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

Qi, Xinyu; Yun, Chuyu; Sun, Lulu; Xia, Jialin; Wu, Qing; Wang, Ying; Wang, Lina; Zhang, Yangming; Liang, Xianyi; Wang, Liying; Gonzalez, Frank J.; Patterson, Andrew D.; Liu, Huiying; Mu, Liangshan; Zhou, Zehong; Zhao, Yue; Li, Rong; Liu, Ping; Zhong, Chao; Pang, Yanli; Jiang, Changtao; Qiao, Jie

doi:10.1038/s41591-019-0509-0

Cited by 515 publications

(535 citation statements)

References 26 publications

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“…Group 3 ILCs (ILC3) produce Th17-and Th22-like cytokines IL-22, IL-17, and RORγt [55]; in PCOS, it directly correlates with serum androgen concentrations and inversely with estradiol levels [56]. Flow cytometry shows a reduction of ILC3 (CD45 + IL-22 + RORγt + ) in both intestinal and blood samples in PCOS individuals and PCOS-like animal models; furthermore, it also exhibits a therapeutic role in PCOS [57]. It is well-known that the gut microbiota and its metabolites may contribute to glucose homeostasis through immune system modulation [58].…”

Section: Innate Lymphoid Cells (Ilcs)mentioning

confidence: 99%

“…Besides, a remarkable abundance of gram-negative anaerobic bacteria inhabits the distal human gut in individuals with PCOS and negative correlated with ILC3 proportion [59]. If transplant interspecific fecal from PCOS women to adult mice, female recipient mice would exhibit the major PCOS cardinal defects: hyperandrogenism, high LH secretion, impairment of reproductive cycles, ovarian dysfunction, and insulin resistance [57]. Though ILC3 functions as a double-edged sword in some autoimmune diseases [60], it can alleviate PCOS progression.…”

Section: Innate Lymphoid Cells (Ilcs)mentioning

confidence: 99%

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Immunophenotypic Profiles in Polycystic Ovary Syndrome

Pang

et al. 2020

Mediators of Inflammation

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Polycystic ovary syndrome (PCOS) a long-known endocrinopathy and one of the most common endocrine-reproductivemetabolic disorders in women, which can lead to infertility. Although the precise etiology remains unclear, PCOS is considered as a complex genetic trait, with a high degree of heterogeneity. Besides, hormones and immune cells, including both innate and adaptive immune cells, are reportedly a cross talk in PCOS. Chronic low-grade inflammation increases autoimmune disease risk. This proinflammatory condition may, in turn, affect vital physiological processes that ultimately cause infertility, such as ovulation failure and embryo implantation. Here, we review the accumulating evidence linking PCOS with inflammatory status providing an overview of the underlying hormone-mediated dysregulation of immune cells. We mainly focus on the correlational evidence of associations between immune status in women and the increased prevalence of PCOS, along with the specific changes in immune responses. Further recognition and exploration of these interactions may help elucidate PCOS pathophysiology and highlight targets for its treatment and prevention.

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Section: Innate Lymphoid Cells (Ilcs)mentioning

confidence: 99%

Section: Innate Lymphoid Cells (Ilcs)mentioning

confidence: 99%

Immunophenotypic Profiles in Polycystic Ovary Syndrome

Pang

et al. 2020

Mediators of Inflammation

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“…Gut bacteria play a profound role in BAs metabolism and are responsible for the modification of BAs via promoting deconjugation, dehydrogenation, and dehydroxylation of primary BAs 9 . Numerous studies have shown that gut microbiota can regulate host physiology by altering BAs metabolism 10‐12 . In addition, the altered BAs metabolism profiles have been considered as a marker of many diseases, such as IBD, Crohn's disease, and Alzheimer's disease 13‐15 …”

