Bupropion administration significantly impacts the gut microbiome, serum metabolites, and immune factors in chronic stress depression rats.

Emerging evidence suggests that the gut microbiota plays a crucial role in the pathogenesis of depression through the microbiota-gut-brain axis. Our previous research demonstrated that oral antidepressants were potent in regulating gut microbiome in depressive rats. Bupropion is a common antidepressant, but its regulatory mechanisms on the gut microbiota in the treatment of depression remain unclear. Here, we evaluated the potential mechanisms underlying the microbe-mediated behavioral effects of oral and injectable bupropion in chronic restraint stress (CRS)-induced depressive rat model through integrated microbiome, metabolome, and biochemical techniques. Oral bupropion modulated the gut microbiota composition in favor of beneficial bacteria such as Romboutsia and Muribaculum, while reducing potentially harmful bacteria, including Staphylococcus, Streptococcus, and Bacteroides. Metabolomic results revealed that oral bupropion improved the abnormal levels of acetic acid, butyric acid, tryptophan and its derivatives, nicotinamide, and biotin. Moreover, oral bupropion significantly reduced the percentage of CD4+ T lymphocytes and the levels of IL-1β and CXCL2. In comparison, injectable administration may not fully replicate the effects of oral administration on these alterations. Moreover, significant changes in the gut microbiota composition, particularly Muribaculum and Bacteroides, as well as tryptophan metabolites (L-tryptophan, 5-hydroxy-L-tryptophan, and indole-3-acetic acid), and immune indicators (CXCL2 levels and CD4+ T lymphocyte percentages), were correlated. Notably, bupropion administration may also selectively exert negative effects on the gut microbiota, metabolites, and immune factors. Collectively, this study presents the first comprehensive overview of changes in the gut microbiome, metabolome, and immune indicators after bupropion treatment, highlighting their role in mediating antidepressant effects.