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.