connection, although this is still early
stages, between the organization of the gut microbiota and
some colon cancers. So colon cancer, and this is a
picture of a colon cancer here, is a huge public health problem. And interestingly, the colon,
the mucosa of the colon, is normally covered by a layer
of mucus that protects it from all the bacteria
that are in the stool.

So it's there, it's free
of bacteria, and it keeps those bacteria from contacting
the surface of the colon. But Cindy's group found that in
about half of all colon cancers, there's a thick complex of
bacteria, called a biofilm, that actually invades through that
mucus and touches the surface of the colon, probably causing a
lot of inflammation, activating the immune system, and causing
other deleterious effects. So this is a slide from
under the microscope, where the bacteria
are shown in pink. And you can see that in
the tumor specimen, there's this thick mat of bacteria, shown in
pink, that are invading through and basically touching
the surface of the colon. This colon epithelium is
shown in the blue here. And you don't see that
same finding in normal patients with no tumors, so
an interesting connection there. Again, we don't know entirely
what this means, but we're investigating it more. What about future directions? Well, I think there's a lot of
excitement about the role of the microbiota in many
different diseases, and I'll give you just
a few examples.

So will microbiota studies in
the future inform our approach to prevention of disease? Maybe, so I already mentioned
that there are studies, and there are other ones as well,
suggesting that there may be a connection
between the microbiota and how well people respond, or how well, at least,
animals respond to vaccines. Secondly, there's been some
research that shows that the microbiota may impact how
plaque develops in our blood vessels, and therefore, our risk
of heart attacks and strokes. Will specific bacteria or
communities of bacteria help us improve our treatments for
disease, such as cancer? So this is another one
where this is touching on the relationship between
the microbiota and the immune system.

So interestingly, in mice, some
mice do not respond very well. Some mice with cancer do not
respond very well to some of our anticancer medications, including some of the new
immunotherapeutics. But if you give them back
specific types of bacteria, their tumors essentially
stop growing. So a really interesting finding
that we think is mediated through T cells and the T cell
response, but early days, but very interesting there. Will microbiota
studies help us to develop individualized medicine? There's an interesting
study where a group, ZV et al, basically monitored people's blood
glucose levels continuously. And then by incorporating
microbiota information and other information,
were able to predict what specific foods would make
people's blood sugar spike. And that was very different
between different individuals. So white bread, for example,
made some people's blood sugar spike significantly,
but others not. And we're able to predict that
by using the gut microbiota information, as well
as other factors. And lastly, can new sequencing
techniques in the microbiota help us to diagnose and
prognosticate disease? These new technologies,
these sequencing technologies that we're using
to study the microbiota have a lot of power in
detecting disease as well.

And so just one example, at
John's Hopkins, we had a patient who came in, a woman in her 60s,
very, very sick. She had multiple lesions, multiple abnormalities in her
brain and her spinal cord. They were enlarging and
she wasn't improving, and despite all of our testing, we could not figure out what
was causing these lesions. And so
sort of as a last ditch effort, she participated in a study
where we used next-generation sequencing to try to figure
out what could be going on. Was there an infectious agent? And with that, we actually
identified that what was causing her problems was tuberculosis. We started her on
anti-tuberculosis medications, and she rapidly improved. So there's one concrete example
of where these new technologies actually help to save
a patient's life. So I think there's a lot of
exciting research going on. This is just a graph showing
you the number of publications over time, if you just search
microbiome in our PubMed, which is sort of a compilation of all
of our biomedical articles. And you can see there's been
an explosion in recent years.

This research really has been
largely dependent on NIH funding, so federal funding
from the National Institutes of Heath, who established
the Human Microbiome Project. And the first phase of that,
which really started in 2007, was just to establish what
is the baseline microbiota, what's the situation
in normal individuals? And now we've moved beyond, which I think is very exciting,
to really try to understand more what is the role of
the microbiota in health and disease, with the ultimate goal
of harnessing the power of microbiota research to
improve patient outcomes.

