Microbial indole-3-acetamide alleviates polycystic ovary syndrome through HIF-2α-ceramide signaling

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease and metabolic disorder in women that is marked by abnormalities in adipose tissue and gut microbial dysbiosis. However, it remains unclear whether and how the gut microbiota affects adipose tissue, thereby leading to the development of PCOS. Here, we find that intestinal Collinsella aerofaciens and its metabolite indole-3-acetamide (IAM) are significantly reduced in PCOS patients. Mechanistically, we demonstrate that C. aerofaciens produces IAM through an IAM synthase, which activates the adipose hypoxia-inducible factor 2α (HIF-2α) signaling pathway and promotes adipose ceramide degradation, thereby ameliorating the PCOS phenotype. A constructed IAM-producing engineered probiotic ameliorates PCOS in a mouse model. Together, our findings elucidate the link between gut dysbiosis and adipose tissue dysfunction in PCOS, while suggesting the potential of IAM as a treatment for PCOS.