Gamma-delta T cells suppress microbial metabolites that activate striatal neurons and induce repetitive/compulsive behavior in mice

Intestinal gamma delta T cells play an important role in shaping the gut microbiota, which is critical not only for maintaining intestinal homeostasis but also for controlling brain function and behavior. Here, we found that mice deficient for gamma delta T cells (gamma delta(-/-)) developed an abnormal pattern of repetitive/compulsive (R/C) behavior, which was dependent on the gut microbiota. Colonization of WT mice with gamma delta(-/-) microbiota induced R/C behavior whereas colonization of gamma delta(-/-) mice with WT microbiota abolished the R/C behavior. Moreover, gamma delta(-/-) mice had elevated levels of the microbial metabolite 3-phenylpropanoic acid in their cecum, which is a precursor to hippurate (HIP), a metabolite we found to be elevated in the CSF. HIP reaches the striatum and activates dopamine type 1 (D1R)-expressing neurons, leading to R/C behavior. Altogether, these data suggest that intestinal gamma delta T cells shape the gut microbiota and their metabolites and prevent dysfunctions of the striatum associated with behavior modulation.