Gut dysbiosis induces the development of asthenozoospermia through butanoate metabolism.

Background: Asthenozoospermia is a leading cause of male infertility with a rising incidence. While gut dysbiosis is implicated in metabolic disease, its role in asthenozoospermia pathogenesis remains unclear. Materials and methods: We conducted a case-control study comparing the fecal microbiomes of men with isolated asthenozoospermia (n=60) and healthy controls (n=60) using shotgun metagenomic sequencing. Causality was assessed by fecal microbiota transplantation (FMT) from patients or controls into germ-free male mice. Metabolic perturbations were profiled by untargeted serum metabolomics and targeted short-chain fatty acid (SCFA) quantification in humans, alongside untargeted testicular metabolomics and serum SCFAs in recipient mice. Results: Metagenomic analysis (LEfSe) identified species-level differences, with marked depletion of butyrate-producing taxa in asthenozoospermia, most notably the prototypical butyrate producer Conclusions: Asthenozoospermia is associated with gut dysbiosis characterized by loss of butyrate-producing bacteria, systemic and testicular disturbances in butyrate metabolism, and microbiota-mediated transmission of impaired sperm quality. These findings implicate the gut-testis axis in asthenozoospermia pathogenesis and nominate butyrate metabolism as a potential therapeutic target.