Imagine a lively town with roughly 100 trillion inhabitants, all going about their daily affairs—eating, working, sleeping, communing with friends, squabbling with foes. This could describe any (albeit slightly overpopulated) corner of our planet. But in fact, it’s a snapshot of your gut.
Meet your microbiome: a jolly congregation of 500-1000 species of bacteria, microbes, archaea, eukaryotes, fungi, and viruses that call your body home. It is an entire micro-universe of tiny powerhouses, complete with their own genes and immune and metabolic profiles, playing a significant role in your health and well-being.
Much about how they accomplish this feat remains a mystery. From what scientists have uncovered so far, the microbiome helps with everything from extracting energy from food and setting up a gut-brain connection to producing key neurotransmitters, enzymes, and vitamins.
Professor of Microbiology Sarkis Mazmanian researches the microbiome at Caltech. “Versatile” is how he chooses to describe the microbiome in a single word. Studying it has changed him in several ways, he says. Notably his diet. He avoids processed foods and consumes between 30 and 40 different plant-based foods each week.
Along with diet, Mazmanian identifies three additional factors that influence the microbiome—and, by extension, brain function: sleep, exercise, and stress management. “The brain does not function in isolation,” he says. “What we expose ourselves to affects our brain.”
Here’s Dr. Mazmanian on the mysteries of the microbiome and how it impacts our well-being.
What supports a healthy and thriving microbiome?
SM: One finding is strikingly consistent across hundreds of conditions and thousands of cohorts: in over 90% of studies, healthy individuals have more diverse microbiomes than those with disease. The data also shows that people who consume high-fiber, plant-based diets have more diverse microbiomes. Taken together, these findings suggest that a diverse diet increases microbiome diversity, which in turn supports health.
How does stress affect brain function through the microbiome?
SM: For many years, the brain was thought to be an immune-privileged environment, largely untouched by the immune system. Now we know that the brain contains resident immune cells, such as microglia, as well as other cells with immune-like properties. Moreover, the peripheral immune system clearly influences brain function, decision-making, and neurodegeneration.
Much of our immune function is linked to stress. In fact, stress and the microbiome intricately shape immune function. I see the immune system as a way to connect microbiome and stress to the brain.
Moreover, the immune system plays a central role in driving, modulating, and sometimes protecting against neurological conditions. One of our core research interests is understanding the extent to which the immune system contributes to chronic disease. For example, we study Parkinson’s disease, Alzheimer’s, anxiety, and autism. All of these conditions, traditionally viewed as disorders of the brain, have important immune components and systemic manifestations in the body.
How are the microbiome and the brain connected?
SM: The microbiome doesn’t cause us to feel, think, or behave in a certain way—it’s not like a wizard in a back room controlling us. Rather, the microbiome sets a physiological baseline for the function of our cells, shaping how cells operate during everyday cognition, decision-making, and emotional processing.
There is growing evidence that many molecules produced by the microbiome enter the brain. Our brains are bathed in these molecules from the microbiome. However, they are unlikely to trigger drastic changes such as cell death or regeneration. Instead, they appear to play a more basic, homeostatic role, essentially feeding ongoing cues that allow cells to perform their particular functions effectively.
A useful analogy is diet and exercise: a healthy diet supports robustness and muscle gain during exercise, while poor nutrition undermines endurance. Maybe the brain cells operate similarly. The microbiome-derived molecules that surround our neurons set these thresholds and then, genetics, development, and personalities enact on that baseline.
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What mechanisms link the microbiome to emotion regulation?
SM: How we get from cells in the brain to emotions still remains a mystery. What we do understand is that two fundamental processes are central: synapse formation and myelination.
Synapse formation shapes the brain’s wiring, particularly in circuits involved in social behavior and cognition. The more wired the brain is, the more connections it has, the more diversity it has in its function. Myelination—the insulating layer around axons—enables efficient signal transmission over long distances. These two fundamental processes of brain physiology are both regulated by the microbiome.
In our work with mice, we find that microbial signals from the gut can influence synapses in brain regions linked to emotional behavior. This likely involves microglia—the immune cells that prune and remodel synapses as the brain continuously adapts. Essentially, these cells allow synapses to retract and reform in new ways. We also see effects of the microbiome on oligodendrocytes—the cells responsible for producing myelin, whose maturation and function depend on microbial signals.
Synapse formation and myelination are closely tied to the microbiome. They are also implicated in emotional regulation and in disorders with emotional components, including anxiety, depression, schizophrenia, autism, and bipolar disorder. I think all the pieces are there for this circuit that emanates from the gut and controls neural physiology, ultimately leading to changes in emotion.
Why is harmony within the microbiome essential for health and how can we support it?
SM: Think of the microbiome like a lush garden: when it’s full of healthy plants and flowers, it’s harder for weeds to take hold. When the garden is bare, weeds can easily grow. Analogously, there are beneficial (“good”) and harmful (“bad”) organisms in the microbiome, and health depends on the interactions among them. These microbes must exist in harmony. We don’t yet fully understand the mechanisms of this coexistance, but we can measure it and correlate with health. If we nourish the good microbes, they tend to thrive and crowd out the harmful ones. “Weeds” never disappear entirely, as microbes constantly compete for nutrients, space, and host-derived resources. Yet, supporting the beneficial organisms—through diet, exercise, sleep and stress management—reduces the chances that harmful ones dominate.
Many diseases arise from a combination of genetic predisposition and environmental influences. I believe the microbiome is a key part of that environmental component, and thus, an important determinant of health. If both are contributing to health and disease, genome is much more intractable than the microbiome. This gives me optimism. If we understand the basic biology, we can manipulate the microbiome in ways that we can’t imagine manipulating the gene.
Many thanks to Sarkis Mazmanian for his time and insight. Dr. Mazmanian is Luis B. and Nelly Soux Professor of Microbiology and Merkin Institute Professor at Caltech.
