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

Cell Host Microbe. 2025 Jan 8;33(1):119-136.e11. doi: 10.1016/j.chom.2024.12.006.

Abstract

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.

Keywords: PCOS; gut microbiota; gut mycobiota; secondary metabolite.

MeSH terms

  • Animals
  • Aspergillus* / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • China
  • Disease Models, Animal
  • Female
  • Gastrointestinal Microbiome*
  • Humans
  • Interleukins / metabolism
  • Intestines / microbiology
  • Intestines / pathology
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Polycystic Ovary Syndrome* / metabolism
  • Polycystic Ovary Syndrome* / microbiology
  • Receptors, Aryl Hydrocarbon* / metabolism
  • Secondary Metabolism*
  • Signal Transduction

Substances

  • Receptors, Aryl Hydrocarbon
  • Interleukins
  • Basic Helix-Loop-Helix Transcription Factors