Your Microbiome and Your Brain

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There are trillions of microbes inside you right now, living out their tiny little lives. They’re a whole complicated community, called your microbiome. Scientists are starting to realize that your microbiome plays a big role in your overall health, and that’s changing the way that doctors treat all kinds of conditions, from prescribing antibiotics to managing IBS. It’s kind of obvious that the microbes living in your guts could play a role in your dietary needs and gastrointestinal health. I mean, they’re a big part of the digestive process.

It just makes sense. But what might not be so obvious is that the microbiome in your gut can also affect your brain. Biologists used to think that was impossible, but now they’re finding out that they were wrong. They’re discovering all kinds of connections, from how stress affects the microbial makeup of your intestines to how the microbiome affects behavior. Your guts might have such a big influence on your brain that funding agencies are pouring millions of dollars into understanding what researchers are calling the microbiome-gut-brain axis. By learning more about this connection, scientists are hoping to better understand human mental health — and maybe even develop some new therapies along the way. We’ve known for a long time that your gut and your brain are pretty tight in some ways. For years, researchers have been studying the enteric nervous system, or ENS, and its dynamic relationship with the central nervous system. The ENS is a massive web spread over your entire digestive tract. It’s made up of more than 500 million neurons that control your guts. This “second brain”, as it’s sometimes called, is pretty self-sufficient, and can take care of most of its job by itself. But it is connected to your central nervous system by your vagus nerve, which is basically an information superhighway between your gut and your brain. We also knew that stress could affect digestion, because who hasn’t experienced some tummy troubles during a stressful week?

Despite this connection, for a while, scientists assumed that the microbes in your gut couldn’t affect your brain because of the blood-brain barrier. Your brain’s blood vessels are structured so they’re packed super close together in a way that keeps your brain’s immune system basically separate from the rest of your body. The blood-brain barrier’s really important, because unlike an infection in your toe or on your skin, which aren’t usually life-threatening, brain infections tend to be pretty deadly. So your brain is structured to keep infections out. It’s hard for almost anything, including microbes, to get through the barrier, except in cases of serious injury or illness, so neuroscientists figured that meant they could pretty much ignore the microbiome. Even though there’s a lot of cross-talk between your ENS and your brain, researchers mostly assumed that microbes didn’t play into it. But more recent breakthroughs are challenging that assumption and changing our understanding of how the blood-brain barrier works. Because we’re learning that your microbiome can affect your brain — in some pretty big ways. Early research starting in the 1970s showed that stress could affect the kinds of microbes found in the guts of mice. One group found that stressing out mice by depriving them of food or water caused them to have more coliform bacteria, like E. coli, and less of another kind of bacteria, called lactobacilli, in their intestines.

Another group found that the stress of dealing with an aggressive cagemate led to changes in the populations of other kinds of bacteria. But even though it was clear that stress could affect the kinds of microbes in the intestines, it wasn’t clear if it was a two-way relationship. Could gut microbes be affecting psychological stress levels? The first big breakthrough on this question came in 2004, when some scientists from Kyushu University in Japan discovered that exposure to certain kinds of microbes had dramatic effects on brain chemical levels. For the study, the scientists used germfree mice: mice that were delivered by C-section and immediately placed in a super clean cage, so they were barely exposed to any microbes at all. Compared to specific pathogen free mice — that is, mice that were exposed to a known set of microbes — the germfree mice got a lot more stressed out when they were restrained. So it seemed like something about the bacteria in the mice was helping keep their stress levels in check. The team found that the brains of the germfree mice had less of a protein called brain-derived neurotrophic factor, or BDNF. BDNF is important for learning, memory, and higher-order thinking, and the germfree mice had less of it in the brain regions that determine how an animal reacts to stress. It’s not clear how, exactly, microbes could be affecting BDNF levels, since we’re still pretty sure they can’t cross the blood-brain barrier under normal circumstances. But something about the presence of bacteria in the gut seems to have a body-wide effect that leads directly to changes in brain chemistry. The results of that study kicked off a bunch of new research projects to better understand the relationship between the microbiome and the brain, mostly using these germfree mice. Some research from the early 2010s found that, while the germfree mice were more affected by certain kinds of acute stress, like restraint, they were less anxious about other kinds of stress — like being placed in a new environment.

