Role of the Gut Microbiome in Polycystic Ovary Syndrome

项目总结/摘要 多囊卵巢综合征（PCOS）是育龄妇女最常见的内分泌疾病 国际吧除了不孕症，许多患有PCOS的女性还存在代谢异常，导致不孕症。 2型糖尿病和心血管疾病的风险增加。研究表明大肠 包含复杂的微生物群落（肠道微生物组），肠道微生物组发生改变 患有肥胖和2型糖尿病等代谢紊乱的人，以及肠道微生物组的变化 可能导致代谢失调最近的两项临床研究表明， 微生物群与PCOS有关。此外，我们和其他人证明，肠道微生物组 在PCOS的啮齿动物模型中，组成发生了显著改变。我们对粪便微生物组的初步数据 在无菌小鼠中的移植以及与健康小鼠共饲养PCOS小鼠模型表明， 肠道微生物组在PCOS中起着因果作用，对肠道微生物组操纵可以改善 PCOS症状此外，研究表明，血清LBP在PCOS妇女中升高， 多囊卵巢综合征小鼠模型，表明肠道通透性可能会改变多囊卵巢综合征。总的来说，这些研究 这表明肠道中的微生物失衡或“生态失调”可能有助于发展和病理 关于PCOS研究肠道微生物组在PCOS小鼠模型中的作用有几个优点， 机制研究，包括控制饮食和遗传学的能力，使用无菌（无菌）小鼠 缺乏微生物组来测试因果关系和敲除感兴趣的基因。我们建议使用来曲唑- 诱导PCOS小鼠模型，以验证雄激素通过雄激素受体发挥作用的假设 导致肠道微生物组和肠道上皮功能失调，这反过来又有助于 PCOS的发生和病理。在目的1中，我们提出使用雄激素受体拮抗剂， 氟替卡松，以确定雄激素受体是否是肠道微生物组，肠道 渗透性和代谢表型。在目标2中，我们将使用无菌小鼠来确定肠道是否 微生物组对于代谢表型的发展是必要的和充分的。最后，在目标3中，我们将使用 粪便微生物组移植以确定肠道微生物组的调节是否可以改善PCOS 生殖或代谢表型。此外，我们将使用宏基因组学与转录组学相结合， 确定来曲唑诱导的PCOS小鼠模型中哪些细菌菌株和功能发生了改变， 以鉴定潜在的前益生菌或益生菌治疗靶点。这项提案的结果有可能回答 关于肠道微生物组在PCOS发展和病理学中作用的基本问题 并加快开发用于PCOS妇女的新治疗方案（例如，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. Two recent clinical studies reported that changes in the gut microbiome were associated with PCOS. In addition, we and others demonstrated that the gut microbiome composition was significantly altered in rodent models of PCOS. Our preliminary data with fecal microbiome transplantation in germ-free mice as well as co-housing a PCOS mouse model with healthy mice suggests that the gut microbiome plays a causal role in PCOS and that manipulation of the gut microbiome may improve PCOS symptoms. In addition, studies demonstrated that serum LBP is increased in women with PCOS and 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 may contribute to the development and pathology of PCOS. Studying the role of the gut microbiome in a PCOS mouse model has several advantages for mechanistic studies including the ability to control for diet and genetics, to use gnotobiotic (germ-free) mice that lack a microbiome to test causality and to knockout genes of interest. 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 transcriptomics to identify which bacterial strains and functions are altered in the letrozole-induced PCOS mouse model in order to identify potential pre- or probiotic 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., pre- or probiotic therapies).