Wu Jiayu, Wang Kai, Qi Xinyu, Zhou Shuang, Zhao Shuyun, Lu Meisong, Nie Qixing, Li Meng, Han Mengwei, Luo Xi, Yun Chuyu, Wang Pengcheng, Li Rong, Zhong Chao, Yu Xiaofei, Yin Wen-Bing, Jiang Changtao, Qiao Jie, Pang Yanli
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.
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.
Cell Host Microbe. 2025 Jan 8;33(1):119-136.e11. doi: 10.1016/j.chom.2024.12.006.
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.
多囊卵巢综合征（PCOS）影响6%-10%的育龄女性，已知与肠道细菌紊乱有关。然而，肠道真菌群在PCOS病理中的作用仍不清楚。使用依赖培养和内转录间隔区2（ITS2）测序方法，我们在中国3个不同地理区域的226名个体（无论是否患有PCOS）中发现可在肠道定殖的真菌土曲霉有所富集。用土曲霉定殖小鼠会导致类似PCOS的表型，这是由于芳烃受体（AhR）信号传导受到抑制以及肠道3型天然淋巴细胞（ILC3s）中白细胞介素（IL）-22分泌减少所致。通过开发基于菌株多样性的活性代谢物筛选流程，我们确定次级代谢物AT-C1是一种内源性AhR拮抗剂和PCOS的关键介质。我们的研究结果表明，一种肠道真菌及其次级代谢物在PCOS发病机制中起关键作用，为改善该疾病的管理提供了一种治疗策略。
