Inflammatory bowel disease leads to long-term ovarian dysfunction via immune-mediated follicular aging.

The rising global incidence of inflammatory bowel disease (IBD) is associated with menstrual cycle irregularities and reduced anti-Müllerian hormone (AMH), a key biomarker for premature ovarian insufficiency (POI), highlighting reproductive risks for women of childbearing age. Using a dextran sodium sulfate (DSS)-induced IBD mouse model, we observed decreased ovarian weight, increased follicular atresia, and disrupted estrous cycles. Ovarian transcriptomics revealed IBD-induced upregulation of aging-associated genes, with enrichment in senescence, oxidative stress response, and senescence-associated secretory phenotypes. Comparative analysis with single-cell RNA-seq data demonstrated transcriptional parallels between IBD and natural ovarian aging. Flow cytometry confirmed elevated ovarian T cells, CD8+ T cells, and macrophages, indicating localized inflammation, while peripheral blood mononuclear cells exhibited similar immune activation. TUNEL assays and qPCR confirmed accelerated ovarian aging, with increased granulosa cell apoptosis and upregulated senescence markers. Despite after an 89-day recovery, persistent follicular depletion, hormonal imbalance, and estrous irregularities suggested irreversible ovarian dysfunction. Our findings establish that IBD induces ovarian inflammation, depletes ovarian reserve, and accelerates aging, leading to long-term fertility impairment. This study clarifies IBD-POI mechanisms, informing potential therapeutic interventions for preserving fertility in affected women.