Importance of Natural Resources

CARTA: Unique Features of Human Skin – Rob Knight: Ecology and Evolution of the Skin Microbiome

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programs. ♪ [music] ♪ – [Narrator] We are the paradoxical ape:
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We shape the future from our shared understanding of the past. CARTA brings
together experts from diverse disciplines to exchange insights on who we are and how
we got here. An exploration made possible by the generosity of humans like you. ♪ [music] ♪ – [Rob] So there’s a tremendous amount of
excitement about the microbiome at the moment in part due to the $173,000,000
dollar NIH Human Microbiome Project where the results catapulted from the pages of
Science and Nature to the cover of Scientific American to the cover of The
Economist in record time and into public consciousness. How did the excitements
that we’re finding due to the decline in cost in DNA sequencing over a million-fold
in the last 15 years? The microbes do all kinds of things that we never suspected.
For example, they determine how attractive we are to mosquitoes. So you’re not crazy
when you go camping. You might really be 10 times as attractive to mosquitoes as
the person you’re camping with. They determine how we respond to drugs. And
they even determine traits like obesity and a wide range of other diseases have
subsequently been linked to the microbiome. So a lot of what we’re trying
to do at the moment is understanding how can we map our microbes across our bodies
or across our planet? And the intuition is here is that as you go to different parts
of the world, you see different species in different locations that immediately
identify a scene that’s coming from one place or another or another. So with
microbes, it’s more or less the same, but we have the problem that they basically
look the same under a microscope, unlike these charismatic mega-fauna [sp]. So
instead what we do is we turn to the DNA to understand them. Now, the Human
Microbiome Project together with a team of about 400 researchers across the country,
we collected about four and a half trillion As, Ts, Gs and Cs. But then the
problem with the data is it looks like this. So this is the first 0.1% of the
first file. There’s another 17,000 of these. It’s pretty hard to tell who lives
where in the environment from that, right? So what we do is we use computational
techniques to develop these kinds of abstract maps where each point summarizes
all of the complexity in a given microbial community summed up by its DNA. And two
points close together are more similar in terms of the evolutionary history of their
microbes. Two that are further apart are more dissimilar in their microbial
evolutionary history. And so when we do this, we see automatically emerging these
major patterns where the mouth is very different from the skin, the vaginal
microbiomes and the fecal microbiome down the bottom there is distinct yet again.
And so what this implies is that two samples from the same person can be real
different in terms of the microbes. So here I’m highlighting one oral sample and
one fecal sample from the first person with the Human Microbiome Project. So
these are pretty different on this map, but we only really understood this when we
cross-referenced the data to the Earth Microbiome Project where we can go out
into different physical environments and ask what two samples are as different from
each other as the mouth and the gut of this one person. And so, if we compare
your mouth to being kind of like a coral reef, you have these complex mineralized
structures covered with biofilms that maybe your dentist pesters you about. The
microbes in the gut are as far away from the microbes in the mouth as the microbes
in this reef are from the microbes in this prairie in Kansas; so essentially,
non-overlapping communities. And what that means is that a few feet along the length
of your GI tract can make as much difference to your microbes as hundreds of
miles across the Earth’s surface. And what I’ll show you is that the skin which is
like yet another microbial continent, has tremendous diversity as well both within
you as an individual and between different people. So this might lead you to wonder
how stable our microbiome is, at least if we’re healthy. And my partner, Amanda
who’s–I’ve got her put up with a lot in the name of microbiome research. And I
addressed this question by sampling our own microbiomes every single day for a
period of six months. So when I project that into a slightly simpler version of
this data frame, basically, the dark points on this are me. The light points
are her. Now, what you can see when I start this going, so each frame on this
animation is one day as we move through this landscape in microbiomes defined by
different people. And you can see immediately how the skin in blue is much
more variable even within one person than the other sites. The mouth in green is the
