Gut Microbial Genetic Variation Regulates Host Reproduction.

The gut-testis axis enables gut microbes to influence host reproduction; nonetheless, the specific role of microbial genetic variation in this process remains elusive. In this study, using Caenorhabditis elegans (C. elegans) as a model organism, we identified 46 Escherichia coli (E. coli) strains that markedly enhanced C. elegans fertility. Of them, 26 strains were mutant variants capable of mitigating cyclophosphamide (CTX)-induced reproductive disorders in C. elegans. To investigate their application, we constructed probiotics to validate their effectiveness in mouse reproduction. The engineering probiotic Ecn Δpal significantly improved spermatogenesis in mice with CTX-induced reproductive disorders. Finally, comprehensive metabolome and transcriptome analysis suggested that the purine metabolism pathway may contribute to ameliorating cyclophosphamide-induced male reproductive toxicity. Overall, our study provides novel insights into the impact of gut microbial genetic variation on host reproduction and elucidates novel therapeutic avenues for mitigating CTX-induced male reproductive toxicity.