| Description |
Male infertility is a significant global concern, with gut microbiota dysbiosis being a critical factor. However, the mediators and regulatory mechanisms by which gut microbiota influences distal testicular cells remain unclear. This study demonstrates that male gamma-glutamyl transferase 1-deletion (Ggt1-/-) mice exhibits infertility, characterized by reduced germ and testicular Leydig cell numbers and increased abnormal sperm rates. Fecal metagenomics shows distinct gut microbiota composition alterations in Ggt1-/- mice and Ggt1-/- fecal microbiota transplantation (Ggt1-/--FMT) results in the similar phenotypes with Ggt1-/- mice including reduced germ cells and increased abnormal sperm rates. Moreover, gut microbial-derived metabolite phenylacetylglycine (PAGly) increases in Ggt1-/- and Ggt1-/--FMT mice by serum metabolomic analysis, and contributes to abnormal spermatogenesis via in vivo injection. Transcriptomic analysis unveils lowered expression of kallikrein family (Klk1bs) members in Ggt1-/- and Ggt1-/--FMT testes. Mechanistically, PAGly activates β2-adrenergic receptor (β2AR) on testicular Leydig cells as an agonist, downregulates the expression of Klk1bs, and damages spermatogenesis. In conclusion, Ggt1 deletion-induced gut microbiota dysbiosis disrupts spermatogenesis via PAGly-mediated β2AR activation. Our findings provide novel mechanisms of the gut-testis interactions and suggest a potential therapeutic strategy for addressing male infertility. |