most constant, and then the gut down at the bottom is intermediate between the
two. You can also see how we retain our
separate microbial identities through the six-month period, and that’s especially
remarkable when you consider we work together and have all kinds of
opportunities to exchange microbes with each other. I’ll just rotate this around
so you can see how we retain those separate microbial identities there. So
all of this might lead you to wonder where do we get these personally unique microbes
from. And if you have dogs or kids as I do, you probably have some dark suspicions
about that all of which are true by the way. So it turns out I can actually match
you up to your dog by the microbes you share. Now that’s not to say that your
microbes are exactly the same as the dog’s. So here what we can see on a map
that includes both humans and dogs is that every site of the body whether it’s the
tongue, the stool, or the skin, the dog and the human are separate from one
another. And again, you can see that the dog’s skin is very variable just like the
human skin is. But in all seriousness, our first microbes depend tremendously on how
we’re born. And so, this is like we did with Maria Gloria Dominguez-Bello now at
NYU, looking at microbes of mothers now before they gave birth and then of their
babies within 20 minutes of birth. And what you can see in red is the vaginal
communities from the mothers and then in pink, we have microbes from all over the
bodies including the skin and including the gut of babies 20 minutes after they
were born. Whereas in contrast, in the dark blue, we have all the skin
communities from the mothers. And in light blue, we have all the habitats from all
over the body of babies delivered by C-section. So what you can see is that if
you’re delivered by C-section, you’re denied the vaginal microbes you would
ordinarily have as you pass through the birth canal. We think that the lack of
that co-evolved microbial community may explain some of the differences in health
between vaginally delivered and C-section babies. Of course, the most likely outcome
if you have a kid by C-section is that your kid will be fine, but there are
slightly somewhat higher risks of all kinds of diseases including ectopic
dermatitis, food allergies and even obesity, all of which have now been linked
to the microbiome. So again with Maria Gloria, we’re doing
this trial at the moment to try to figure out, can you restore the microbial
community to kids delivered by C-section. And so, what we’re doing here is
essentially collecting the vaginal microbes from mothers then delivering them
to the babies. And this is very preliminary data at this point, but we are
able to show partial restoration of the microbial community both in the gut and in
the skin by applying this procedure. And so, we’re hoping to develop this into a
large enough study to develop clinical recommendations based on this microbial
restoration. So you might be wondering, “Well, what happens after that?” What I’m
going to show you now is the trajectory of one child–this is what we did with Ruth
Lee [sp], tracking one child over the first two and a half years of life. And so
what we’re going to be looking at his gut community. He was delivered vaginally, and
you can see that his initial fecal sample is up there in the vaginal region with
perhaps a little skin contribution as well. And so the question is, “How long
does it take him to move through this landscape towards the adult fecal
community over two and a half years? How complete is that progression down towards
the bottom? And is it smooth or is it chaotic?” So what you can see is at some
weeks, he changes a little bit whereas other weeks, he changes a lot. And
remember what matters on these plots is the distance from one point to another. So
it really is true that one week to the next, your kid can look like a completely
different person at least when you compare the distances between these points to the
distances between healthy adults in the Human Microbiome Project which are those
points in brown at the bottom. Now, coming up here is something fascinating. So he
gets antibiotics for the ear infection. See that tremendous regression of the
microbiome and then the recovery. That went by pretty fast, so I’m just going to
rewind it for you and play it again. So what you can see is on administration of
oral amoxicillin for an ear infection, you see this tremendous regression of the gut
microbiome and during months of normal development, followed in this case, by
rapid recovery. Then by the time he gets to two and a half
years, he’s more or less in the healthy adult distribution. But we just don’t know
in general what the effects of antibiotics are on the rest of the body and on the
sites they’re targeted and whether those early life changes can have profound and
lasting effects. There’s some evidence in both humans and experimental animal models
