Metagenomic Studies of the Gut Microbiomes of Obese and Lean Twins

总体描述(由申请人提供)： 我们的“超基因组”是由智人基因和存在于成虫体内的数万亿种微生物基因组中的基因组合而成的。我们的微生物基因组(微生物组)编码了代谢功能，我们不必自己进化，但在很大程度上仍然没有被探索：它们包括降解我们现代饮食中原本无法消化的成分。我们对诺生菌小鼠和人类的研究揭示了肥胖和肠道微生物生态之间的动态联系，并提供了证据，表明肥胖小鼠的肠道微生物群比瘦小动物的微生物群更有效地获取能量。这项跨学科计划项目申请涉及三个有着密切互动历史和独特专业组合的小组，旨在为肠道微生物区系在调节人类能量平衡中的作用提供新的见解，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区系的新策略，以帮助治疗肥胖症。同卵双胞胎(MZ)代表了测试有关微生物区系和微生物组与肥胖一致性的关键程序假设的理想设计，世界上最顶尖的双胞胎研究人员之一将从他正在进行的对中西部女性同性双胞胎队列的研究中招募他们。项目1使用比较元基因组学(16S rRNA计数、总粪便微生物群落DNA和表达的cDNA测序、代谢物的测量)，加上从肥胖和瘦小鼠的元基因组研究中开发的计算方法，以检查肥胖(BMI=35)和瘦(BMI 18.5-25)MZ和欧洲同卵双胞胎和非裔美国双胞胎及其母亲的微生物区系和微生物群中是否存在一组共同的生物体和基因谱系。项目2结合了比较基因组杂交和大规模DNA测序，以确定在肥胖和瘦的MZ双胞胎中，人类肠道微生物区系的两个重要成员的泛基因组的个体间差异程度，这两个成员在多糖发酵中发挥重要作用。项目3使用新的/强大的统计工具，结合项目1-2的数据集，测试人类肠道群落中是否存在与宿主遗传学和肥胖症相关的系统性差异，以及肠道环境中强大的选择性压力是否通过侧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。它还将把瘦人和肥胖者的肠道微生物区系与其他哺乳动物和不同物理环境中的肠道群落联系起来，以追踪对人类肠道关键代谢能力做出贡献的基因和基因组的来源。生物学家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作为中央数据储存库。行政核心将促进项目和人员之间的沟通。

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.