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: 9127927
• 负责人: JEFFREY I GORDON
• 金额: $ 161.22万
• 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/9127927
• 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; Same-sex; Sampling; Scientist; Series; Serum; Taxon; Testing; Therapeutic; Time; Tissues; Translational Research; Transplantation; Twin Multiple Birth; Universities; Urine; Variant; base; design; fecal transplantation; feeding; fruits and vegetables; functional restoration; global health; gut microbiome; gut microbiota; human subject; humanized mouse; innovation; insight; insulin sensitivity; member; metabolic phenotype; metabolic profile; metabolomics; microbial; microbial community; microbial host; microbiome; microbiota; mouse model; pre-clinical research; prebiotics; prevent; repaired; research study; restoration; saturated fat; tool; transcriptome sequencing; transmission process

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.

描述H2 -微生物群包含对肥胖症和肥胖症相关的代谢功能障碍（包括胰岛素抵抗）两者都有影响的细菌分类群，以及对肥胖状态下受干扰的能量储存或代谢活动发挥选择性影响的分类群; H3 -饮食影响这些生物群活动的表达; H4-在有和没有代谢功能障碍的肥胖个体的微生物群中看到的减少的多样性可以通过添加微生物群的微生物群来“修复”，这些微生物群的微生物群没有得到很好的代表，并且饮食成分允许这些微生物建立自己并表达促进健康的功能。DK 078669将使用普遍适用的转化研究管道进行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]，创新特征包括（i）招募和详细的生理/代谢表型分析同性女性不一致双胞胎，对于瘦与肥胖双重或单一不一致，代谢健康与不健康（胰岛素抵抗）状态（缩写为LnMH/ObMUN，LnMH/ObMH，ObMH/ObMUN），并实施受控的家庭饮食研究（项目2）;（ii）移植其完整的未培养的肠道群落，随后广泛收集来自其微生物群的细菌培养物，对gnotobiotic小鼠喂食与不和谐双胞胎在其家庭饮食研究中消耗的相同的基于NHANES的饮食，评估人类肠道群落是否可以将人类供体表型传播给受体小鼠，以及这些传播的表型对饮食的敏感性（项目1）;（iii）共养小鼠，其携带来自LnMH/ObMUN、LnMH/ObMH、ObMH/ObMUN对的移植微生物群以鉴定来自LnMH的分类群（然后是ObMH），其改善与ObMUN微生物群相关的增加的肥胖和/或代谢表型，并确定其影响是否具有家族特异性（解决肠道修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，用于分析人类和小鼠的多组学时间序列研究（项目3）。核心A是一个已建立的代谢组学单位，将提供广泛的覆盖范围和分析精度的组合，用于定义人类受试者和衍生的gnotobiotic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沉积的数据存储库。我们的团队高度互动，跨学科， 基础和临床转化科学家在当前资助期内发表了57篇PPG论文。我们的研究结果表明，在一些肥胖的人中，肠道微生物群转移到一种可以维持肥胖及其相关代谢异常的状态， 具有Ln衍生分类群的Ob微生物群中的小生境需要允许这些分类群建立并表达其健康促进功能的饮食。