Metagenomic Studies of the Gut Microbiomes of Obese and Lean Twins

描述（由申请人提供）：本更新申请测试了几个假设H1 -人类肠道微生物群与肥胖及其相关代谢异常有因果关系；H2 -微生物群包括对肥胖和肥胖相关代谢功能障碍（包括胰岛素抵抗）有影响的细菌类群，以及对肥胖状态下能量储存或代谢活动紊乱有选择性影响的类群；H3 -饮食影响这些生物群的活性表达；H4-在有或没有代谢功能障碍的肥胖个体中，微生物群多样性的减少可以通过添加那些生态位没有得到很好代表的微生物和允许这些微生物自我建立并表达促进健康功能的饮食成分来“修复”。DK078669将使用普遍适用的转化研究管道进行微生物群导向的诊断和治疗[发现新的益生菌，益生元和合成菌]，创新特征包括(i)招募和详细的生理/代谢表型的同性女性不一致双胞胎，双或单不一致瘦与肥胖，代谢健康与不健康（胰岛素抵抗）状态（简称LnMH/ObMUN， LnMH/ObMH, ObMH/ObMUN）；实施对照家庭饮食研究（项目2）；（ii）将其完整的未培养肠道菌群，以及随后从其微生物群中提取的大量细菌培养物，移植到与不和谐双胞胎在家庭饮食研究中食用的相同的nhanes饮食的非生小鼠中，以评估人类肠道菌群是否可以将其人类供体表型传递给受体小鼠，以及这些传递的表型对饮食的敏感性（项目1）；（iii）共同饲养小鼠，从LnMH/ObMUN、LnMH/ObMH、ObMH/ObMUN对移植的微生物群中鉴定LnMH（然后是ObMH）的分类群，这些分类群改善了与ObMUN微生物群相关的肥胖和/或代谢表型的增加，并确定这种影响是否具有家族特异性（以解决肠道修复是否必须是家族内部事件的问题）（项目1）；（iv）开发新的分析工具，用于分析人类和小鼠的多组学时间序列研究（项目3）。Core A是一个已建立的代谢组学单元，将为定义人类受试者和衍生的非生物小鼠模型的代谢表型提供广泛覆盖和分析精度的组合。Core B是多组学数据集的数据存储库，并将其存储在公共数据库中。我们的团队高度互动，跨学科，

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.