PR003021 (Project)

Description:Varicocele is a common cause of male subfertility, but clinical outcomes after varicocelectomy vary and underlying mechanisms remain disputed. We tested whether a varicocele drives dysbiosis in the male reproductive tract and impairs sperm function via production of spermatotoxic metabolites. We first profiled the seminal microbiome in men before and after varicocelectomy and found significant taxonomic differences including acinetobacter. Next, we established causality between varicocele and dysbiosis using a validated rodent surgical model and performed tissue bacterial localization and untargeted metabolomics. Varicocele induction was associated with global microbial shifts in the testis and epididymis and increased bacterial signal in the peritubular and adventitial microenvironments. Human sperm incubated with conditioned media from pathogenic Acinetobacter and noted impaired motility, whereas symbiotic conditioned media from Lactobacillus crispatus exerted a protective effect. Metabolomics implicated polyamine metabolites including cadaverine, which caused a clear dose-dependent impairment in sperm function and spermidine, which partially rescued motility. These findings implicate the microbiome and its associated polyamine metabolome as a potential mechanistic basis for varicocele-associated subfertility and support further work to explore medical therapies to complement surgical varicocele repair.