Estropausal gut microbiota transplant improves measures of ovarian function in adult mice

The decline in ovarian function with age affects fertility and is associated with increased risk of age-related diseases, including osteoporosis and dementia. Notably, earlier menopause is linked to shorter lifespan, yet the molecular mechanisms underlying ovarian aging remain poorly understood. Recent evidence suggests the gut microbiota may influence ovarian health. Here we show that ovarian aging is associated with distinct gut microbial profiles in female mice and that the gut microbiome can directly influence ovarian health. Using fecal microbiota transplantation from young or estropausal female mice, we demonstrate that heterochronic microbiota transfer remodels the ovarian transcriptome, reduces inflammation-related gene expression and induces transcriptional features consistent with ovarian rejuvenation. These molecular changes are accompanied by enhanced ovarian health and increased fertility. Integrating metagenomics-based causal mediation analyses with serum untargeted metabolomics, we identify candidate microbial species and metabolites that may contribute to the observed effects. Our findings reveal a direct link between the gut microbiota and ovarian health. To investigate the link between the gut microbiome and ovarian health, here the authors transplant gut microbiota from estropausal female mice to young adult female mice. Microbial transplantation improves ovarian hormone profiles, follicle metrics and fertility-related outcomes, highlighting a causal role for the aging gut microbiome in regulating ovarian function.