Distinct effects of different Bacteroides strains on depressive-like behavior via a gut-Th1/Th17 cells-brain axis.

Extensive evidence links gut microbiota to the pathogenesis of major depressive disorder (MDD), yet the specific microbial species involved remain unclear. Here, we identify distinct roles of three Bacteroides species-B. uniformis, B. vulgatus, and B. thetaiotaomicron-in depression. B. uniformis increases susceptibility to depression in mice, significantly enhances Th17 cell differentiation in vivo and in vitro, and upregulates hippocampal IL-17A level. However, treatment with SR1001, a Th17 cell inhibitor, alleviates B. uniformis-induced depressive-like behaviors. Conversely, B. thetaiotaomicron and B. vulgatus attenuate depressive behaviors in mice, significantly suppresse the differentiation of Th1 and Th17 cells in vivo, and reduce the levels of hippocampal cytokines, including IL-17A, IFN-γ, and TNF-α. Clinical analyses reveal increased Th1 and Th17 cells in MDD patients, correlating with depression severity. B. uniformis is enriched in MDD fecal samples and positively associated with Th17 levels, whereas B. thetaiotaomicron showes an inverse correlation. Mechanistically, targeted metabolomic shows that B. uniformis reduces butyric acid and cholesterol sulfate, whereas B. thetaiotaomicron increases butyric acid, propionic acid, and biotin, all of which are linked to Th1 and Th17 regulation. These findings highlight the role of Bacteroides species in depression via a gut-Th1/Th17 cells-brain axis, providing mechanistic insights and ideas for therapeutic strategies.