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Gut metabolite found to affect brain function through reduction of glial cells

A Caltech research team has demonstrated how gut metabolite, 4-ethylphenyl sulfate (4EPS), induces anxiety-like behaviors in mice through the reduction of oligodendrocytes.

For the last decade, many papers have been published providing evidence of a connection between the gut microbiome and alterations to both the immune system and brain function. Additionally, individuals with certain neurological disorders have been shown to have specific microbiome compositions.

A research team from California Institute of Technology has identified a possible mechanism for why this gut-brain connection may occur. The researchers identified a molecule produced by bacteria and showed how it enters the bloodstream, travels to the brain, and induces anxiety in mice.

In a previously published paper, the team identified the microbial molecule 4-ethylphenyl sulfate (4EPS) as a metabolite capable of neuromodulation. Continuing down this path, the researchers bioengineered gut bacteria in mice to selectively produce 4EPS, and observed the specific neuronal effects that occurred.

Brittany Needham, a member of the Mazmanian lab and first author of the new study, told Caltech Today, “It’s been really difficult to show causation between something that’s happening in the gut and the brain, rather than just associations between the disease states and the presence or absence of certain microbes. We were interested in trying to understand the molecular messages that are going between the gut and the brain, and how these signals may lead to changes in behavior.”

The researchers found that when 4EPS enters the brain, oligodendrocyte function decreased, along with a decrease in myelination of neuronal axons. Associated with these affects was a display of increased anxiety-like behaviors. When given pharmaceuticals to increase oligodendrocyte function, these behaviors were reduced. The study demonstrates one way in which gut metabolites may be having neuromodulatory effects on the brain.

“It’s an exciting proof-of-concept finding that a specific microbial metabolite alters the activity of brain cells and complex behaviors in mice, but how this is happening remains unknown,” says Mazmanian, a Professor of Microbiology and head of the lab. “The basic framework for brain function includes integration of sensory and molecular cues from the periphery and even the environment. What we show here is similar in principle but with the discovery that the neuroactive molecule is of microbial origin. I believe this work has implications for human anxiety or other mood conditions.”

The team plans to continue researching the gut metabolite, hoping to further identify the mechanism by which 4EPS causes these effects on oligodendrocytes.


The study was published in Nature on February 14th, 2022.

Abstract. Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota and gut-derived metabolites are disseminated to all organs, including the brain. In mice, the gut microbiota impacts behaviour, modulates neurotransmitter production in the gut and brain, and influences brain development and myelination patterns. The mechanisms that mediate the gut–brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte–neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.

Needham, B.D., Funabashi, M., Adame, M.D. et al. A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature 602, 647–653 (2022). https://doi.org/10.1038/s41586-022-04396-8

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