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Nat Med. 2019 Aug;25(8):1225-1233. doi: 10.1038/s41591-019-0509-0. Epub 2019 Jul 22.

Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome.

Qi X1, Yun C1,2, Sun L1,2, Xia J1,2, Wu Q1,2, Wang Y1,3,4, Wang L1,3,4, Zhang Y1,2, Liang X1,2, Wang L1,3,4, Gonzalez FJ5, Patterson AD6, Liu H1,2, Mu L1,3, Zhou Z1,3, Zhao Y1,3,7, Li R1,3,4,7, Liu P1,3,4,7, Zhong C8, Pang Y9,10,11, Jiang C12,13, Qiao J14,15,16,17,18,19.

Author information

1
Department of Obstetrics and Gynecology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Third Hospital, Peking University, Beijing, China.
2
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
3
Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China.
4
National Clinical Research Center for Obstetrics and Gynecology, Beijing, China.
5
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
6
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
7
Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China.
8
Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Tumor Systems Biology, Beijing, China.
9
Department of Obstetrics and Gynecology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Third Hospital, Peking University, Beijing, China. yanlipang@bjmu.edu.cn.
10
Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China. yanlipang@bjmu.edu.cn.
11
Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. yanlipang@bjmu.edu.cn.
12
Department of Obstetrics and Gynecology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Third Hospital, Peking University, Beijing, China. jiangchangtao@bjmu.edu.cn.
13
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China. jiangchangtao@bjmu.edu.cn.
14
Department of Obstetrics and Gynecology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Third Hospital, Peking University, Beijing, China. jie.qiao@263.net.
15
Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China. jie.qiao@263.net.
16
National Clinical Research Center for Obstetrics and Gynecology, Beijing, China. jie.qiao@263.net.
17
Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. jie.qiao@263.net.
18
Beijing Advanced Innovation Center for Genomics, Beijing, China. jie.qiao@263.net.
19
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. jie.qiao@263.net.

Abstract

Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.

PMID:
31332392
DOI:
10.1038/s41591-019-0509-0

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