Collaborative Cross of the Microbiome and Metabolic Disease

微生物组与代谢疾病的协作交叉

• 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
• 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

 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（通过应用程序提供）：居住在人类肠道的微生物（即微生物群）对发育，生理和健康具有深远影响。肠道菌群的改变有助于代谢疾病，包括肥胖和糖尿病。肠道微生物至少部分通过代谢胆汁酸（BAS）影响我们的生理。 BAS是肠道微生物和宿主之间代谢通信的关键节点。它们是在宿主肝脏中合成的，具有抗菌作用，促进脂质的抽象，作为马作为马以调节葡萄糖稳态，脂质代谢，能量消耗和肠运动性。肠道微生物又代谢BAS并调节其合成及其对宿主生理的影响。但是，调节肠道菌群组成和BAS单个物种的抽象的基因在很大程度上未知。我们建议将多样性杂种（DO）小鼠面板的力量结合起来，这是一种新开发的资源，其中包含与人口一样多的遗传变异，以及对BAS和肠道菌群分析的生化分析，以识别识别基因和途径，以调节肠道肠道微生物微生物的组成和BAS和疾病的吸收，与疾病的疾病相关。 DO小鼠的表型多样性和高分辨率的遗传图将指导我们使用具有不同遗传背景的精选gnotobiotic宿主，以实验验证这些基因和途径对肠道微生物组成的贡献，BAS的抽象和疾病易感性。拟议的研究基于三个中心假设：（i）宿主遗传变异改变了微生物群的组成； （ii）微生物群组成的差异导致BA组成和BA依赖性宿主信号的变化； （iii）BA信号的改变有助于代谢疾病的发展。我们对一小部分DO小鼠队列的初步研究表明，与糖尿病相关性状，粪便bas和肠道菌群组成的表型多样性水平非常多，以响应长时间的“西方风格的”高脂肪/高脂肪饮食。我们在gnotobiotics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使新型遗传型寄养的宿主相互作用可调节饮食疾病的发展，从而发现新颖的遗传型宿主相互作用。