Can Microbes in the Gut Influence the Brain?

An artist's image of the human mind. — (Image credit: agsandrew/Shutterstock.com)

Lindsay 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.

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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.

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 ]

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.

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.: 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.

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.

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 ]

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.

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.

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.

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.

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.

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.

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