2. Academic Validation
  3. The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice

The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice

  • Nat Metab. 2024 May;6(5):947-962. doi: 10.1038/s42255-024-01041-8.
Chuyu Yun # 1 2 3 4,  Sen Yan # 1 2 3 4,  Baoying Liao 1 2 3,  Yong Ding 5,  Xinyu Qi 1 2 3 4 6,  Min Zhao 1 2 3,  Kai Wang 5,  Yingying Zhuo 5,  Qixing Nie 5,  Chuan Ye 5,  Pengyan Xia 7,  Ming Ma 8,  Rong Li 9 10 11 12 13,  Changtao Jiang 14 15 16,  Jie Qiao 17 18 19 20 21,  Yanli Pang 22 23 24 25 26
Affiliations

Affiliations

  • 1 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
  • 2 National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China.
  • 3 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China.
  • 4 Institute of Advanced Clinical Medicine, Peking University, Beijing, China.
  • 5 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 6 Research Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest, Chinese Academy of Medical Sciences, Beijing, China.
  • 7 Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, China.
  • 8 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 9 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. roseli001@sina.com.
  • 10 National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China. roseli001@sina.com.
  • 11 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. roseli001@sina.com.
  • 12 Institute of Advanced Clinical Medicine, Peking University, Beijing, China. roseli001@sina.com.
  • 13 Research Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest, Chinese Academy of Medical Sciences, Beijing, China. roseli001@sina.com.
  • 14 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. jiangchangtao@bjmu.edu.cn.
  • 15 Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, China. jiangchangtao@bjmu.edu.cn.
  • 16 Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China. jiangchangtao@bjmu.edu.cn.
  • 17 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. jie.qiao@263.net.
  • 18 National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China. jie.qiao@263.net.
  • 19 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. jie.qiao@263.net.
  • 20 Institute of Advanced Clinical Medicine, Peking University, Beijing, China. jie.qiao@263.net.
  • 21 Research Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest, Chinese Academy of Medical Sciences, Beijing, China. jie.qiao@263.net.
  • 22 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. yanlipang@bjmu.edu.cn.
  • 23 National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China. yanlipang@bjmu.edu.cn.
  • 24 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. yanlipang@bjmu.edu.cn.
  • 25 Institute of Advanced Clinical Medicine, Peking University, Beijing, China. yanlipang@bjmu.edu.cn.
  • 26 Research Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest, Chinese Academy of Medical Sciences, Beijing, China. yanlipang@bjmu.edu.cn.
  • # Contributed equally.
PMID: 38769396 DOI: 10.1038/s42255-024-01041-8
Abstract

Polycystic ovary syndrome (PCOS), an endocrine disorder afflicting 6-20% of women of reproductive age globally, has been linked to alterations in the gut microbiome. We previously showed that in PCOS, elevation of Bacteroides vulgatus in the gut microbiome was associated with altered bile acid metabolism. Here we show that B. vulgatus also induces a PCOS-like phenotype in female mice via an alternate mechanism independent of bile acids. We find that B. vulgatus contributes to PCOS-like symptoms through its metabolite agmatine, which is derived from arginine by arginine decarboxylase. Mechanistically, agmatine activates the farnesoid X receptor (FXR) pathway to subsequently inhibit glucagon-like peptide-1 (GLP-1) secretion by L cells, which leads to Insulin resistance and ovarian dysfunction. Critically, the GLP-1 Receptor agonist liraglutide and the arginine decarboxylase inhibitor difluoromethylarginine ameliorate ovarian dysfunction in a PCOS-like mouse model. These findings reveal that agmatine-FXR-GLP-1 signalling contributes to ovarian dysfunction, presenting a potential therapeutic target for PCOS management.

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