that early life antibiotics in the first six months can lead to increased rates of
obesity, but we don’t know about the impact on the skin, on the mouth and on
other sites on the body yet. We can also do this sort of thing cross-culturally. So
here in which we have gotten and we’ve got an African population in red, South
American population in green and then the US population in blue, the gut communities
converged on one another after the first three years of life. However, where they
wound up in the three populations was very different. So the rate of approach to the
adult stage is very similar cross-culturally, but the final stage
where you end up can be very different. And you can see the Western population in
that right-hand panel in blue is very different from the two non-Western
populations. And in that respect, it’s important to remember that even
large-scale projects like the Human Microbiome Project have largely only
looked at healthy Western adults. And as soon as you start to go into children and
as soon as you start to go to non-Western populations, you see very different
things. This is true not just in the gut, but in every site in the body. So for
example, this is what we did with Maria Gloria Dominguez looking at previously
uncontacted Yanomami in South America. And what you can see is the Yanomami
population is more diverse in the skin, so that’s the left panel, than the US
population. And then the microbes that they have on the skin are completely
different. So those green points separate completely from the yellow points of the
US population. So this might lead you to wonder, “Well,
we’ve seen that the skin can vary cross-culturally, but how does it vary
over the human body?” And this is like we’ve been doing with Pieter Dorrestein
here at UCSD in the Skaggs School of Pharmacy. And across the skin, it’s just
so fascinating. It’s this interface between ourselves and the physical
environment that we’re in contact with. So Pieter was interested in how microbes were
over the skin. So he recruited two subjects one of which was him, and sampled
the skin at 500 sites over the body and then analyzed each of those sites using
two kinds of mass spectrometry. And re-sequenced the DNA of the bacteria to
give a readout of where they are all over the body. And one thing that was
fascinating is that all of the microbes can differentiate the two subjects from
one another. They’re not nearly as distinct subject to subject as the
metabolites are. So you can see that the metabolites from these two completely
separate clouds, one from the male in blue and one from the female in red. And so,
the metabolites we can track down where they are in the body. And some of them are
broadly distributed all over the body. Some are localized to the armpit or to the
groin or to the toenails or other particular sites. And we can do the same
kind of thing for the microbes. So for example, staphylococcus is mostly in the
moist regions like you’d expect so the nose and feet. Propionibacterium are on
the head and shoulders and corynebacterium broadly over the body. So one thing that
was really fascinating about this was when we built these molecular networks to try
to figure out how the chemicals related to one another, what we could see is that
most of the chemicals we found on human skin did not come from pure bacterial
cultures or from human skin cell cultures, but instead came from beauty products. And
in fact, 90% of chemicals that we identified on skin in the study came from
sunscreen and moisturizer and shampoo and other things that our subjects applied to
their bodies. So that’s just fascinating, right? That 90% of the identifiable
chemicals on your body probably come from consumer products that you apply. So to
address this problem, I’ve been working with the Hadza in Tanzania together with
Jeff Leach through the Human Food Project. And so, these are people who have not been
exposed to any of these products at all. And essentially, what we’ve been doing is
sampling a wide range of things there including the gut, the skin, the various
dwellings and so forth on different projects. And so what you can see is that
the Hazda, shown here in yellow, have very different metabolic communities from the
Westerners even when we were out at the field site. So we’re at the same location,
but you see these very different skin metabolite profiles. And what you can see
is of the metabolites that we saw, only about 25% of what was identified was
shared by the Hadza skin and the skin of Westerners. You can also see that the
Hadza skin is much closer to the environmental samples, mostly water
samples that we collected on-site in green there. They also have a fairly large
contribution from honey which can make up a lot of their calories in the dry season
which is when we were doing the sampling. And we can also see a number of plants
that are contributing to the Hadza and not to the Westerner metabolites. And so these
are things like baobabs and other major sources of food that we can track down the
