dsay Borthwick, writer and editor for The Kavli Foundation, contributed this

article to Live Science's Expert Voices: Op-Ed & Insights.

The trillions of microbes that inhabit the human body, collectively called the
microbiome, are estimated to weigh two to six pounds — up to twice the weight
of the average human brain. Most of them live in the gut and intestines, where
they help us to digest food, synthesize vitamins and ward off infection. But
recent research on the microbiome has shown that its influence extends far
beyond the gut, including to the brain. During the past 10 years, studies have
linked the gut microbiome to a range of complex behaviors, such as mood and
emotion, appetite and satiety, and even learning and memory. Not only does the
gut microbiome appear to help maintain brain function, but it may also influence
the risk of psychiatric and neurological disorders, including anxiety, depression
and autism.

The big question is how?

Recently, The Kavli Foundation brought together three researchers at the

forefront of this emerging field to discuss the microbiome-brain connection and
whether we can treat disorders of the brain through the gut.

The participants were:

Tracy Bale, a professor of neuroscience at the University of Pennsylvania

School of Veterinary Medicine and Perelman School of Medicine. She is
studying the effects of early prenatal stress on fetal brain development and has
shown that this is partly mediated by the microbiome.

Christopher Lowry, is an associate professor in the Department of Integrative

Physiology and Center for Neuroscience at the University of Colorado Boulder
and director of the Behavioral Neuroendocrinology Laboratory. Lowry is
developing new strategies to prevent and treat anxiety and depression,
including the use of beneficial microbes that live in the gut.

Sarkis Mazmanian, is a professor of Microbiology at the California Institute of

Technology and a 2012 MacArthur Fellow. A microbiologist and immunologist by
training, Mazmanian studies how the brain, the immune system and the
microbiome interact in health and disease, including its affects on autism
spectrum disorder.

On January 15, 2015, at 3:00 p.m. ET, join The Kavli Foundation for a live
webcast with Christopher Lowry and Sarkis Mazmanian, in which they discuss
new discoveries about the gut-microbiome-brain connection and answer your
question. Submit your questions via e-mail at any time
to info@kavlifoundation.org or via Twitter using the hashtag #KavliLive.

The following is an edited transcript of a roundtable discussion that took place

via teleconference in December 2014. The participants have been provided the
opportunity to amend or edit their remarks.

The Kavli Foundation: The idea that the microbes living in our gut have an
effect on the brain is a relatively new one. What set you down the path to
studying this relationship? And how has your thinking evolved since then?

Sarkis Mazmanian: For more than a decade, my laboratory has been studying
the interaction between microbes and the immune system. I took this path in the
last five years because, through conversations with neuroscientists here at
Caltech, I realized there are many parallels between the immune and nervous
systems. For example, immune cells and neurons produce and sense many of
the same chemicals. Since microbes were having such a profound effect on the
immune system, I wondered whether they were having an effect on the brain,
too. I thought that we would find that microbes interact with the brain via the
immune system. But the data we've generated so far have shown that microbes
interact with the brain by producing molecules that impact behavior without
altering the immune system. Though we haven't ruled out an immune link, we
have discovered mechanisms by which microbial molecules may directly
interact with the nervous system.

Christopher Lowry: My lab has been studying interactions between bacteria,

the nervous system and emotional behavior for about 15 years. We've found,
for example, that mice exposed to an inactivated soil bacterium
called Mycobacterium vaccae increase production of the neurotransmitter
serotonin in the brain, which has antidepressant-like effects.

