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 reduced levels of anti-Müllerian hormone (AMH), a key biomarker for premature ovarian insufficiency (POI), highlighting reproductive risks for women of childbearing age. To investigate the connection between IBD and ovarian aging, we used a dextran sodium sulfate (DSS)-induced mouse model of IBD and assessed reproductive outcomes, including ovarian reserve, folliculogenesis, hormone profiles, and estrous cyclicity. Transcriptomic analysis of ovarian tissue showed that IBD upregulates genes associated with aging. Gene Ontology enrichment pointed to signaling pathways involved in cellular senescence, oxidative stress response, and senescence-associated secretory phenotypes. By integrating our ovarian transcriptomic data with single-cell RNA-seq datasets from young (3-month) and aged (9-month) mouse ovaries, we found significant parallels between IBD-induced transcriptional changes and natural ovarian aging. Flow cytometry confirmed elevated levels of T cells, CD8+ T cells, and macrophages in the ovaries, indicating localized immune activation. Similar systemic immune changes were observed in peripheral blood mononuclear cells, with expanded T cell and macrophage populations. TUNEL assays and qPCR further validated accelerated ovarian aging in IBD mice, showing increased granulosa cell apoptosis and upregulated aging-related markers. Notably, even after an 89-day recovery period following DSS treatment, persistent deficits in follicular counts, hormonal balance, and estrous regularity indicated irreversible ovarian dysfunction. Our findings demonstrate that IBD triggers ovarian inflammation, depletes ovarian reserve, and accelerates aging processes, leading to long-term reproductive impairment. This study elucidates the mechanistic links between IBD and POI, providing insights for therapeutic strategies to mitigate fertility risks in affected women. Overall design: RNA seq profiling of ovaries from four groups of wildtype C57BL/6J mice and dextran sodium-induced mice was performed at the end of modeling and after 89 days of rest in both groups.