The intestinal fungus Aspergillus tubingensis promotes polycystic ovary syndrome through a secondary metabolite

Polycystic ovary syndrome (PCOS) affects 6%–10% of women of reproductive age and is known to be associated with disruptions in the gut bacteria. However, the role of the gut mycobiota in PCOS pathology remains unclear. Using culture-dependent and internal transcribed spacer 2 (ITS2)-sequencing methods, we discovered an enrichment of the gut-colonizable fungus Aspergillus tubingensis in 226 individuals, with or without PCOS, from 3 different geographical areas within China. Colonization of mice with A. tubingensis led to a PCOS-like phenotype due to inhibition of Aryl hydrocarbon receptor (AhR) signaling and reduced interleukin (IL)-22 secretion in intestinal group 3 innate lymphoid cells (ILC3s). By developing a strain-diversity-based-activity metabolite screening workflow, we identified secondary metabolite AT-C1 as an endogenous AhR antagonist and a key mediator of PCOS. Our findings demonstrate that an intestinal fungus and its secondary metabolite play a critical role in PCOS pathogenesis, offering a therapeutic strategy for improving the management of the disease. [Display omitted] •Gut-colonizable fungus Aspergillus tubingensis was enriched in PCOS patients•A. tubingensis induced mouse PCOS-like phenotype through gut AhR-IL-22 axis in ILC3s•Secondary metabolite AT-C1 from A. tubingensis is an endogenous AhR antagonist•AT-C1 positively correlated with PCOS symptoms in patients Wu et al. found the enrichment of gut-colonizable fungus Aspergillus tubingensis in PCOS patients from 3 different geographical areas within China. A. tubingensis led to a PCOS-like phenotype in mice, through the secondary metabolite AT-C1, which is an endogenous AhR antagonist and inhibits gut AhR-IL-22 pathway in ILC3s.