Collaborative Cross of the Microbiome and Metabolic Disease

微生物组与代谢疾病的协作交叉

基本信息

批准号：
9545554
负责人：
Federico E Rey
金额：
$ 40.27万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-23 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9545554
关键词：
Affect Antimicrobial Effect Bacteria Bile Acids Bile fluid Binding Biochemical Biological Cholesterol Chromosome Mapping Collection Communication Development Diabetes Mellitus Diet Disease susceptibility Duodenum Eating Energy Metabolism Enzymes Family Fat-Soluble Vitamin Fatty acid glycerol esters Food G-Protein-Coupled Receptors Gallbladder Genes Genetic Genetic Variation Genomics Genotype Gnotobiotic Health Hepatic Heterozygote Hormones Human Inbreeding Individual Insulin Resistance Integration Host Factors Intestinal Motility Intestines Link Lipids Liver Mammalian Genetics Mediating Metabolic Metabolic Diseases Metabolism Metagenomics Microbe Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Nutritional Obesity Organism Outcome Pathogenicity Pathway interactions Phenotype Physiological Physiology Plasma Play Population Predisposition Probiotics Process Production Quantitative Trait Loci Recombinants Resolution Resources Role Sampling Signal Transduction Sucrose System Toxic effect absorption base blood glucose regulation cohort complex biological systems dehydrogenation dehydroxylation design feeding genetic analysis gut microbes gut microbiome gut microbiota host-microbe interactions lipid metabolism metabolic phenotype metabolomics microbial microbial community microbiome microbiome composition microbiota microbiota profiles microbiota transplantation next generation novel nutrition prevent public health relevance rRNA Genes receptor response trait

项目摘要

DESCRIPTION (provided by applicant): The collections of microbes (i.e., microbiota) that inhabit the human intestine have profound effects on development, physiology and health. Alterations in the gut microbiota contribute to metabolic disorders including obesity and diabetes. Gut microbes affect our physiology at least in part by metabolizing bile acids (BAs). BAs are key nodes of metabolic communication between gut microbes and the host; they are synthesized in the host liver, have antimicrobial effects, facilitate the absorption of lipids, andact as hormones to modulate glucose homeostasis, lipid metabolism, energy expenditure, and intestinal motility. Gut microbes in turn metabolize BAs and regulate their synthesis and their influence on host physiology. However, the genes that modulate the composition of the gut microbiota and abundance of individual species of BAs remain largely unknown. We propose to combine the power of the Diversity Outbred (DO) mouse panel, a newly developed resource that contains as much genetic variation as the human population, with biochemical analyses of BAs and gut microbiota profiling to identify genes and pathways that modulate gut microbial composition and abundance of BAs, and are associated with disease susceptibility. The phenotypic diversity and high-resolution genetic mapping of the DO mice will direct our use of select gnotobiotic hosts of different genetic backgrounds to experimentally validate the contributions of these genes and pathways on gut microbial composition, abundance of BAs and disease susceptibility. The proposed studies are based on three central hypotheses: (i) host genetic variation alters microbiota composition; (ii) differences in microbiota composition result in changes in BA composition and BA-dependent host signaling; and (iii) altered BA signaling contributes to the development of metabolic disease. Our preliminary studies on a small cohort of DO mice have revealed an extraordinary level of phenotypic diversity of diabetes-related traits, fecal BAs and gut microbiota composition in response to a prolonged feeding of a "western-style" high-fat/high-sucrose diet. Our collective expertise in gnotobiotics and gut microbiome (Rey), nutrition, obesity and diabetes (Attie, Keller), metabolomics (Wang) and statistical genetics (Broman) will enable the discovery of novel genetically-driven host-microbe interactions that modulate the development of diet-induced metabolic disease.

描述（由申请人提供）：居住在人体肠道中的微生物（即微生物群）对发育、生理和健康具有深远影响。肠道微生物群的改变会导致包括肥胖和糖尿病在内的代谢紊乱。肠道微生物会影响我们的生理机能。至少部分通过代谢胆汁酸（BA），胆汁酸是肠道微生物和宿主之间代谢通讯的关键节点，它们在宿主肝脏中合成；具有抗菌作用，促进脂质的吸收，并作为调节葡萄糖稳态、脂质代谢、能量消耗和肠道蠕动的激素，进而代谢 BA 并调节其合成及其对宿主生理的影响。我们建议将多样性远交 (DO) 小鼠面板的力量结合起来，这是一种新开发的资源，其中包含通过对 BA 的生化分析和肠道微生物群分析来识别调节肠道微生物组成和 BA 丰度的基因和途径，并与疾病易感性相关，DO 的表型多样性和高分辨率遗传图谱与人类群体存在很大差异。小鼠将指导我们使用不同遗传背景的精选知生宿主来通过实验验证这些基因和途径对肠道微生物组成、BA 丰度和疾病易感性的贡献。基于三个中心假设：(i) 宿主遗传变异改变微生物群组成；(ii) 微生物群组成的差异导致 BA 组成和 BA 依赖性宿主信号传导的变化；(iii) BA 信号传导有助于代谢疾病的发展。对一小群 DO 小鼠的初步研究表明，长期喂养“西式”高脂肪/高蔗糖后，糖尿病相关性状、粪便 BA 和肠道微生物群组成具有非凡水平的表型多样性。我们在抗生素和肠道微生物组 (Rey)、营养、肥胖和糖尿病 (Attie、Keller)、代谢组学 (Wang) 和统计遗传学 (Broman) 方面的集体专业知识将有助于发现基因新颖驱动的调节宿主微生物相互作用。饮食引起的代谢疾病的发展。