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.
Jiayu Wu  1 ,  Kai Wang  1 ,  Xinyu Qi  2 ,  Shuang Zhou  1 ,  Shuyun Zhao  3 ,  Meisong Lu  4 ,  Qixing Nie  5 ,  Meng Li  6 ,  Mengwei Han  7 ,  Xi Luo  6 ,  Chuyu Yun  2 ,  Pengcheng Wang  8 ,  Rong Li  2 ,  Chao Zhong  9 ,  Xiaofei Yu  10 ,  Wen-Bing Yin  11 ,  Changtao Jiang  12 ,  Jie Qiao  13 ,  Yanli Pang  14
Affiliations
  • 1. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China; Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
  • 2. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China; Institute of Advanced Clinical Medicine, Peking University, National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China.
  • 3. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
  • 4. The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
  • 5. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
  • 6. Department of Physiology and Pathophysiology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
  • 7. Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Tumor Systems Biology, Beijing, China.
  • 8. Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
  • 9. Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
  • 10. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China.
  • 11. State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 12. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China; Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
  • 13. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China; Institute of Advanced Clinical Medicine, Peking University, National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. Electronic address: [email protected].
  • 14. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China; Institute of Advanced Clinical Medicine, Peking University, National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. Electronic address: [email protected].
PMID: 39788092 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.
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