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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：
10328267
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328267
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 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/文摘