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Hello and welcome. You are listening to a
podcast by the Milner Centre for Evolution at the
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University of Bath. I'm Professor Turi King your
host, and today I'm talking to Guillaume Méric,
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an associate professor whose research focuses
on the human microbiome. Guillaume, for those
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who don't know, what is the microbiome?
So, we as human have co-evolved with the
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microbial communities that colonize us and
probably from even before we were human.
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And this has resulted in a complex assembly of
trillions of microbial cells from thousands of
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species that are inhabiting on or in our body.
The gut is a particularly heavily colonized body
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site of ours. Microbes there fulfil very important
role for our health. They help digest our food,
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they produce vitamins, they interact with our
immune system, and they protect us against a
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whole range of gastrointestinal pathogenic
infection. And they even communicate with
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different organs, which can include our brain.
Our gut is actually our largest immune organ.
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About 80% of the body's immune cells are there,
partly because of the constant negotiation that
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our body has with these trillions of microbial
organisms. And in the last few decades,
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researchers have found and characterized,
that disruptions in the balance of these
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microbiota seem to be linked to a wide
range of diseases and health conditions.
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So, let's go back to this a little bit, because
people are really starting to clock just how
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important the microbiome is. So, you've got
like these trillions of cells haven't you,
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in your gut, what are they doing in there?
A lot of them are there since our birth.
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There is debate to know whether they are there
before our birth as well. But there's a lot of
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various different species that are inherited from
our mothers that are transmitted vertically, as
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we say. Those are very interesting in themselves,
because we have a sort of inkling that they are
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more linked to our genetics and our ancestry and
our population we belong to. And there are others
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that are also coming from external inputs, such
as, you know, diet or exposure to various things.
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Under pinning what the bacteria are doing is a
very difficult task. There is a sort of consensus
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now that the bacteria that are producing good
things for our health seem to be producing some
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small molecule metabolites that are called short
chained fatty acids. And those have been linked in
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a lot of population studies and population health
cohorts with positive health outcomes, and notably
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with positive cardiovascular health outcomes.
And we all have our own personal microbiomes,
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that are the product of, as you say, so some
coming down to us vertically from, you know,
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birth, ancestry and other bits from what
we're eating. So, we all presumably have
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our own personalized microbiomes. And how do
they help us in terms of health? Because you've
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just been mentioning about cardiovascular
disease, how do they affect our health?
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So how they affect our health is not very much
known, aside from this production of short chain
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fatty acid that I mentioned, the mechanisms
are a bit more elusive. And at the moment
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what is being done is just to try and robustly
associate particular taxa, particular species,
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particular functions with health outcomes and
with positive or negative health outcomes.
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And the reason why it's difficult to pinpoint
these things down is exactly what you said.
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It's that it's immensely variable in people.
You have commonalities in different people.
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We will be colonized, for instance, the
both of us by the same species of bacteria,
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perhaps different strains of these bacteria,
but we will have the same species. And normally
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speaking, the dominant bacteria are roughly
the same, if you just look at what's there.
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The quantities might vary, and also the dynamic
of these different interactions between these
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bacteria might vary. And sometimes depending on
the different conditions of health, depending on
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your culture, depending on your diet, depending
on your genetics, you will have sets of important
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bacteria that are different from each other.
And so these individuality in the microbiota
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profiles is something that makes it very difficult
to know what's good, what's not in people,
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but it's also making a sort of population
scale approach of research have more sense,
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because if you look at a lot of different people,
if you could try to control for various different
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factors like this, you can try to compare
things and, you know, find commonalities
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or things that are different between people.
And that's basically what you're trying to do.
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So how do you do that? How do you tackle
this huge question as to what's going on?
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It's not easy, but it's exciting. So, my
group is at the intersection of various
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different domains. I'm a microbiologist
myself, but the work we do is at the
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intersection of population health of clinical
microbiology, bioinformatics and epidemiology.
