Intestinal probiotic fungi improve PCOS by sensing metformin signaling and inhibiting gut derived ceramide levels

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. Although metformin improves metabolic dysfunction in PCOS, its therapeutic potential in non-insulin-resistant patients and the role in mediating gut fungi remain unexplored. We followed up with PCOS patients who received metformin for clinical treatment, and the results showed that metformin significantly improved reproductive function in non-insulin resistant PCOS patients. We identified Alternaria alternata (A. alternata) as a metformin-enriched gut fungus that alleviates PCOS in mice by suppressing the intestinal SMPD3, thereby reducing ceramide levels and endoplasmic reticulum stress in granulosa cells to improve ovarian function. Notably, we validated γ-tocotrienol as the key A. alternata metabolite mediating these therapeutic effects, and conformed its upregulation post-metformin treatment in PCOS patients, correlating with improved clinical characteristics. Our findings reveal that metformin improves PCOS by modulating gut fungi and inhibiting ceramide synthesis, offering a promising therapeutic strategy for non-insulin-resistant PCOS.