Role of the Gut Microbiome in Polycystic Ovary Syndrome

项目摘要/摘要 多囊卵巢综合征(PCOS)是育龄妇女最常见的内分泌疾病 全世界。除了不孕不育外，许多患有多囊卵巢综合征的女性还存在代谢异常，导致 增加患2型糖尿病和心血管疾病的风险。研究表明，大肠 包含一个复杂的微生物群落(肠道微生物群)，肠道微生物群在其中发生变化 患有代谢紊乱的人，如肥胖症和2型糖尿病，以及肠道微生物群的变化 可能导致代谢失调。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，肠道微生物群的变化与多囊卵巢综合征有关。我们还展示了 这些变化与多囊卵巢综合征妇女和来曲唑诱导的高雄激素血症有关 多囊卵巢综合征小鼠模型，提示雄激素升高可能调节雌性动物的肠道微生物群。我们的 初步研究表明，来自来曲唑处理的小鼠的粪便微生物组移植增加了 无菌小鼠体重和来曲唑治疗小鼠与安慰剂小鼠共住导致 PCOS代谢表型的改善。我们的研究结果支持了这样一种观点，即 肠道微生物群和多囊卵巢综合征，也表明肠道微生物群的操纵可能会改善多囊卵巢综合征 症状。研究还表明，患有多囊卵巢综合征的女性和多囊卵巢综合征小鼠模型的血清LBP水平较高， 提示多囊卵巢综合征患者肠道通透性可能发生改变。总的来说，这些研究表明，一种微生物 与高雄激素有关的肠道中的不平衡，或“生物失调”，可能有助于发育和 多囊卵巢综合征的病理学。我们建议使用来曲唑诱导的多囊卵巢综合征小鼠模型来检验这一假设 雄激素通过雄激素受体的作用导致肠道微生物群和肠道的失调。 上皮性功能，进而促进多囊卵巢综合征的发展和病理。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雄激素受体是否必要 用于肠道微生物群、肠道通透性和代谢表型的变化。在《目标2》中，我们将使用细菌- 释放小鼠以确定肠道微生物群是否对新陈代谢的发育是必要的和充分的 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 肠道微生物组可改善多囊卵巢综合征的生殖或代谢表型。此外，我们还将使用 元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 建立来曲唑诱导的多囊卵巢综合征小鼠模型，以确定潜在的治疗靶点。由此产生的结果 该提案有可能回答有关肠道微生物群在 多囊卵巢综合征的发生和病理，并加快为患有多囊卵巢综合征的妇女开发新的治疗方案 多氯联苯(例如，生物活性分子、前或益生菌疗法)。

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).