The turning point for looking at gut-microbiome-brain interactions in my lab

really came with our first collaboration with Rob Knight, who leads the American
Gut Project here at CU-Boulder. Together, we've been investigating ways of
modulating the immune system to prevent stress-related psychiatric disorders,
such as anxiety and mood disorders. Although this work is still in progress, it's
clear that the microbiota plays an important role in stress-induced chronic
anxiety, at least in animal models. [5 Ways Gut Bacteria Are Good for More
Than Just Your Gut ]

Tracy Bale: My lab works on the impact of stress during pregnancy on the
developing brain using a mouse model of early maternal stress. There was
a Radiolab episode on NPR that provoked a conversation in the lab about the
vaginal microbiome, which is the main source of the bacteria that first populate
a newborn baby's gut. We started thinking about the environmental factors,
such as stress, that could change the vaginal microbiome and wondering if that
would have an impact on our model of brain development. It blossomed from
there because the relationship between a newborn's gut microbiome and his or
her mother's vaginal microbiome is almost one-to-one, with a newborn's
microbiome changing in direct response to its mother's. We wondered, how
does this interaction alter the way a baby's brain develops in our mouse model
of early prenatal stress? [The Truth About How Mom's Stress Affects Baby's
Brain ]

It turns out that stress changes the levels of Lactobacillus, a gut-dwelling lactic
acid-producing bacteria that affects the brain's chemistry, in both mothers and
their offspring.

TKF: What are the big questions about the gut-microbiome-brain connection
that researchers are trying to answer right now?

T.B.: Now that we know the microbiome changes in response to stress, I think
the field is trying to understand the processes by which the gut microbiome
alters the brain.

C.L.: I totally agree. The big question right now is how the microbiome exerts its
effects on the brain. Some questions we're all still trying to answer include the
composition of the gut microbiota, its effects on the permeability of the lining of
the gastrointestinal tract, its effects on whole-body inflammation, and its effects
on neuronal signaling from the gut to the brain.

S.M.: Another big question is whether we can treat brain disorders, such as
autism, by aiming therapies at the gut. One of the barriers to treating psychiatric
and neurological disorders is that we often don't understand the underlying
disease mechanisms; in other words not only what to target but where those
targets are in the body. If the therapeutic targets are in the brain then it
becomes particularly challenging because of the blood-brain barrier, a network
of blood vessels that protects the brain from harmful substances. But if a
neurological condition actually originates in the gut, which we believe is the
case for some individuals with autism, then delivering therapeutics is much
easier. In my lab, we've been able to alter some of the symptoms associated
with autism, such as repetitive behaviors, in mice by feeding them specific
bacterial species. These bacteria modulate molecules in the gut and in the
blood that affect the nervous system.
TKF: That leads me to my next question. Sarkis, how do you think the microbes
in the gut are communicating with the brain and driving behavior? Have your
experiments using mice with autism-like symptoms offered any clues?

S.M.: There are at least three ways gut microbes are communicating with the
brain: the first is directly through the vagal nerve, which connects the network of
nerves in the gut to the brain; the second is through circulating immune cells
that are primed, or educated, in the gut and then travel to the brain; and the
third may be metabolites, molecules that are produced by microbes in the gut
that enter the blood and circulate to regions of the brain where they affect
behavior. We've shown, for example, that a metabolite produced by gut bacteria
is sufficient to cause behavioral abnormalities associated with autism and with
anxiety when it is injected into otherwise healthy mice. This suggests that
microbial molecules may connect the gut to the brain via the circulatory system.
[Autism's Rise: Researchers Look at Why Cases Are Increasing ]

T.B.: Sarkis covered most of what people currently understand about what's
happening in the gut. But keep in mind that there's a developmental window
that is also important. We've shown in our mouse model of early maternal
stress, for example, that short-term changes to the microbiome during a critical
period of development can result in brain changes.

TKF: Has anyone actually traced changes in the human brain back to the
microbiome?

S.M.: Emeran Mayer and his colleagues at the University of California, Los
Angeles, used functional magnetic resonance imaging, or fMRI, to look at the
effects of specific microorganisms on brain activity. He showed that treating
healthy people with fermented milk products containing probiotics, or healthy
bacteria, altered brain activity in regions linked to emotion.

T.B.: Developmentally, that's a harder question, because you can't do controlled

experiments in newborns. But there are plenty of studies ongoing in Europe and
in Canada where researchers are giving vaginal lavages to the newborns
delivered by C-section to ensure that they are getting a nice dose of their
mother's microbiome.

