The microbiota extends the reproductive lifespan of mice by safeguarding the ovarian reserve
Sarah K. Munyoki, Julie P. Goff, Amanda Reshke, Erin Wilderoter, Nyasha Mafarachisi, Antonija Kolobaric, Sheng Yi, Steven J. Mullett, Gabrielle E. King, Jacob D. DeSchepper, Richard J. Bookser, Carlos A. Castro, Stacy L. Gelhaus, Mayara Grizotte-Lake, Kathleen E. Morrison, Anthony J. Zeleznik, Timothy W. Hand, Miguel A. Brieño‐Enríquez, Eldin Jašarević
Abstract
Infertility affects one in six people, but the underlying mechanisms remain unclear. We show that the microbiota governs female reproductive longevity in mice. Germ-free mice have fewer primordial follicles, increased atresia, and ovarian fibrosis, leading to smaller litters, fewer offspring, and a shorter reproductive lifespan. Germ-free mice are born with a similar ovarian reserve but display excessive activation, impaired progression, and increased atresia during post-natal development. Microbiome colonization during a critical post-natal window rescues premature ovarian reserve loss by normalizing follicle kinetics and gene expression patterns. These changes parallel increased short-chain fatty acids (SCFAs), and SCFA administration mitigates ovarian dysfunction in germ-free mice. Similar oocyte dysfunction occurred in conventionally raised mice fed a high-fat diet, but additional dietary fiber helped preserve oocyte quality and embryo competence. Thus, host-microbe interactions shape female fertility, and microbiota-targeted interventions may offer strategies to address reproductive disorders.