A Gpr35 tuned gut-brain metabolic axis regulates depressive-like behavior

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 outcomes, preventing the development of targeted therapies. Here we report that Gpr35 engages a gut microbe-to-brain metabolic pathway to modulate neuronal plasticity and depressive behavior in mice. Chronic stress decreases gut epithelial Gpr35, the genetic deletion of which induces despair and social impairment in a microbiome-dependent manner. We identify a dominant role for the imbalance of microbe-derived indole-3-carboxaldehyde (IAld) and indole-3-lactate (ILA) in the behavioral symptoms with Gpr35 deficiency. Mechanistically, these bacterial metabolites counteractively modulate dendritic spine density and synaptic transmission in the nucleus accumbens. Supplementation of IAld, which is similarly decreased in depressive patients, produce anti-depressant effects in mice with stress or gut epithelial Gpr35 deficiency. Together, these findings identify a genetics-shaped gut-brain connection underlying the susceptibility to depression and suggest a microbial metabolite-based therapeutic strategy to genetic predisposition.