specific metabolic links between the food and the person. So this is a kind of
molecular network where essentially you can think of this as basically being like
constellations of the different metabolites where you connect up the ones
that are related to each other and match them up to different kinds of
environmental samples. And so what we can do with this is we can identify clusters
that their specific to particular niches. So for example, we can see plant
flavonoids. We can see monostearate which is more on the healthcare products in the
US population. And we can zoom in and for example, look at the flavonoids and how
the profiles are somewhat similar, but then with subtle differences between the
US and the Hadza individuals in the study. And then similarly, we can do this sort of
thing with seterols which again are mostly coming from plant metabolites and from
sucrose from the beehive which is found predominantly in the Hadza. So we can also
do this sort of thing looking at the bacteria. And what I’m doing here is just
coloring it by body site. So for example, the green is stool. The pink is skin, and
you can see this tremendous heterogeneity in the skin. And we also got some samples
from three collaborators at the Yerkes Primates Center, and I’m just going to
make some of the balls bigger for the chimpanzees. Those of you familiar with
chimpanzee anatomy will understand why. And so, what you can see is that the fecal
samples from the chimps are distinct from the fecal samples from the humans. Then
correspondingly, the few skin samples we have from one chimpanzee individual, those
large pink balls, are substantially distinct from the skin samples from any of
the humans including the Hadza. And then within the human population like you can
see here basically the gray samples of skin are samples from Westerners, and the
colored balls are from Hadza from different camps. And you can see that
again, like the South American Yanomami group I showed you before, the Hadza skin
samples are distinct from what we see in Westerners. So we’re just starting to
uncover the links between microbiology and different lifestyles. I should point out
that most of this data from the Hadza and from the chimpanzees was assembled over
the past week, and many of these figures we made last night on the spot, so this is
still very preliminary data. We’re still trying to fully understand the results. So
anyway, one thing that’s exciting about matching up the metabolite and the
bacterial profiles is we can get an idea of what bacteria are doing what functions.
So if I show you something like proprionibacterium which is mostly on the
head and shoulders and then–sorry, mostly on the head and shoulders and then
something like oleic acid which is on the head and on the hands. You can see in the
third figure that oxidized oleic acid, which is a metabolic product of oleic
acid, that’s on the head where you see proprionibacterium but not on the hands
where you don’t see it. And then similarly with palmitic acid, we
can see it getting degraded to monoolein, monopalmitin only with proprionibacterium
mostly. So what we can do then is we can test that hypothesis by taking the
bacteria cultured off skin, and then incubating it with a precursor and just
verifying that that particular bacterium in the lab can do the chemical reaction
that we attribute to it. Okay, so I’m just going to talk very briefly about how we
exchange our skin microbes with our environment. And for example, we can match
up the keys on your computer keyboard to the tips of your fingers and the palm of
your hand with your computer mouse with up to 95% accuracy based on the microbes you
share. So this came out in the scientific journal PANS a few years ago. Here, I’m
just showing you the skin of the fingertips from the keyboard keys
clustering together by subject for three different people. But more importantly, it
was on the TV show, CSI: Miami so you really know it’s true. In any case, we can
use this kind of mapping technique towards sources of pathogens in the kitchen where
you can see in that top panel that you’re leaving your skin communities primarily on
the door handles and the trash can and other things that you touch. We can do the
same kind of thing in bathrooms. So here you can see that the skin’s mostly on the
door handles and the toilet seats. Our stool’s fortunately mostly confined to the
bathroom. Then there’s a big signal from soil on the floor and intriguingly also on
the flush handle where apparently, a lot of people were using their feet to flush.
And coming from New Zealand, I had never heard of this cultural practice, but
apparently it’s fairly common in the US. We can also do the same sort of thing in
homes. So this is what we did with Jack Gilbert looking at what happens when you
move into a new house, and you can imagine some different scenarios. So for example,
you might stay the same, and the house might stay the same.
