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

• Published in: Cell host & microbe Vol. 32; no. 2; pp. 227 - 243.e6
• Main Authors: Cheng, Lingsha, Wu, Haoqian, Cai, Xiaoying, Zhang, Youying, Yu, Siqi, Hou, Yuanlong, Yin, Zhe, Yan, Qingyuan, Wang, Qiong, Sun, Taipeng, Wang, Guangji, Yuan, Yonggui, Zhang, Xueli, Hao, Haiping, Zheng, Xiao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.02.2024
• Subjects: Animals; Bacteroidetes; Brain; depressive disorder; Gastrointestinal Microbiome - physiology; genetic risk; Gpr35; gut microbiome; gut-brain axis; indole-3-carboxaldehyde; indole-3-lactate; Mice; Microbiota; neural plasticity; Parabacteroides distasonis; tryptophan metabolism; Parabacteroides distasonis; gut microbiome; tryptophan metabolism; indole-3-lactate; neural plasticity; Gpr35; genetic risk; depressive disorder; gut-brain axis; indole-3-carboxaldehyde
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2023.12.009

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. [Display omitted] •Gut epithelial Gpr35 deficiency triggers depressive-like behaviors in mice•Colonization with P. distasonis, which is enriched in Gpr35−/− mice, elicits depression•P. distasonis alters IAld and ILA balance, which regulates synaptic plasticity and depression•IAld supplementation alleviates depressive symptoms in Gpr35−/− and stressed mice How host genetics interplay with environmental factors to shape depression remains largely unknown. Cheng et al. report that Gpr35 deficiency triggers depressive symptoms in mice due to microbiome alterations, specifically Parabacteroides distasonis. These changes are linked to diminishment of a bacterial metabolite indole-3-carboxaldehyde, affecting neuroplasticity in the nucleus accumbens.