Section: Introductionmentioning

confidence: 99%

Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

et al. 2020

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Bile acids (BAs) have been implicated in regulation of intestinal epithelial signaling and function. This study aimed to investigate the effects of hyodeoxycholic acid (HDCA) on intestinal epithelial cell proliferation and explore the underlying mechanisms. IPEC‐J2 cells and weaned piglets were treated with HDCA and the contributions of cellular signaling pathways, BAs metabolism profiles and gut bacteria were assessed. In vitro, HDCA suppressed IPEC‐J2 proliferation via the BAs receptor FXR but not TGR5. In addition, HDCA inhibited the PI3K/AKT pathway, while knockdown of FXR or constitutive activation of AKT eliminated the inhibitory effects of HDCA, suggesting that FXR‐dependent inhibition of PI3K/AKT pathway was involved in HDCA‐suppressed IPEC‐J2 proliferation. In vivo, dietary HDCA inhibited intestinal expression of proliferative markers and PI3K/AKT pathway in weaned piglets. Meanwhile, HDCA altered the BAs metabolism profiles, with decrease in primary BA and increase in total and secondary BAs in feces, and reduction of conjugated BAs in serum. Furthermore, HDCA increased abundance of the gut bacteria associated with BAs metabolism, and thereby induced BAs profiles alternation, which might indirectly contribute to HDCA‐suppressed cell proliferation. Together, HDCA suppressed intestinal epithelial cell proliferation through FXR‐PI3K/AKT signaling pathway, accompanied by alteration of BAs metabolism profiles induced by gut bacteria.

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“…Damaged metabolic health is associated with relatively low microbiota gene expression levels and decreased microbial diversity [10]. New studies have shown that the occurrence of PCOS is associated with changes in the intestinal flora [11][12][13]. The changes in PCOS-related intestinal flora and its metabolites may provide new mechanistic insights into the pathogenesis and targets for the treatment of PCOS.…”

Section: Introductionmentioning

confidence: 99%

PCOS without hyperandrogenism is associated with higher plasma Trimethylamine N-oxide levels

et al. 2020

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Background: Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder, and its pathogenesis is still under debate. Trimethylamine-N-oxide (TMAO) is a small, organic compound generated by the gut microbiome with a hypothesized relation to insulin resistance (IR) and low-grade inflammation in PCOS. By comparing plasma TMAO levels in non-PCOS participants and PCOS patients without hyperandrogenism (HA), we aimed to determine whether plasma TMAO levels correlate with PCOS without HA and to analyze their relationship with low-grade inflammation and IR. Methods: A total of 27 PCOS patients without HA and 23 non-PCOS participants were enrolled in this study and subdivided into "nonobese" and "obese" arms for each group. Levels of plasma TMAO were quantified, and basic clinical characteristics and plasma biomarkers of inflammation were assessed. Results: First, plasma TMAO levels, insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values were higher in PCOS patients without HA, especially in the obese subgroup. Second, the levels of the inflammatory factors interleukin (IL)-17A, IL-18 and interferon gamma (IFN-γ) were significantly increased in obese PCOS patients without HA. Third, plasma TMAO levels were associated with body mass index (BMI) in the normalweight groups, and the obese groups had higher fasting plasma insulin (FINS) and HOMA-IR values. Finally, logistic regression showed that the plasma levels of TMAO and luteinizing hormone/follicle-stimulating hormone (LH/FSH) were independent predictors of PCOS and indicated an increased risk of PCOS. Conclusions: Elevated plasma TMAO levels may be associated with the pathogenesis of PCOS without HA and correlated with increased systemic inflammation. Further studies are needed to determine the suitability of TMAO as a predictive biomarker and to identify possible therapies for PCOS.

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

Cited by 515 publications

References 26 publications

Immunophenotypic Profiles in Polycystic Ovary Syndrome

Immunophenotypic Profiles in Polycystic Ovary Syndrome

Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

PCOS without hyperandrogenism is associated with higher plasma Trimethylamine N-oxide levels

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