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 microbiome-dependent 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.

基因与环境的相互作用塑造行为和抑郁症的易感性。然而，人们对整合遗传和环境输入影响神经行为结果的信号通路知之甚少。我们报告肠道 G 蛋白偶联受体Gpr35参与微生物到大脑的代谢途径来调节小鼠的神经元可塑性和抑郁行为。心理压力会降低肠上皮Gpr35 的水平，其基因缺失会以微生物组依赖性方式诱导抑郁样行为。Gpr35 ^{-/−小鼠和患有抑郁症的个体体内的}Parabacteroides distasonis有所增加，并且它在野生型小鼠中的定植会诱发抑郁症。Gpr35 ^-/−和Parabacteroides distasonis定植的小鼠表现出吲哚 3-甲醛 (IAld) 减少和吲哚 3-乳酸 (ILA) 增加，这些物质是沿着色氨酸细菌分解代谢途径的相对分支产生的。IAld 和 ILA 反向调节伏隔核的神经可塑性，伏隔核是与抑郁症相关的大脑区域。IAld 补充剂对患有应激或肠道上皮Gpr35缺乏的小鼠产生抗抑郁作用。总之，这些发现阐明了导致抑郁症易感性的肠道微生物-大脑信号传导机制。