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The goal of our research is to understand how
the human microbiome interacts with health. And
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particularly when I was mentioning different
diseases, particularly with non-communicable
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diseases like heart disease, diabetes
or more recently, liver disease for us.
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So, the way that we do this is, in my group,
entirely computational. We use large scale,
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secured, anonymized human population cohort
datasets that are including a microbial component.
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So that would typically be metagenomics data sets
from the gut. We sequence everything we can find
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from the gut. We try to assign what is there, you
know, in terms of bacteria, and we analyse this.
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We work as part of consortia, big collaborations
with Nordic population cohorts, mainly from Sweden
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and Finland, but also other locations. One of the
interesting aspects of these Nordic cohorts is
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that they are extremely well phenotyped.
We have lots of matching data for every
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participant that is enrolled in the cohort.
Whether in the form of questionnaire data,
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food habits or lifestyle habits, but also
prescription data, adverse health outcomes,
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electronic health records. Everything
is matched for these participants. And
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even more interesting is that for one of our
cohorts of interest that is called FINRISK,
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from Finland, we have a very long follow up.
We have up to 25 years of follow up after the
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sampling of the microbiota in the
people. So, we know what happened
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to these people who gave a sample of their
poop in 2002. And we can use this formidable
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wealth of data to sort of look at possible
links between the gut microbiota and future
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health. And so, the type of research we have
is very generalistic and very generalist but
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uses these sorts of frameworks to look at
various aspects of health and the microbiota.
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But that's really cool because presumably what
you can do is because you've got these long-term
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studies, you can go, well, these people had these
particular bacteria, and they were more likely
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to go on to develop this particular condition
versus these people. And are you in the early
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stages of trying to understand that I'm guessing
because this is a relatively new field, isn't it?
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It is one of the things that is actually very
exciting about it, I find that the field is
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renewing itself really quite a lot. There's a
lot of technological enhancements or novelties
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that have arrived in the last decade, I would say,
that make things maybe not conceptually very new,
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but much more unscalable. You can start looking
at very large sample sizes. You can start
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looking more in depth in those samples as well.
And this allows, you know, not to reinvent the
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wheel, but to confirm a lot of things that we
could have inferred from smaller sample sizes,
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from smaller groups of people. But if
you contextualize them in the context
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of populations, that's when you can
start having these findings basically.
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So, this is a bit why it feels like we are at the
beginning all the time, because we are constantly
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refining what we suspect and what we have seen
with low statistical power, low sample size,
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but we are confirming it or infirming it in
various different populations, various different
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contexts. The more this is done, you know, I was
talking about Nordic populations, now they were
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the first, the Nordic countries were the first
to establish very good electronic health records
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and very good sampling of populations. This is
why we are working with them. But of course,
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now other countries are starting to do this.
And the more we do this, the more we try to
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represent human populations as a whole. The more
we see the differences, the more we see that it is
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a complex thing. And of course, when you talk
about countries like the UK, countries where
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there's a lot of people, but the population
is diverse, there's many different sorts of
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microbiota in there. You can see the challenge of
making generalistic statements about health. It is
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difficult still at this stage to link anything
that the microbiota is doing generally in the
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population. But we are having quite a lot of ideas
now. We're starting to have a good picture of it.
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So, I was going to ask you that. Are you
seeing any trends yet, or is it still
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really early in the research and you're not
seeing anything particularly at the moment?
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So, it's very hard to say anything very general,
generally speaking, in the gut microbiota field,
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because there's so much of this variability.
However, there seem to be some strong facts
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that are emerging, which is I was mentioning
earlier, those bacteria that are able to
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produce short chain fatty acids, that are small
metabolites that have been linked to a lot of
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positive health outcomes. Those bacteria are very
diverse. They come from a very sort of different
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taxonomies. They have phylogenetic diversity.
It's not just one species. It's not just a
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group of species. There's quite a lot of them.
