[www.caltech.edu]

A Caltech-led team of researchers has discovered that a small-molecule metabolite, produced by bacteria that reside in the mouse gut, can travel to the brain and alter the function of brain cells, leading to increased anxiety in mice. The work helps uncover a molecular explanation for recent observations that gut microbiome changes are associated with complex emotional behaviors.

studies in the last few years have linked the microbiome to brain function and mood. People with certain neurological conditions have distinctly different gut bacteria communities.

"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," says Brittany Needham, first author of the new study

This study focused on a bacterial metabolite (a by-product of microbes) called 4-ethylphenyl sulfate, or 4EPS. Initially produced by microbes in the intestines, 4EPS is then absorbed into the bloodstream and circulates throughout the body in both humans and mice. In 2013, the Mazmanian lab showed that this particular molecule was present in higher levels in mice with altered neurological development, specifically, a mouse model of autism and schizophrenia.

Additionally, in a screen of human blood samples from 231 individuals, 4EPS levels were about seven times higher in children on the autism spectrum than in neurotypical children.

In this work, the team focused on the effects of 4EPS on mouse models of anxiety. While anxiety disorders in humans are complex, animal models provide a way to study the precise changes in the brain and body that lead to anxious behaviors.

However, when the 4EPS mice were treated with a drug known to increase myelin production in oligodendrocytes, the drug was able to overpower the negative effects of 4EPS—the mice regained normal myelin production, and the anxious behaviors were reduced.

Looking closer at brain cells within these altered regions, the team found that particular cells called oligodendrocytes were altered. These cells are important in part because they produce a protein called myelin, which acts as a protective coating around neurons and nerve fibers called axons, like insulation around an electrical wire. The team found that in the presence of 4EPS, oligodendrocytes are less mature and consequently produce less myelin, leading to thinner insulation around axons.