A Gpr35 tuned gut-brain metabolic axis regulates depressive-like behavior (PRJCA020466)
Gene-environment interactions shape animal behavior and the susceptibility to neurobehavioral symptoms such as depression. However, little is known about the signaling pathway that integrates genetic and environmental inputs with neurobehavioral responses especially at the systems level. Here we report that Gpr35 engages a gut microbe-to-brain metabolic signaling to modulate nucleus accumbens (NAc) neuronal plasticity and depressive behavior in mice. Chronic stress decreased gut epithelial Gpr35 expression, genetic deletion of which induces despair and social impairment in a gut microbiome-dependent manner. We identify a dominant role for Parabacteroides distasonis in conferring the behavioral symptoms, which dictates the balance of bacterial metabolite indole-3-aldehyde and indole-3-lactate, which enter the brain to counteractively modulate dendritic spine density and synaptic transmission in the NAc and depression-like behavior. Together, our findings identify a genetics-shaped gut-brain pathway underlying the susceptibility to depression and suggest a potential therapeutic strategy via metabolic regulation.