And so I hope I've helped to
convey some of the excitement and the interesting
things that are happening in microbiome research. I think there's a lot
of promise, and I'm happy to take any questions. >> [APPLAUSE] >> The effect that you mentioned of the mucus covering of
the colon made me wonder, do you see anything like
that in Crohn's disease? >> So the role of the microbiota
in Crohn's disease is a hugely hot topic that
has been studied a lot. Now, specifically with
respect to the biofilm, there's a little bit
of research on that. But more of it has actually been
focused on what is the overall composition of the microbiota in
patients with Crohn's Disease or inflammatory bowel disease. And we certainly have found that
there are striking differences. So the microbiota in patients
with inflammatory bowel disease is much less diverse, and
then there's specific bacteria.

The results are a little
bit conflicting, but there's specific bacteria
that seems to be increased or decreased in patients with
inflammatory bowel disease, as opposed to normal patients. So I think all of the
connections, in terms of what that actually means, and how we
could translate that to patients and things that could actually
improve health for our patients, that's a long way to go. But certainly, initially, we know there
are significant differences. >> What aspect of the microbiome
does your work focus on? >> So my research actually is
on a very different niche of the microbiome,
it's on the vaginal microbiota. And I come at this because I
started out being interested in sexually transmitted infections,
things like gonorrhea, chlamydia, syphilis, etc. And it turns out that
the vaginal microbiota are very important for
being the body's first line of defense against colonization
with these organisms. So it turns out that differences
in the vaginal microbiota actually predict your risk of
acquiring things like gonorrhea or chlamydia if you're
exposed to them.

So I'm very interested in that,
but it's a little beyond
the focus of the talk today. >> So it seems like we're coming
to understand that a lot of different things can
perturb the microbiota. But I wonder if there's any work
on types of interventions that can actually stick, like beyond
just the changes we can observe with a different diet, different
environment, travel, etc. What sorts of things
can actually lead to a permanent change? >> Right, so
that's a great question, so I will say that there's a lot of
promise in microbiome research. So the goal, right, is to potentially be able to
manipulate the microbiota in a positive way to
improve our health.

And so far, we're relatively
far from that, except for one particular example, which I'm
sure you may have heard about. So there's the infection called
Clostridium difficile, and basically, what we think happens
is that people get antibiotics. And those antibiotics basically
mess up the microbiota and perturb the microbiota, and
allow the opportunity for a Clostridium difficile, which
is a very nasty bacteria which causes a terrible and, often,
life-threatening diarrhea, to come in, invade that
community, and overgrow, and take over, basically.

And unfortunately, antibiotic
therapies are somewhat effective, but
people often relapse. So as you imagine,
giving more antibiotics for something that was kind of
caused by antibiotics in the first place is not entirely
successful a lot of the time. But what we have found is that
fecal microbiota transplant, FMT, so basically taking stool
from a healthy person and putting it into the person
with recurrent C diff, the diseased person,
is very, very effective.

In some studies, up to 90% of
people experience remission of their symptoms, and
that does seem to be sticking. We're now doing the studies to
see how long that microbiota actually stays around,
from the healthy person. But that's one example where
we've actually been able to change the microbiota in a
positive way to affect disease. The rest of it, I think we're
doing a lot of research. For various reasons, the idea
of a stool transplant is, maybe, not that palatable to many,
[LAUGH] understandably. So the goal is to really try to
come up with targeted therapies, like using a particular strain
or species of bacteria that you can then put into the diseased
person and improve their health. But we're a long way
from that so far.

>> That was actually my
question, is the transplant of stools the only way to
administer it, currently? Because I suspect you wouldn't
wanna do sort of a cross-body immunization of a very
specific gut bacteria. It exposes the rest of the body, cuz it's very specific
to that region. Yeah, I guess that's
what my question is. >> Right, I mean, there are a
few different variations on this transplant of stool. And there have been studies
looking at just using a combination of bacteria or
bacterial spores, and transplanting those
into a patient, that show a lot of promise. But so far, the one that's
been the most steady and the most used is really
just transplanting, it's a not very sophisticated
[LAUGH] technology.

It's really just transplanting
stool from a healthy patient into a diseased patient. But I think everybody's goal is
really to make that much more refined and transplant certain
strains of bacteria that can have positive effects..

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