Metagenomic Studies of the Gut Microbiomes of Obese and Lean Twins

描述(由申请人提供)：这份续订申请测试了几个假设：H1--人体肠道微生物区系与肥胖及其相关代谢异常有因果关系；H2-微生物区系包含对肥胖和肥胖相关代谢功能障碍(包括胰岛素抵抗)有影响的细菌分类群，以及对肥胖状态下扰乱的能量储存或代谢活动施加选择性影响的分类群；H3-饮食影响这些生物体组的活动的表达；H4-有或没有代谢功能障碍的肥胖者的微生物区系中减少的多样性可以通过添加其生态位不能很好地代表的微生物和允许这些微生物确立自身并表达促进健康的功能的饮食成分来“修复”。DK078669将为微生物群导向的诊断和治疗[发现新的益生菌、益生菌和合生菌]使用普遍适用的翻译研究流水线，创新特征包括(I)同性女性不协调双胞胎的招募和详细的生理/代谢表型，瘦与肥胖、代谢健康与不健康(胰岛素抵抗)状态的双重或单一不协调(简写为LnMH/ObMUN、LnMH/ObMH、ObMH/ObMUN)，以及实施受控家庭饮食研究(项目2)；(2)将其完整的未培养肠道群落，以及随后从其微生物群中提取的大量细菌培养集合，移植到以NHANES为基础的饮食与不和谐双胞胎在家中饮食研究期间所食用的相同的灵知生菌小鼠中，以评估人类肠道群落是否可以将其人类供体表型传递给受体小鼠，以及这些被传递的表型对饮食的敏感性(项目1)；(Iii)共居小鼠，携带来自LnMH/ObMUN、LnMH/ObMH、ObMH/ObMUN对的移植微生物群，以确定来自LnMH(然后是ObMH)的改善肥胖增加的分类群和/或与ObMUN微生物群相关的代谢表型，并确定其影响是否具有家庭特异性(以解决肠道恢复是否必须是家庭内部事务的问题)(项目1)；(Iv)开发新的分析工具，用于分析对人和小鼠的多时间序列研究(项目3)。核心A是一个成熟的代谢组学单位，它将提供广泛的覆盖面和分析精度的组合，以确定人类受试者和衍生的灵知生菌小鼠模型的代谢表型。核心B是多组学数据集及其随后在公共数据库中的存储的数据储存库。我们的团队高度互动，跨学科， 在当前的资助期间，基础和临床翻译科学家发表了57篇PPG论文。我们的结果表明，在一些肥胖的人类中，肠道微生物区系转移到了一种能够维持肥胖及其相关代谢异常的状态，并且填充空腹 在具有Ln衍生分类群的Ob微生物区系中的生态位需要一种允许这些分类群建立并表达其促进健康功能的饮食。

DESCRIPTION (provided by applicant): This renewal application tests several hypotheses H1 -The human gut microbiota is causally related to obesity and its associated metabolic abnormalities; H2 - The microbiota contains bacterial taxa that have effects on both adiposity and obesity-associated metabolic dysfunction including insulin-resistance, as well as taxa that exert selective effects on energy storage or metabolic activities disturbed in obese states; H3 - Diet influences expression of the activities of these groups of organisms; H4- The reduced diversity seen in the microbiota of obese individuals with and without metabolic dysfunction can be 'repaired' by adding microbes whose niches are not well-represented and dietary components that allow these microbes to establish themselves and express health-promoting functions. DK078669 will use a generally applicable translational research pipeline for microbiota-directed diagnostics and therapeutics [discovery of new probiotics, prebiotics, and synbiotics], Innovative features include (i) recruitment and detailed physiologic/metabolic phenotyping of same-sex female discordant twin-pairs, doubly or singly discordant for lean versus obese, and metabolic healthy versus unhealthy (insulin-resistant) states (abbreviated LnMH/ObMUN, LnMH/ObMH, ObMH/ObMUN), and implementation of controlled in-home diet studies (Project 2); (ii) transplantation of their intact uncultured gut communities, and subsequently extensive bacterial culture collections derived from their microbiota, into gnotobiotic mice fed the same NHANES-based diets as those consumed by the discordant twins during their in-home diet studies, to assess whether human gut communities can transmit their human donor phenotypes to recipient mice and the sensitivity of these transmitted phenotypes to diet (Project 1); (iii) co-housing mice, harboring transplanted microbiota from LnMH/ObMUN, LnMH/ObMH, ObMH/ObMUN pairs to identify taxa from LnMH (and then ObMH ) which ameliorate the increased adiposity and/or metabolic phenotypes associated with ObMUN microbiota, and to determine whether or not the effects are family-specific (to address the question of whether gut restoration has to be a within-family affair) (Project 1); (iv) development of new analytic tools for analyzing multi-omics time series studies of humans and mice (Project 3). Core A is an established metabolomics unit that will provide a combination of broad coverage and analytical precision for defining metabolic phenotypes in human subjects and derived gnotobiotic mouse models. Core B is a data repository for multi-omics datasets and their subsequent deposition in public databases. Our team of highly interactive, interdisciplinary, basic and clinical translational scientists has published 57 PPG papers during the current funding period. Our results suggest that in some obese humans, the gut microbiota is shifted to a state that can sustain obesity and its associated metabolic abnormalities, and that filling empty niches in Ob microbiota with Ln-derived taxa requires an diet that allows these taxa to be established and express their health-promoting functions.