Gut microbial metabolite indole-3-propionic acid alleviates polycystic ovary syndrome in mice by regulating the AhR-NLRP3 axis

Polycystic ovary syndrome (PCOS) is a complex disorder that significantly impacts female reproductive health and increases the risk of metabolic and reproductive diseases. Emerging evidence suggests that alterations in gut microbiota and their metabolic activities contribute to PCOS pathogenesis, although the underlying mechanisms remain elusive. In the current study, we found that patients with PCOS had altered metabolic profiles, particularly characterized by reduced levels of indole-3-propionic acid (IPA). Administration of IPA alleviated dehydroepiandrosterone (DHEA)-induced PCOS in mice, as demonstrated by improved estrus cycle, insulin sensitivity, ovarian morphology and hormone levels. Additionally, IPA treatment alleviated DHEA-induced oxidative stress in the ovaries and enhanced thermogenesis in brown adipose tissue. Furthermore, IPA attenuated DHEA-induced inflammation both in vivo and in vitro. Mechanistically, IPA treatment suppressed DHEA-induced inflammatory responses and inhibited NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation by activating the aryl hydrocarbon receptor (AhR). Collectively, our findings indicate that IPA ameliorates DHEA-induced PCOS through modulation of the AhR-NLRP3 pathway in mice, suggesting that regulating gut microbial tryptophan metabolism and AhR activation may represent a promising therapeutic strategy for PCOS prevention.