Gut-Derived Exosomes Mediate the Microbiota Dysbiosis-Induced Spermatogenesis Impairment by Targeting Meioc in Mice

Diseases like obesity and intestinal inflammation diseases are accompanied by dysbiosis of the gut microbiota (DSGM), which leads to various complications, including systemic metabolic disorders. DSGM reportedly impairs the fertility of male mice; however, the regulatory mechanism is unclear. Exosomes are molecular mediators of intercellular communication, but the regulation of spermatogenesis by non-reproductive tissue-originated exosomes remains unknown. The present study shows that DSGM altered the miRNA expression profile of mouse circulating exosomes and impaired spermatogenesis. Moreover, the single-cell sequencing results indicate that circulating exosomes from mice with DSGM impaired spermatogenesis, while circulating exosomes from wild mice improved spermatogenesis by promoting meiosis. Further study demonstrates that DSGM leads to abnormal upregulation of miR-211-5p in gut-derived circulating exosomes, which inhibited the expression of meiosis-specific with coiled-coil domain (Meioc) in the testes and impaired spermatogenesis by disturbing meiosis process. In summary, this study defines the important role of gut-derived exosomes in connecting the "gut-testis" axis. This study proposes a new concept of the gut exosome testis axis. Following dysbiosis of gut microbiota, miR-211-5p loaded in the gut-derived circulating exosomes is increased abnormally and transported to the testicular seminiferous tubules through the blood circulation, targeting and inhibiting the expression of Meioc, consequently disturbing the meiosis process and impairing spermatogenesis. image