The trend that has been shown is that they seem
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to be overrepresented. They seem to be growing
in our gut, when we have a diverse diet that
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contains a lot of fibre. That's why you hear about
eating a lot of fibres, and fibre is good for you,
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and particularly different kinds of fibre,
not just one kind of fibre. The more you can,
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the better. But this is something that
has been shown to promote those short
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chain fatty acid producing bacteria with
positive cardiovascular health outcomes.
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One interesting aspect as well is fermented
food. Fermented foods have been shown not
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only to contain a lot of short chain
fatty acids themselves, but also to
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have those bacteria that are producing
quite a lot of short chain fatty acids.
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So generally having a balanced diet full of fibre,
possibly with fermented foods of many kinds,
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you know, kimchi, sauerkraut, stuff like
that. This is, we think, the link between
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health and the gut microbiota at the moment.
And this is where the western diet is terrible,
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isn't it? Because this is all about how
different cultures will have different diets,
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which will have more or less fibre in. And
you hear this a lot at the moment, this…
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Generally speaking, I don't know if I'm a fan
of calling it the western diet, because I find
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that it's a bit confusing. What I prefer to
say is that foods that would contain a lot of
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ultra processed ingredients. Typically, if you
look at, you know, a pack of triangle sandwich,
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you know, that you can buy and you look at the
ingredients behind it, of course there's a lot
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of ingredients in that sandwich, but there's a
lot of ingredients as well that will not be food,
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that will just be preservatives.
We sort of inherently know that it's
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potentially probably bad for you, but we don't
really know why. And there has been research
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for this and notably, research into aging, not
necessarily so much with the gut microbiota,
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but research on healthy aging, for instance,
has shown that those particular consumptions
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of ultra processed foods seem to be very bad. It
seems to be something that is associated with a
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worse aging than if you have raw food, if you have
fibre food, and things like this. So, I wouldn't
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be surprised also that the microbiota is affected
by this. So, it's better to think about how much
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processing goes into your food and how closer
you are to the fresh product or not, really.
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So, one of the things you mentioned early on is
that it's not just the microbiome that you've got,
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but how it interacts with your
own genome. So, this is something
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that you're looking at, isn't it?
Yeah, yeah. We've had some effort
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trying to look at this ourselves and also
in collaboration. So, we were part of a
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collaborative work recently that was published
in Nature Genetics, and this was led by the same
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Swedish colleagues that I was mentioning
about, on the links between human genetic
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variation and the gut microbiome variation.
So that study was the largest of its kind to
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date, and it was the sort of prolongation also of
another microbiome GWAS study we have led in 2022,
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when I was in Australia, and we were looking at
roughly the same things in different settings,
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but those results in 2026 were
more detailed and consistent.
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So, what did we do there? What we did was
we asked, does your DNA and do your genes
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influence which bacteria live in your gut? We
scanned the entire genome of over 16,000 people,
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and we compared it to what bacteria were
found in their gut. We found 15 robust genetic
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associations. So, specific spots in the genome
that are reliably linked to having more or less
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of a particular species of a bacterium.
So, there were some expected results
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from past studies. There is a well-known
association between LCT or the lactase gene,
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which governs whether others can digest milk
and the species Bifidobacterium. We also found
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specific bacteria linked to the ABO locus, which
is governing blood type, which is also sort of
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known and it was fascinating in itself. But we
also found new ones that were quite interesting.
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There was a sort of discovery that
I found particularly elegant. So,
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we found variants that were near pair
of genes that encode receptors for those
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short chain fatty acids that I was mentioning
earlier. So, there are molecules that the gut
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bacteria produce themselves. And they were linked
to how diverse the gut microbiome is overall. So,
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our genome appears to contain the sensors
that are talking to our bacteria like this.
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There were other findings. We found the
connections to genes that are involved
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in the mucus layer compositions. Our gut
epithelium is covered with mucus, also with
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bile acid production or hormone signalling, a
lot of different things. The takeaway message
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from these studies and this work that we're
doing, is that the gut environment, that our
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own genome creates the sort of micro changes
in the environment that our own genome creates,
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can shape which bacteria can thrive there. And
we are only starting to understand it for the
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reasons that we mentioned about sample size and
technologies. So yeah, it's exciting work there.