You might unpack your microbes all over the house with the rest of your
belongings. Maybe the house instead contributes microbes to you, or finally,
maybe you and the house blend into a new community state. One thing we saw was that
the house microbes were very highly correlated with human microbes from the
same dwelling. There was one case where there were two lodgers–sorry, where there
was a couple and a lodger, and to everyone’s immense relief, the two people,
the couple were more similar to one another in their microbial community than
either was to the lodger. And so there was no difficult explaining to do. But one
thing we can do is we can track the individual contribution to different
surfaces. So here what we’re looking at is each individual and each dog’s
contribution to different surfaces like the bathroom doorknob, the bedroom floor
and so. You can see that black line. That’s where person one went away on a
trip, and you can see their particular contribution to all of these surfaces
disappearing during that period when they’re away. So we can even tell who’s
inhabiting a particular space by the microbes that they’re leaving behind. But
more seriously, we can apply this sort of thing in the hospital environment to where
the hospital acquired infections. And we can also apply these techniques to really
compelling questions in animal health. So for example in the Earth Microbiome
Project, we’ve been looking at a huge number of different microbial samples so
over 30,000 samples provided to them by members of the community. And for example,
looking at komodo dragons–so this is me swabbing a baby komodo dragon at the
Denver zoo called Bintang. What we can see is that each komodo dragon in their
enclosure shares a whole lot of microbes with the particular enclosure it’s in just
like we do as humans with the enclosures in which we capture ourselves. But what’s
fascinating is that the microbial communities of the captive komodo dragon’s
soil don’t resemble at all the communities that we see in soil in the wild. So you
see these two completely distinct clouds of points. And what’s interesting is the
degree of sharing is pretty similar to the degree of sharing we see between humans
and pets in the same houses, but not the degree of sharing that we see with wild
amphibians and their environment where a constant input of microbes seems to be
really important for health. Speaking of amphibian health, one thing
that’s really important is this fungal disease called Bd which is leading to
amphibian declines worldwide. And one thing that’s fascinating–and this is with
Val McKenzie at Boulder–is that we can look at a whole lot of different
amphibians and actually put them along this axis of resistance from the least
resistant to the most resistant to Bd based on the skin microbial community. And
then the really cool part is like Rich showed you in humans, we can actually
transfer the microbes from one frog to another and confer resistance to the skin
fungus. And so, this idea of microbial transplants is turning out to be
incredibly compelling. So I’ll just wrap up very briefly by mentioning that you can
put yourself on these kinds of microbial maps now through this project called
American Gut, that will also accept skin and other samples. And not everyone wants
to know what’s in there, these middle schoolers reacting to the idea we’re going
to use robots and lasers to look at their poop. But just to re-orient you on the map
in cases like clostridium difficile, what you can see is this extreme dysbiotic
microbial community if you have this profound form of diarrhea where you’re
going to the bathroom many times a day. I just want to show you what happens when
you do ecosystem restoration where you have one donor who’s down on the healthy
state there and transmit that to four patients. So this is with Mike Sadowsky
and Alex Khoruts of the University of Minnesota. And what you can see is that on
transmission of that microbiome from the healthy donor to the four of these
patients, and each frame on this is just going to be one day in the life of the
microbiome. What you can see is essentially immediately, they go from the
unhealthy stage into the healthy stage, and then they stay there. And so the
prospects to do this kind of thing–and this is [inaudible 00:23:59] to clinical
remission of their symptoms within a day or two.
The ability to do this sort of thing in all body habitats whether it’s the gut or
the skin or elsewhere is an incredibly compelling area of medicine today given
the large number of diseases we now know are linked to the microbiome. But what we
really have to do is develop not just these microbial maps, but the kind of
microbial GPS that tells you not just where are you right now but where do you
want to go in terms of your microbiome, and what do you need to do step by step in
order to get there. We need to develop this and make it so easy to use that even
our children can use it. So you can imagine the kind of smart toilet that’s
going to do an analysis of your microbes and your metabolites. It’s going to
deliver it to your smartphone which, let’s face it, I bet you’re using it in there
anyway. And it’s going to tell you whether you’re going in a good direction or a bad
direction and maybe what, specifically, you need to do in order to improve the
health of any of your microbiomes whether it’s your gut or your skin. So with that,
I’ll briefly thank again the many people who contributed to the specific week I
showed you, the large number of amazing people I’ve had working with me in my lab
currently and formerly, and finally, thanks for your attention. ♪ [music] ♪

Reader Comments

  1. I use my foot to flush in public places too. Rather not touch the handles in a bathroom you know, after someone else has pooped =p

  2. I'm having a hard time understanding the spatial deviation of the points on the 3D plots and exactly what each data point represents. I understand the variation regarding skin/oral/gut/vaginal samples, just not their spatial representation. Can someone explain?

  3. I believe what Dr. Knight is trying to indicate is what and where the habitat of the microbiome resident community can be very extreme just inches apart…

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