New in Neuroscience: Microglia in your brain put their trust in your gut

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Ancient humans often referred to the “bowels” as the seat of emotional experience. We now attribute higher functions such as thought and emotion exclusively to our brains, but the idea that what’s going on in your gut may control your instincts may actually have some biological credibility. A few neuroscientists who have recently ventured to think outside the brain have revealed that the bacteria that reside in your digestive system – your gut microbiota – have the capacity to influence emotions and even behavior. For instance, mice that are born and raised entirely without exposure to bacteria have reduced sociability and elevated stress responses. However, the line of communication between the bacteria that call your gut home and your brain remains largely mysterious.

The types of bacteria in the gut have been shown to influence immune cells circulating throughout the body in the bloodstream, but these immune cells rarely enter the tightly restricted brain. Instead, the brain is protected by its own distinct population of immune cells, called microglia. Microglia respond to brain injury and disease as well as help to regulate brain development and plasticity. Marco Prinz’s team at the University of Freiburg in Germany saw microglia as a potential mediator of gut-brain messages, and tested this hypothesis in a recent article published in the journal Nature Neuroscience. They accomplished this by studying microglia in “germ free” mice, which have no gut bacteria, using gene expression analysis and 3D reconstruction of microglia cell structure.

Compared to mice with normal gut bacteria, the researchers found that germ free mice have more microglia, and that these are distinct in physical form and in the levels at which they express certain genes. In order to assess the function of these abnormal microglia, the researchers activated the immune responses of germ free mice by injecting either bacteria or virus directly into the brain. In both cases, microglia in germ free mice had weaker or abnormal responses to the assault compared to in normal mice.

Germ free mice develop completely without bacterial colonization, so Prinz’s group also investigated whether the differences in their microglia had to be established during development, or whether gut bacteria could also influence mature microglia. It turns out that microglia show altered gene expression and functional properties even in mice that grow up with normal gut microbiota but are given strong antibiotics later on. Further, allowing the intestines of germ free mice to be recolonized by complex bacterial populations restored microglial abundance, gene expression, and morphology to the same levels observed in normal mice. These results suggest that even after development, fluctuations in the composition of the gut microbiome send signals all the way to the brain to influence microglial function.

What might these signals actually be? The researchers hypothesized that microglia might be responding to short-chain fatty acids, which are released by gut bacteria as they break down dietary fiber in the colon. Introducing these short-chain fatty acids into the drinking water of germ free mice restored microglial abundance, gene expression, and cell structure to the levels observed in normal mice.

Prinz and colleagues comprehensively show that gut microbiota complexity can dramatically alter microglial cells in the brain, even in adulthood. What their study didn’t show is if and how gut bacteria regulate the many functions of microglia, such as responding to disease or regulating neuronal communication, in the mature brain.

Mice in this study that received very strong antibiotics experienced microglial changes. Could taking antibiotics to fight off an infection deplete some of our gut bacteria and possibly alter the microglia in our own brains? This is an important possibility to consider, since other research suggests that the activities of our microglia can influence our moods and behavior. However, further research is needed to show how sensitive microglial functions are to smaller changes in the gut microbiome composition, and whether gut-microglial communication is what underlies the microbiome’s effect on behavior and emotion.