Associations of free testosterone and gut Bifidobacterium with depressive symptoms among women with PCOS

Abstract Polycystic ovary syndrome (PCOS) impairs not only women’s reproductive health but also their mental health, placing affected individuals at increased risk for depressive disorder (DD). Growing evidence suggests the gut microbiota may be involved. In this study, 64 participants with PCOS were stratified into a DD group ( n = 23) and a non-DD group ( n = 41). We measured serum free testosterone (FT), profiled gut microbiota via 16 S rRNA sequencing, and ran correlation and mediation analyses, with additional validation in corticosterone-challenged SH-SY5Y cells. The DD group exhibited higher serum FT ( p < 0.01), gut dysbiosis, and reduced Bifidobacterium abundance. FT correlated negatively with Bifidobacterium levels and positively with depression severity. Mediation analysis showed Bifidobacterium partially mediated the association between FT and DD, a finding supported by in-vitro data. In summary, PCOS-related DD is marked by elevated FT and distinct gut dysbiosis, and Bifidobacterium functions as a partial mediator linking FT to DD.