TKF: Tracy, you've talked about the close connection between a mother's
vaginal microbiome, which a baby encounters as it passes through the birth
canal, and her newborn baby's. Can you expand on how this natural form of
inoculation helps lay the foundation for brain development?
T.B.: There are key developmental windows when the brain is more vulnerable
because it's setting itself up to respond to the world around it. At the same time,
as Sarkis pointed out, the gut microbiome is helping to prepare the baby's
immune system. So, if mom's microbial ecosystem changes – due to infection,
stress or diet, for example – her newborn's gut microbiome will change too, and
that can have a lifetime effect. It could alter how the gut, and the immune
system within the gut, develops and how the brain develops.

What's interesting, from our experiments on the effects of exposure to early

maternal stress in mice, is that if you look at those babies in adulthood, their
microbiome may be completely normalized, but if you then stress them or give
them an immune challenge, you see big differences again in the way their
bodies respond. So even acute exposure to prenatal stress seems to alter how
an organism responds to changes in its environment in the long term.

TKF: I find that a little scary. Pregnant women already have so much to worry
about.

S.M.: I can understand that reaction. Just the very concept that microbes can
have profound effects on the brain may be hard for a lot of people to believe.
But I tend to think that by understanding these effects, one can do something
about the epidemics of anxiety, autism and attention deficit and hyperactivity
disorder, also known as ADHD, that we're seeing in today's society. We're
learning that society may be doing things that are not in the best interest of a
child's health and by understanding those things we can change practices and
prevent, for a lack of a better term, mistakes during critical periods of
development. So my take is a little bit more positive.

T.B.: I agree. I think that it's an awareness more than a fear factor.

TKF: Christopher, you've suggested that a lack of exposure to the many

bacteria we evolved with may be contributing to our ills, including psychiatric
disorders such as depression and anxiety. If that's the case, can we make up
for the past?

C.L.: There are certain psychiatric disorders like post-traumatic stress disorder,
or PTSD, and depression that seem to be associated with increased
inflammation, a ramped-up immune response in the body and in the brain. So
microbes that can modulate the immune system and limit inflammation may
have some benefit, either by alleviating the symptoms of certain types of
psychiatric disorders or, in the best possible scenario, preventing them. So yes,
I think taking or being exposed to these types of bacteria during adulthood can
be beneficial, although clearly their major influences are during development, as
Tracy and Sarkis have pointed out. [Gut Feeling? Probiotics May Ease Anxiety
and Depression ]

TKF: Are you testing any probiotics for stress or depression?

C.L.: Our current studies use heat-killed bacteria rather than probiotics, which
the World Health Organization defines as live microorganisms that confer a
health benefit to the host when administered in adequate amounts. We have a
series of studies that we're getting ready to publish that suggest that certain
types of heat-killed microbes can prevent syndromes that you would expect
following chronic stress. We're hoping to conduct similar studies using
probiotics in animals and humans.

TKF: Have you changed your behavior as a result of your research into the
connection between the microbiome and a healthy body and brain?

C.L.: I've certainly altered mine. I eat more fresh vegetables, and we have a
small garden at our house. It's becoming clear from the American Gut Project
that an important source of gut microbial diversity is the number of different
plants we eat. Fresh vegetables are a significant source of bacteria. For
example, the leaves of a spinach plant are estimated to harbor more than 800
different species of microbes. These are microbes that you can't sterilize from
the plant because they're actually inside of it. And so having access to this kind
of microbial diversity through the things that we eat is probably very important.
I've also added sand from ocean beaches to my children's sandbox, I let my
kids swim in lakes, and we take probiotics.

S.M.: As we all know, it's still the very early days in terms of trying to understand
the effects of the microbiome, even for inflammatory bowel disease or obesity,
which have been studied much more than any neurological condition. That
being said, as Chris mentioned, diet is a major driver of microbiome
configuration and so I think that there is enough reason to believe that specific
foods “are better” for the microbiome than others: eating a high fiber diet with
lots of fruits and vegetables, resistant starches such as those from seeds and
nuts, and, in general, a diet that is closer to the one we evolved to eat, including
foods that were available before agriculture and fast food restaurants came
along. So what I've done is nothing really dramatic.

