Metagenomic Studies of the Gut Microbiomes of Obese and Lean Twins

摘要 这一更新应用程序测试了几个假设H1--人类肠道微生物区系与肥胖有因果关系 及其相关的代谢异常；H2-微生物区系包含的细菌分类群对 肥胖和肥胖相关的代谢功能障碍，包括胰岛素抵抗，以及 对肥胖状态下的能量储存或代谢活动产生选择性影响；H3饮食的影响 这些生物群的活性的表达；H4-微生物区系中看到的减少的多样性 有代谢功能障碍和无代谢功能障碍的肥胖患者可以通过添加其利基环境的微生物来修复 不是很好的代表和饮食成分，使这些微生物建立自己和 明确健康促进功能。DK078669将使用普遍适用的翻译研究管道 对于微生物区系导向的诊断和治疗[发现新的益生菌、益生菌和合生菌]， 创新特征包括：(1)同性女性的招募和详细的生理/代谢表型 不和谐的双胞胎，瘦与肥胖的双不和谐或单不和谐，以及新陈代谢健康与 不健康(胰岛素抵抗)状态(缩写为LnMH/ObMUN、LnMH/ObMH、ObMH/ObMUN)，并实施 受控家庭饮食研究(项目2)；(2)移植其未培养的完整肠道群落，以及 随后，从它们的微生物群中提取大量的细菌培养物，放入喂食了 以NHANES为基础的饮食，与不和谐的双胞胎在他们的家庭饮食研究中摄入的相同，以 评估人类肠道群落是否可以将其人类供体表型传播给受体小鼠和 这些传播的表型对饮食的敏感性(项目1)；(3)共居小鼠，窝藏移植 来自LnMH/ObMUN，LnMH/ObMH，ObMH/ObMun对的微生物区系，以从LnMH(然后是ObMH)中鉴定 改善与ObMun微生物区系相关的肥胖增加和/或代谢表型，并 确定影响是否为家庭特有(以解决肠道修复是否 家庭内部事务)(项目1)；(4)开发用于分析多组学时间的新分析工具 人类和老鼠的系列研究(项目3)。核心A是一个成熟的代谢组学部门，将提供 广泛的覆盖面和分析的精确度相结合来确定人类受试者的代谢表型 并衍生出灵知生菌小鼠模型。核心B是多组学数据集及其 随后在公共数据库中的证词。我们的团队高度互动，跨学科，基础和临床 在当前的资助期间，翻译科学家已经发表了57篇PPG论文。我们的结果表明 在一些肥胖的人类中，肠道微生物区系转变为一种能够维持肥胖及其相关的状态 代谢异常，以及用Ln来源的分类群填充Ob微生物区系中的空白生态位需要饮食 这使得这些分类群得以建立并表达其促进健康的功能。

SUMMARY 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 heath-promoting functions.