Microbial and Metabolic Correlates of Endometrial Dysfunction in Polycystic Ovary Syndrome: A Translational Study

ABSTRACT Objective Women with polycystic ovary syndrome (PCOS) exhibit a substantially increased risk of miscarriage, yet the underlying mechanisms remain inadequately understood. This study aimed to investigate whether specific gut microbial dysbiosis and metabolic disturbance are associated with and may potentially contribute to endometrial dysfunction and adverse pregnancy outcomes in women with PCOS. Design Prospective cohort study integrated with mechanistic experiments. Setting Women's Hospital, School of Medicine, Zhejiang University, China (2022–2024). Population A total of 110 women with PCOS and 110 age‐ and body mass index‐matched controls were enrolled. Methods We performed 16S rRNA and metagenomic sequencing of gut microbiota, with untargeted and targeted serum metabolomics. Functional validation was conducted using primary human endometrial stromal cells and a PCOS rat model intervened with Parabacteroides merdae ( P. merdae ) supplementation or faecal microbiota transplantation. Main Outcome Measures Gut microbiota composition, serum metabolites, endometrial senescence markers, and pregnancy outcomes. Results Women with PCOS exhibited significantly higher miscarriage rates than controls, accompanied by a marked depletion of P. merdae abundance and elevated serum levels of branched‐chain amino acids, particularly isoleucine. Exogenous isoleucine induced cellular senescence in human endometrial stromal cells in a dose‐dependent manner. Restoration of P. merdae levels in the PCOS rat model resulted in decreased serum isoleucine levels, amelioration of the senescent endometrial phenotype, and reduction in the fetal resorption rate. Conclusions These findings suggest that P. merdae depletion and the concurrent accumulation of isoleucine may be associated with endometrial senescence and elevated risk of miscarriage, suggesting the possible involvement of a gut microbiota–metabolite pathway in PCOS‐related reproductive dysfunction. These results also provide a mechanistic basis for future translational investigations.