T.B.: As a parent, I would also say I've spent a lot more time thinking before
allowing my child to take antibiotics. There's no disputing their utility or efficacy
but we shouldn't just throw antibiotics at every illness.
TKF: Sarkis, you've called recent discoveries “harbingers of extensive, currently
undescribed, links between gut bacteria and the nervous system.” Can you
speculate on what other links between the gut microbiome and the brain might
emerge? Are we going to find that the microbiome also plays a role in cognition
or neurodegenerative diseases, for example?

S.M.: It's already been shown that cognition in germ-free mice is reduced in
comparison to normal mice. While the microbiome has not yet been implicated
in neurodegeneration, there's a lot of speculation about this issue because
there are data showing that a Mediterranean diet protects against Alzheimer's, a
neurodegenerative disease. And because we know diet helps shape the
microbiome, one can imagine that eating a Mediterranean diet could affect the
microbiome in a way that protects against neurodegeneration. We have a
program in the lab that's very, very early looking at Alzheimer's and Parkinson's
diseases in mouse models, but there's nothing solid to report yet.

If you're a topical expert — researcher, business leader, author or innovator — and would like to
contribute an op-ed piece, email us here.
View full size image

There are other anecdotal reasons to believe that neurodegeneration may have
some connection to the microbiome, or vice versa, because the three major
neurodegenerative disorders – Alzheimer's, Parkinson's and amyotrophic lateral
sclerosis, or ALS – all have a GI component to them. In fact, many patients who
are ultimately diagnosed with Parkinson's are known to have had GI
disturbances decades before they develop motor symptoms. And a recent study
showed that patients with Parkinson's disease have different microbiomes than
matched controls. While this is an exciting finding, this kind of study needs to be
interpreted with caution as it is an association and does not prove a causative
link. So there are flash bulbs going off in the dark, suggesting that very complex
neurodegenerative disorders may be linked to the microbiome. But once again
this is very speculative. These seminal findings, the flash bulbs, are only just
beginning to illuminate our vision of the gut-microbiome-brain connection.

TKF: In addition to more funding, what would help accelerate progress in the
field?
C.L.: There are regulatory issues related to giving live or dead bacteria for
treatment of psychiatric and neurological disorders, and those are significant
issues that will have to be dealt with.

T.B.: Another is that not all neuroscientists have embraced this idea. It's
definitely getting better: I just spoke at the American College of
Neuropsychopharmacology meeting; it's quite surprising that they had a session
on microbiome this year. But I can tell you that there are still vast numbers of
people, especially in psychiatry, who don't believe this is real. And I think that is
a hurdle.

S.M.: I have a similar story. We had a session on the microbiome at the annual
meeting of the Society for Neuroscience this year but it was our third year
submitting it. I think that's a sign there is a sea change taking place in the field.
With that being said, if you talk to most neuroscientists, they have a hard time
finding any credibility in the link between the microbiome and neurobiology. It's
still a very, very new concept with much more experimental validation
necessary, and honestly I have no issue with that.

T.B.: I agree. I think the field is now at the point where we've established the
validity of our models and are beginning to show how the microbiome affects
the brain. That is when the big change in attitude will happen. But it's going to
require some hard-core studies of the mechanisms involved.

S.M.: I think the skepticism is healthy. It keeps us honest and makes sure that
the science remains rigorous. At the same time, I've been surprised and
gratified by the fact that our work hasn't received widespread rejection by the
neuroscience community. It certainly hasn't received widespread acceptance
either, but when I discuss my research with card-carrying neuroscientists they
seem to be quite open-minded about the possibility. It's not that they believe it,
but they're intrigued to see more.

T.B.: Right. The fecal transplant jokes have subsided!

Follow all of the Expert Voices issues and debates — and become part of the
discussion — on Facebook, Twitter and Google+. The views expressed are
those of the author and do not necessarily reflect the views of the publisher.
This version of the article was originally published on Live Science.

Editor's Recommendations
 Health Check: What’s Your Gut Feeling About Probiotics? (Op-Ed)
 The Microbes in Your Gut May be Making You Fat

 5 Ways Gut Bacteria Affect Your Health