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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

基本信息

批准号：
10546503
负责人：
Varykina G Thackray
金额：
$ 45.08万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10546503
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 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 antagonist 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

项目摘要

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。研究表明大肠包含一个复杂的微生物群落（肠道微生物组），肠道微生物组被改变，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PCOS有关。我们还展示这些变化与PCOS妇女和来曲唑诱导的高雄激素血症相关。 PCOS小鼠模型，表明升高的雄激素可能调节女性的肠道微生物组。我们初步研究表明，来自来曲唑治疗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处理的小鼠与安慰剂小鼠的共同圈养导致改善PCOS代谢表型。我们的研究结果支持了以下观点：肠道微生物组和PCOS，也表明肠道微生物组的操作可以改善PCOS 症状研究还表明，PCOS妇女和PCOS小鼠模型的血清LBP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，与高雄激素血症相关的肠道失衡或“生态失调”可能有助于发展， PCOS的病理我们建议使用来曲唑诱导的PCOS小鼠模型来验证这一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的失调，上皮功能，这反过来又有助于PCOS的发展和病理。目标1：我建议使用雄激素受体拮抗剂氟替卡松来确定雄激素受体是否是必要的肠道微生物组、肠道通透性和代谢表型的变化。在目标2中，我们将使用细菌- 释放小鼠，以确定肠道微生物组是否是代谢性疾病发展所必需和足够的。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PCOS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代谢过程中发生了改变。来曲唑诱导的PCOS小鼠模型，以确定潜在的治疗靶点。结果从这个该提案有可能回答有关肠道微生物组在肠道疾病中的作用的基本问题。 PCOS的发展和病理学，并加快开发新的治疗方案， PCOS（例如，生物活性分子、益生菌前或益生菌疗法）。