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

Gene -environment interactions shape behavior and susceptibility to depression. However, little is known about the signaling pathways integrating genetic and environmental inputs to impact neurobehavioral outcomes. We report that gut G -protein -coupled receptor, Gpr35, engages a microbe -to -brain metabolic pathway to modulate neuronal plasticity and depressive behavior in mice. Psychological stress decreases intestinal epithelial Gpr35, genetic deletion of which induces depressive -like behavior in a microbiomedependent manner. Gpr35-'- mice and individuals with depression have increased Parabacteroides distasonis, and its colonization to wild -type mice induces depression. Gpr35-'- and Parabacteroides distasonis- colonized mice show reduced indole-3-carboxaldehyde (IAld) and increased indole-3-lactate (ILA), which are produced from opposing branches along the bacterial catabolic pathway of tryptophan. IAld and ILA counteractively modulate neuroplasticity in the nucleus accumbens, a brain region linked to depression. IAld supplementation produces anti -depressant effects in mice with stress or gut epithelial Gpr35 deficiency. Together, these findings elucidate a gut microbe -brain signaling mechanism that underlies susceptibility to depression.