Metagenomic Studies of the Gut Microbiomes of Obese and Lean Twins

肥胖和瘦双胞胎肠道微生物组的宏基因组研究

• 批准号: 8142195
• 负责人: JEFFREY I GORDON
• 金额: $ 138.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-16 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142195
• 关键词: Metagenomic; Studies; Gut; Microbiomes; Obese

DESCRIPTION, OVERALL (provided by applicant): Our 'metagenome' is a composite of H. sapiens genes and genes present in the genomes of the trillions of microbes that colonize our adult bodies. 'Our' microbial genomes (microbiome) encode metabolic functions we have not had to evolve on our own, but remain largely unexplored: they include degradation of otherwise indigestible components of our modern diet. Our studies of gnotobiotic mice and humans have revealed a dynamic linkage between adiposity and gut microbial ecology, and provided evidence that the gut microbiota of obese mice is more efficient at harvesting energy than the microbiota of lean animals. This interdisciplinary program project application, involving three groups with a history of close interactions and a unique combination of expertise, seeks to provide new insights about the role of the gut microbiota in regulating energy balance in humans, and to help lay experimental and computational foundations for the human microbiome project, with the ultimate goal of establishing new strategies for targeting the microbiota to help treat obesity. Monozygotic (MZ) twin pairs, who represent an ideal design for testing key program hypotheses about the concordance of the microbiota and microbiome with obesity, will be recruited by one of the world's foremost twin researchers from his ongoing study of a mid-western cohort of female like-sex twin pairs. Project 1 uses comparative metagenomics (16S rRNA enumerations, sequencing of total fecal microbial community DNA and expressed cDNAs, measurement of metabolites), plus computational approaches developed from metagenomic studies of obese and lean mice, to examine whether there is a set of shared organisms and gene lineages present in the microbiota and microbiomes of obese (BMI=35) versus lean (BMI 18.5-25) MZ and dizygotic European-ancestry and African-American twin pairs and their mothers. Project 2 combines comparative genome hybridization and large-scale DNA sequencing to determine the extent of inter-individual variation in the pan-genomes of two prominent members of the human gut microbiota that play an important role in polysaccharide fermentation, in obese vs. lean MZ twins. Project 3 uses new/powerful statistical tools, together with Project 1-2 datasets, to test whether there are systematic differences in human gut communities related to host genetics and obesity, and whether strong selective pressure in the gut environment results in adaptation through the acquisition of genes with specific functions (e.g. carbohydrate metabolism) through lateral gene transfer. It will also relate the gut microbiota of lean and obese individuals to gut communities in other mammals and different physical environments, to trace the provenance of genes and genomes that contribute key metabolic capabilities to the human gut. A Biospecimen Collection Core will recruit twins and collect fecal samples. A Microbiome Data Management Core will serve as a central data repository. An Administrative Core will facilitate communications between projects and personnel.

总体描述（由申请人提供）： 我们的“宏基因组”是智人基因和存在于我们成人体内的数万亿微生物基因组中的基因的复合体。 “我们的”微生物基因组（微生物组）编码我们不必自行进化的代谢功能，但在很大程度上仍未被探索：它们包括现代饮食中其他难以消化的成分的降解。我们对无菌小鼠和人类的研究揭示了肥胖与肠道微生物生态之间的动态联系，并提供了证据，证明肥胖小鼠的肠道微生物群在获取能量方面比瘦动物的微生物群更有效。这一跨学科项目申请涉及三个具有密切互动历史和独特专业知识组合的小组，旨在提供有关肠道微生物群在调节人类能量平衡中的作用的新见解，并帮助为人类微生物组项目奠定实验和计算基础，最终目标是建立针对微生物群以帮助治疗肥胖的新策略。同卵（MZ）双胞胎代表了测试关于微生物群和微生物组与肥胖的一致性的关键程序假设的理想设计，世界上最重要的双胞胎研究人员之一将从他正在进行的中西部女性同性双胞胎队列研究中招募这些双胞胎。项目 1 使用比较宏基因组学（16S rRNA 计数、粪便微生物群落总 DNA 和表达的 cDNA 测序、代谢物测量）以及从肥胖和瘦小鼠宏基因组研究中开发的计算方法，来检查肥胖（BMI = 35）与瘦小鼠的微生物群和微生物组中是否存在一组共享的生物体和基因谱系 (BMI 18.5-25) 同卵双胞胎、欧洲血统和非裔美国人的异卵双胞胎及其母亲。项目 2 结合了比较基因组杂交和大规模 DNA 测序，以确定人类肠道微生物群中两个重要成员的泛基因组的个体间变异程度，这两个成员在肥胖与瘦弱的同卵双胞胎中的多糖发酵中发挥着重要作用。项目3使用新的/强大的统计工具，与项目1-2数据集一起，测试人类肠道群落是否存在与宿主遗传学和肥胖相关的系统性差异，以及肠道环境中的强选择压力是否通过横向基因转移获得具有特定功能（例如碳水化合物代谢）的基因而导致适应。它还将瘦和肥胖个体的肠道微生物群与其他哺乳动物和不同物理环境的肠道菌群联系起来，以追踪为人类肠道提供关键代谢能力的基因和基因组的来源。生物样本收集核心将招募双胞胎并收集粪便样本。微生物组数据管理核心将充当中央数据存储库。管理核心将促进项目和人员之间的沟通。