Collaborative Cross of the Microbiome and Metabolic Disease

 描述(申请人提供)：生活在人体肠道的微生物(即微生物区系)对发育、生理和健康有深远的影响。肠道微生物区系的改变会导致代谢紊乱，包括肥胖和糖尿病。肠道微生物至少部分通过代谢胆汁酸(BA)来影响我们的生理。BA是肠道微生物和宿主之间代谢交流的关键节点，它们在宿主肝脏中合成，具有抗菌作用，促进脂质的吸收，并作为激素调节葡萄糖稳态、脂肪代谢、能量消耗和肠道运动。肠道微生物反过来代谢BAs并调节它们的合成和对宿主生理的影响。然而，调节肠道微生物区系组成和个体物种丰度的基因在很大程度上仍然未知。我们建议将多样性异种繁殖(DO)小鼠小组的力量与对BAs和肠道微生物区系的生化分析相结合，以确定调节肠道微生物组成和BAs丰度的基因和途径，并与疾病易感性相关。DO是一种新开发的资源，包含与人类种群一样多的遗传变异。DO小鼠的表型多样性和高分辨率遗传图谱将指导我们使用不同遗传背景的精选灵芝宿主来实验验证这些基因和途径对肠道微生物组成、Bas丰度和疾病易感性的贡献。这些研究基于三个中心假设：(I)寄主遗传变异改变微生物区系组成；(Ii)微生物区系组成的差异导致BA组成和BA依赖的宿主信号的变化；(Iii)BA信号的改变有助于代谢性疾病的发展。我们对一小群DO小鼠进行的初步研究显示，由于长期喂食“西式”高脂肪/高蔗糖饮食，糖尿病相关性状、粪便bas和肠道微生物区系组成的表型多样性达到了非凡的水平。我们在生物质和肠道微生物组(Rey)、营养学、肥胖症和糖尿病(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我们能够发现新的基因驱动的宿主-微生物相互作用，调节饮食诱导的代谢性疾病的发展。

 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.