Role of the Gut Microbiome in Polycystic Ovary Syndrome

肠道微生物组在多囊卵巢综合症中的作用

• 批准号: 10117273
• 负责人: Varykina G Thackray
• 金额: $ 45.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117273
• 关键词: 16S ribosomal RNA sequencing; Androgen Receptor; Androgens; Bacteria; Bacteroidetes; Cardiovascular Diseases; Communities; Complex; Coupled; Development; Diet; Endocrine System Diseases; Feces; Female; Firmicutes; Flutamide; Germ-Free; Gestational Diabetes; Housing; Human; Hyperandrogenemia; Hyperandrogenism; Infertility; Insulin Resistance; Intestinal permeability; Irregular Menstruation; Large Intestine; Letrozole; Link; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Metagenomics; Microbe; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Non-Steroidal Aromatase Inhibitor; Obesity; Pathology; Phenotype; Placebos; Play; Polycystic Ovary Syndrome; Prevalence; Prevention; Reporting; Research Project Grants; Risk; Rodent; Rodent Model; Role; Serum; Symptoms; Testing; Testosterone; Transplantation; Weight Gain; Woman; aged; dysbiosis; fecal transplantation; gastrointestinal epithelium; gut microbiome; improved; metabolic phenotype; metabolomics; microorganism; mouse model; non-alcoholic fatty liver disease; novel; probiotic therapy; reproductive; symptomatic improvement; therapeutic target

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).

项目摘要/摘要 多囊卵巢综合征（PCOS）是复制妇女中最常见的内分泌疾病 全世界。除不育外，许多患有PCOS的女性具有代谢异常，导致 增加2型糖尿病和心血管疾病的风险增加。研究表明大肠大 包含一个复杂的微生物群落（肠道微生物组），肠道微生物组已改变 患有代谢性疾病的人，例如肥胖和2型糖尿病，并且肠道微生物组的变化 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，报道说 肠道微生物组的变化与女性和啮齿动物模型中的PCOS有关。我们也表明 这些变化与PCOS女性和letrozole诱导的女性的超雄激素相关 PCOS小鼠模型，表明升高的雄激素可以调节女性的肠道微生物组。我们的 初步研究表明，从letrozole处理的小鼠中粪便微生物组移植增加了 无菌小鼠的重量和与安慰剂小鼠共扎的letrozole治疗小鼠的重量导致 PCOS代谢表型的改进。我们的结果支持这样的想法，即 肠道微生物组和PCOS，还表明对肠道微生物组的操作可能会改善PCOS 研究还表明，PCOS女性和PCOS小鼠模型中的血清LBP较高， 表明在PCOS中可能会改变肠道渗透性。总的来说，这些研究表明微生物 与超雄激素有关的肠道中的失衡或“营养不良”可能有助于发展和 PCOS的病理学。我们建议使用letrozole诱导的PCOS小鼠模型检验假设 通过雄激素受体的雄激素作用导致肠道微生物组和肠道的失调 上皮功能依次有助于PCOS的发育和病理。在AIM 1中，我们 使用雄激素受体拮抗剂，氟丁酰胺来确定是否需要雄激素受体 肠道微生物组的变化，肠道渗透性和代谢表型。在AIM 2中，我们将使用细菌 - 自由小鼠以确定肠道微生物组是否必要且足以发展代谢 表型。最后，在AIM 3中，我们将使用粪便微生物组移植来确定是否调制 肠道微生物组可以改善PCOS生殖或代谢表型。此外，我们将使用 宏基因组和代谢组学结合确定哪些微生物和代谢产物发生了变化 Letrozole诱导的PCOS小鼠模型以识别潜在的治疗靶标。结果 提案有可能回答有关肠道微生物组作用的基本问题 PCOS的发展和病理，并加快针对患有女性的新型治疗选择 PCOS（例如，生物活性分子，预或益生菌疗法）。