Role of the Gut Microbiome in Polycystic Ovary Syndrome

项目概要/摘要 多囊卵巢综合症（PCOS）是育龄妇女最常见的内分泌疾病 全世界。除了不孕之外，许多患有 PCOS 的女性还存在代谢异常，导致 2 型糖尿病和心血管疾病的风险增加。研究表明，大肠 包含一个复杂的微生物群落（肠道微生物组），肠道微生物组在以下过程中发生改变 患有肥胖和 2 型糖尿病等代谢紊乱的人类，以及肠道微生物组的变化 可能会导致代谢失调。最近的几项研究（包括我们实验室的两项研究）报告说 在女性和啮齿动物模型中，肠道微生物组的变化与多囊卵巢综合症相关。我们还展示了 这些变化与 PCOS 女性和来曲唑诱导的高雄激素血症相关 PCOS 小鼠模型，表明雄激素升高可能调节雌性肠道微生物组。我们的 初步研究表明，来自来曲唑治疗的小鼠的粪便微生物组移植增加了 无菌小鼠的体重以及来曲唑治疗小鼠与安慰剂小鼠共同饲养的结果 改善 PCOS 代谢表型。我们的结果支持以下观点：两者之间存在直接联系 肠道微生物组和 PCOS 之间的关系，还表明控制肠道微生物组可能会改善 PCOS 症状。研究还表明，患有 PCOS 的女性和 PCOS 小鼠模型的血清 LBP 较高， 表明 PCOS 患者肠道通透性可能发生改变。总的来说，这些研究表明微生物 与高雄激素血症相关的肠道不平衡或“生态失调”可能会导致发育和 多囊卵巢综合症的病理学。我们建议使用来曲唑诱导的 PCOS 小鼠模型来检验该假设 雄激素通过雄激素受体的作用导致肠道微生物组和肠道失调 上皮功能，进而促进 PCOS 的发展和病理学。在目标 1 中，我们 建议使用雄激素受体拮抗剂氟他胺来确定是否需要雄激素受体 用于肠道微生物组、肠道通透性和代谢表型的变化。在目标 2 中，我们将使用 germ- 释放小鼠以确定肠道微生物组对于代谢的发展是否是必要和充分的 表型。最后，在目标 3 中，我们将使用粪便微生物组移植来确定是否调节 肠道微生物组可以改善多囊卵巢综合症的生殖或代谢表型。此外，我们将使用 宏基因组学与代谢组学相结合，以确定哪些微生物和代谢物在环境中发生了改变 来曲唑诱导的 PCOS 小鼠模型，以确定潜在的治疗靶点。结果由此 该提案有可能回答有关肠道微生物组在肠道菌群中的作用的基本问题 多囊卵巢综合症的发展和病理学，并加快为患有多囊卵巢综合症的女性开发新的治疗方案 PCOS（例如生物活性分子、益生菌疗法或益生菌疗法）。

Project Summary/Abstract Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women worldwide. In addition to infertility, many women with PCOS have metabolic abnormalities that result in an increased risk of type 2 diabetes and cardiovascular disease. Studies have shown that the large intestine contains a complex community of microorganisms (the gut microbiome), that the gut microbiome is altered in humans with metabolic disorders such as obesity and type 2 diabetes, and that changes in the gut microbiome may contribute to metabolic dysregulation. Several recent studies, including two from our lab, reported that changes in the gut microbiome were associated with PCOS in women and in rodent models. We also showed that these changes correlated with hyperandrogenism in women with PCOS and in the letrozole-induced PCOS mouse model, suggesting that elevated androgens may regulate the gut microbiome in females. Our preliminary studies showed that fecal microbiome transplantation from letrozole-treated mice increased the weight of germ-free mice and that co-housing letrozole-treated mice with placebo mice resulted in improvement of the PCOS metabolic phenotype. Our results support the idea that there is a direct link between the gut microbiome and PCOS and also suggest that manipulation of the gut microbiome may improve PCOS symptoms. Studies also showed higher serum LBP in women with PCOS and in PCOS mouse models, suggesting that gut permeability may be altered in PCOS. Collectively, these studies suggest that a microbial imbalance, or “dysbiosis”, in the gut linked to hyperandrogenism may contribute to the development and pathology of PCOS. We propose to use the letrozole-induced PCOS mouse model to test the hypothesis that androgen action via the androgen receptor results in dysregulation of the gut microbiome and gut epithelial function, which in turns contributes to the development and pathology of PCOS. In Aim 1, we propose to use the androgen receptor antagonist, flutamide to determine if the androgen receptor is necessary for changes in the gut microbiome, gut permeability and the metabolic phenotype. In Aim 2, we will use germ- free mice to determine whether the gut microbiome is necessary and sufficient for development of a metabolic phenotype. Finally, in Aim 3, we will use fecal microbiome transplantation to ascertain whether modulation of the gut microbiome can improve PCOS reproductive or metabolic phenotypes. In addition, we will use metagenomics coupled with metabolomics to identify which microbes and metabolites are altered in the letrozole-induced PCOS mouse model in order to identify potential therapeutic targets. Results from this proposal have the potential to answer fundamental questions concerning the role of the gut microbiome in the development and pathology of PCOS and expedite development of novel treatment options for women with PCOS (e.g., bioactive molecules, pre- or probiotic therapies).