So it seems like the relationship between microbes and stress is kind of complex. Mice without a microbiome aren’t always more sensitive to stress. Other studies have looked into what happens when you colonize germfree mice with bacteria — like whether their behavior changes, or how the bacteria affect certain stress-related genes in the brain. For example, in a study from 2011, one group of scientists found that exposing germfree mice to the microbiomes of other mice could influence their behavior. Like, a shy germfree mouse might do more exploring if it was implanted with microbes from a more adventurous mouse. Which is just weird. And the behavioral changes corresponded to an increase in that BDNF protein, meaning that the microbiome transplant had direct effects on brain chemistry. So it’s clear that the connection is there. The microbiome does affect the brain. And now, all kinds of scientists are investigating the microbiome-gut-brain axis. They’ve started to learn a lot about how your microbial balance can affect the levels of specific chemical messengers in your body and brain. The microbes in your guts produce a whole bunch of different molecules. And somehow, despite the blood-brain barrier, these chemicals affect your brain. Take serotonin, for example. It’s a critical messenger in your brain, and it’s especially well known for influencing mood. That’s why a lot of the drugs prescribed for depression and anxiety affect serotonin signaling in the brain. But it turns out that the majority of your body’s serotonin isn’t made in your brain. Up to 80% of it is made in your gut, and the microbes living there can affect how much serotonin is produced. So changes in the numbers of microbes that produce serotonin could have big effects on overall levels of serotonin in your body, and could also affect your brain. Even when they aren’t producing important neurotransmitters, microbes can trigger responses from the immune system, and the immune response can have a big impact on the brain.

See, the microbiome can affect the production of cytokines, which are proteins produced by immune system cells. And some of those proteins, like one called interleukin-6, are known to influence stress. Researchers have also discovered that microbes can release molecules that affect the behavior of the blood-brain barrier, like making it more or less permeable to outside molecules, which can affect what’s allowed in and out of the brain. But even as scientists are picking out individual pieces of the puzzle, they still can’t really see the big picture yet. The germfree mice studies have been important and informative, but it’s hard to translate them to humans, because … mice aren’t humans. There’s really no situation where a human would be totally microbe-free. But these studies do show that the microbiome has an effect on the brain, and they’re still useful because they give researchers total control over what kinds of bacteria the mice are or aren’t exposed to. There’s not a whole lot of research that is super clear on the relationship between the gut and brain in humans, though. These discoveries are so new that no one’s been able to do any large-scale studies in humans yet. But small studies have tried treating volunteers with probiotics, deliberately introducing new microbes to their guts, as well as prebiotics, which are fiber supplements designed to feed good bacteria.

And the microbes and fiber affected the subjects’ mood and cognition. So there might be a relationship between your microbiome and your mental health. Although the studies haven’t been able to look closely at what, exactly, the prebiotics and probiotics are doing to the microbes in the guts, or how that might be translating into changes in mood. So in the future, researchers will be getting more into the nitty-gritty of these relationships and trying to figure out if their discoveries can translate into medical treatments. Other scientists are working on humanizing the mouse microbiome — basically, making the microbiomes of the mice more human-like. They do this by taking fecal transplants from both healthy and sick human patients and inserting them into mice to study the effects. That kind of experiment can let researchers pick apart how differences in the microbiome connect with changes in mental health. And they can get right into the brains of the mice in ways they can’t with human patients, using dissected tissue to look directly at the structures of brain cells and how they connect. Some researchers are also trying to figure out how specific kinds of microbes are affecting our brains, and how we can tailor our microbiomes to maximize the health benefits. Others are starting to ask questions about how other things that affect our microbiomes, like antibiotic treatments, could be affecting our mental health and cognition. So there’s still a lot we don’t know about how our microbiomes affect our brains! But there are a ton of new studies in the works, and scientists and doctors are hoping that as our knowledge of the microbiome-gut-brain axis grows, so will our ability to tweak it — and hopefully improve some lives along the way. Thanks for watching this episode of SciShow. If you’re as fascinated by this microbiome stuff as we are, check out this episode to learn more about how your microbiome affects the whole rest of your body.

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