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: 8742497
• 负责人: JEFFREY I GORDON
• 金额: $ 167.96万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742497
• 关键词: Address; Adult; Animal Housing; Bacterial Genome; Blood; Clinical; Collection; Communities; Complement; Computing Methodologies; Country; Data; Data Set; Databases; Dependence; Deposition; Development; Diagnostic; Diet; Diet Records; Dietary Component; Disease; Family; Feces; Female; Functional disorder; Funding; Gene Expression Profile; Genes; Genome; Germ-Free; Gnotobiotic; Health; Home environment; House mice; Housing; Human; Individual; Insulin Resistance; Lead; Life; Metabolic; Metabolism; Metagenomics; Methods; Microbe; Mining; Mus; National Health and Nutrition Examination Survey; Nature; Obesity; Organism; Paper; Pathogenesis; Pattern; Phenotype; Physiological; Physiology; Preclinical Testing; Probiotics; Production; Public Health; Publishing; Ribosomal RNA; Role; Sampling; Scientist; Series; Serum; Taxon; Testing; Therapeutic; Time; Tissues; Translational Research; Transplantation; Twin Multiple Birth; Universities; Urine; Variant; base; design; feeding; fruits and vegetables; functional restoration; global health; gut microbiota; human subject; innovation; insight; insulin sensitivity; member; metabolomics; microbial; microbial community; microbial host; microbiome; mouse model; pre-clinical research; prebiotics; prevent; public health relevance; repaired; research study; restoration; saturated fat; sex; tool; transcriptome sequencing; transmission process

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.

总结 这项更新申请测试了几个假设H1 -人类肠道微生物群与肥胖有因果关系 及其相关的代谢异常; H2 -微生物群含有对 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 -饮食影响 H4-这些微生物群的多样性减少， 有代谢功能障碍和没有代谢功能障碍的肥胖个体可以通过添加微生物来“修复”， 并没有很好的代表性和饮食成分，使这些微生物建立自己， 表现出保健功能。DK 078669将使用普遍适用的转化研究管道 用于微生物菌群导向的诊断和治疗[发现新的益生菌、益生元和合生元]， 创新功能包括（i）招募和详细的生理/代谢表型的同性女性 不一致的双胞胎对，瘦与肥胖的双重或单一不一致，代谢健康与 不健康（胰岛素抵抗）状态（缩写为LnMH/ObMUN，LnMH/ObMH，ObMH/ObMUN），以及实施 对照家庭饮食研究（项目2）;（ii）移植其完整的未培养肠道群落，以及 随后，从它们的微生物群中获得大量的细菌培养物， 与不和谐双胞胎在家庭饮食研究中所食用的相同的基于NHANES的饮食， 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， 这些传播的表型对饮食的敏感性（项目1）;（iii）共同饲养小鼠，携带移植的 从LnMH/ObMUN、LnMH/ObMH、ObMH/ObMUN对中识别来自LnMH（然后是ObMH）的分类群， 改善与ObMUN微生物群相关的增加的肥胖和/或代谢表型，以及 确定影响是否是家族特异性的（以解决肠道恢复是否具有 （项目1）;（四）开发新的分析工具，用于分析多组学时间 人类和小鼠的系列研究（项目3）。核心A是一个既定的代谢组学单位，将提供一个 用于定义人类受试者中代谢表型的广泛覆盖和分析精度的组合 和衍生的无菌小鼠模型。核心B是多组学数据集及其 随后存入公共数据库。我们的团队高度互动，跨学科，基础和临床 翻译科学家在当前资助期间发表了57篇PPG论文。我们的研究结果表明 在一些肥胖的人中，肠道微生物群被转移到一种可以维持肥胖及其相关疾病的状态。 代谢异常，以及用Ln衍生的分类群填充Ob微生物群中的空小生境需要饮食 使这些分类群得以建立并表达其促进健康的功能。