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But that's really interesting because if it's
interacting with your own personal genome,
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is the idea that eventually that could be
used in a sort of personalized medicine
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sort of way. Is that the ultimate aim?
It is a goal. The goal is to understand the
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diversity in humans, the diversity in their
genes, the diversity in their disease risk,
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the diversity in their disease history,
maybe, in their medication history,
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as we say, it can have an impact. But if you add
on to this the complexity of the gut microbiota,
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which is very much influenced by diet and
what you eat and who you meet and what
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you do, it becomes extremely complex.
So, one of the ways that is very good,
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and seems to be one of the most promising
ways to shed some light on this, is to do
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large population studies to try and see in a
large number of people, what commonalities can
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we see? What can we see when we make groups of
people and we compare them, all else being equal.
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What we can do as well is to organize clinical
trials where we are trying to investigate
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the function of those particular microbes.
When some people have particular microbes,
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or when they are given particular microbes,
as in probiotics for instance, but not just,
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what is the effect? Can we measure this effect?
One important thing that is deriving from more
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controlled studies, like in vivo
studies or clinical trial studies,
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is that we can have a sense about
causality. Causality is the elephant in
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the room in every microbiome study that you see.
Basically, when you link a particular microbiome
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state or particular microbes to a particular
disease, you have no idea whether the microbe
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is causing the disease or the disease is causing
the differences in the microbiota that you see. We
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can see a lot of these associations. You know, you
can make correlations and you can see that things
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are associated, trying to derive meaning, trying
to derive useful information from this goes far
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beyond the correlation work that we are starting
to do. You need to go through the process of doing
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smaller scale studies, to do them in vitro, in the
lab, in animal models, in patients with clinical
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trials, it takes a long time to derive meaning
from microbiome studies. But we're getting there.
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So, what's next for you?
So, there are many things, as
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you can imagine, that we can look at, but there's
a particular focus that is coming to fruition for
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us and that is kind of close to my heart. We
have been looking at a particular fraction of
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the human gut microbiome, which is represented by
archaea. So, archaea are a totally different type
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of organisms. They are not bacteria, they are not
eukaryotes, they are completely a third domain of
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life. And in our body, they are mainly thought to
be linked to methanogenesis. They produce methane.
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So, what they do basically is that they associate
very intimately with these bacteria that we were
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talking about that are consuming fibre from
the diet. So, bacteria that ferment fibre will
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produce all of the molecular components that are
required for these archaea to produce the methane.
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And there is an interesting thing to look at
there because of this metabolic interaction,
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we can have very, very, very robust associations
and co abundance association between particular
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archaea and particular bacteria. We have these
sort of co abundance networks as we call them.
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And what is very interesting is that until now
archaea had been very disregarded in, well,
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probably any field of science, mainly because
it was very difficult to study them. It's very
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hard to culture them. We are collaborating
for this with a lab in Austria that is led
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by Professor Christine Moissl-Eichinger, and
they are the best lab working on human archaea
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in the world. They have the way to culture these
archaea. These archaea grow in total anaerobiosis.
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They grow with hydrogen, you know,
you have to inject hydrogen. So,
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imagine having canisters of hydrogen in the
lab. This is not really 21st century science,
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but they have all of these set up.
And they managed to grow these archaea.
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And they have invaluable knowledge for this. And
we're about to publish a paper on this. And we
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think it's a very exciting sort of like first
foray into the variability of the archaeome.
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Basically, one of the results that we find is
that humans seem to be colonized by different
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groups of archaea with different potentially
health associations. But this is all very
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exciting stuff, and I hope that we will be
able to develop that further in the future.
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Guillaume, thank you so much for talking
with me. This was a podcast by the Milner
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Centre for Evolution at the University of Bath.
I'm Turi King and thank you for listening. If you
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have any thoughts or comments on this or any other
episodes, please contact us via our social media.
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00:19:52,043
For more information about the Miller Centre
for Evolution, you can visit our website.
