Project 2 - Metabolic and controlled diet studies of obesity-discordant and conco

项目 2 - 肥胖不一致和肥胖的代谢和控制饮食研究

• 批准号: 9314539
• 负责人: ANDREW C. HEATH
• 金额: $ 48.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9314539
• 关键词: Acute; Address; Adipose tissue; Advanced Development; Basic Science; Biological; Blood; Blood specimen; Body Composition; Body mass index; Branched-Chain Amino Acids; Chronic; Communities; Consumption; Data; Development; Diet; Dizygotic Twins; Eating; Eligibility Determination; Ensure; Euglycemic Clamping; Evaluation; Fatty acid glycerol esters; Feces; Female; Food Patterns; Functional disorder; Germ-Free; Glucose; Gnotobiotic; Health; Home environment; Housing; Human; Individual; Infusion procedures; Insulin Resistance; Intake; Intervention; Intra-abdominal; Joints; Metabolic; Metabolic Control; Metagenomics; Microbe; Mus; National Health and Nutrition Examination Survey; Obese Mice; Obesity; Outcome; Pattern; Phase; Phenotype; Physiological; Population; Prevention; Procedures; Productivity; Property; Recruitment Activity; Research; Resources; Ribosomal RNA; Sampling; Serum; Shapes; Stable Isotope Labeling; Structure; Technical Expertise; Testing; Therapeutic; Thinness; Tracer; Transplantation; Triglycerides; Twin Multiple Birth; Urine; Work; base; cardiovascular disorder risk; defined contribution; disorder risk; experimental study; fecal transplantation; food consumption; fruits and vegetables; functional restoration; good diet; gut microbiome; gut microbiota; humanized mouse; indexing; insulin sensitivity; intrahepatic; lean body mass; metabolic phenotype; metabolic profile; metabolomics; microbial; microbiome; microbiota; mouse model; prevent; restoration; saturated fat; therapeutic development; tool; trait; transmission process; young adult

This Project, synergistic with Project 1, will evaluate the association between the gut microbiota and obesity and its associated metabolic phenotypes. Background: In work by Project 1, when fecal microbiota from obese (Ob) and lean (Ln) twins from discordant pairs (not metabolically phenotyped) were transplanted to germ-free mice, Ob microbiota transmitted increased adiposity and metabolic features that accompany human insulin- resistant states (e.g., increased circulating levels of serum branched-chain amino acids). In addition, co- housing mice harboring Ob co-twin microbiota with mice containing transplanted Ln microbiota prevented development of these body composition and metabolic phenotypes in the Ob cagemate: prevention was associated with unidirectional invasion of bacterial taxa from the Ln to the Ob cagemate's gut community, indicative of unfilled niches in Ob microbiota that could be occupied, but only under certain dietary contexts (observed under a low saturated fat/high fruit & vegetable [LoSF-HiFV) diet, but not under a HiSF-LoFV diet). Results were consistent with previous findings of reduced diversity in the microbiota of Ob individuals and suggest that fecal transplants from discordant twin pairs to gnotobiotic mice could help guide development of therapeutic strategies (microbial or diet-based) for restoration of the gut microbiota of the microbiota donor population to a pre-obese or metabolically healthy state. Approach: To better define the contributions of the microbiota to obesity and its associated metabolic dysfunctions, and to advance development of microbiota- directed interventions for treatment or prevention, we will identify, from a large panel of young adult female dizygotic twin pairs, three informative groups: pairs dually discordant for obesity and metabolically healthy/unhealthy (MH/MUN: indexed by hyperinsulinemic/euglycemic clamp [HEC]), pairs singly discordant for obesity, and pairs singly discordant for metabolic health (LnMH/ObMUN, LnMH/ObMH and ObMH/ObMUN pairs, Ln=BMI 18.5-24.9 kg/m2, Ob=BMI 30-44.9). Pairs will undergo HEC and body-composition analyses to quantify insulin-resistance and confirm group assignment. Pairs will provide fecal, urine and blood (serum) samples under free diet (1 week), with daily recording of diet intake, then complete an in-home cross-over controlled diet study, eating in random order a controlled HiSF-LoFV diet (2 weeks), and a controlled more healthy diet (LoSF-HiFV, 2 weeks), with continuing provision of fecal, urine, and end-of-diet blood samples. Human-to- mouse fecal transplant experiments (Project 1), using donor feces collected under LoSF-HiFV versus HiSF- LoFV diet conditions, will be used to characterize transmissibility of donor phenotypes, their sensitivity to diet and the degree of prevention of transmitted ObMUN and ObMH phenotypes achievable with co-housing with Ln mice (as a function of bacterial invasion pattern and diet type). Metabolomic analyses (Core A) will be used to test whether metabolic phenotypes observed in mice fed diets similar in composition to the human diets, represent those present in the humans. Increased recruitment of twin pairs will ensure adequate power.

该项目与项目 1 协同作用，将评估肠道微生物群与肥胖之间的关联 及其相关的代谢表型。背景：在项目 1 的工作中，当肥胖者的粪便微生物群 来自不一致配对（未代谢表型）的 (Ob) 和瘦 (Ln) 双胞胎被移植到无菌环境中 小鼠中，Ob 微生物群传递了伴随人类胰岛素而来的肥胖和代谢特征增加—— 耐药状态（例如，血清支链氨基酸的循环水平升高）。此外，共同 饲养含有 Ob 双胞胎微生物群的小鼠与含有移植 Ln 微生物群的小鼠可预防 Ob 笼中这些身体成分和代谢表型的发展：预防是 与细菌类群从 Ln 到 Ob 笼内动物肠道群落的单向入侵有关， 表明 Ob 微生物群中尚未填补的生态位可以被占据，但仅在某些饮食环境下 （在低饱和脂肪/高水果和蔬菜 [LoSF-HiFV）饮食下观察到，但在 HiSF-LoFV 饮食下没有观察到）。 结果与之前关于 Ob 个体微生物群多样性降低的发现一致， 表明将不一致双胞胎的粪便移植到无菌小鼠体内可能有助于指导 用于恢复微生物供体肠道微生物群的治疗策略（基于微生物或饮食） 使人口达到肥胖前或代谢健康状态。方法：更好地定义 微生物群对肥胖及其相关代谢功能障碍的影响，并促进微生物群的发展 我们将从一大群年轻成年女性中确定治疗或预防的定向干预措施 异卵双胞胎，三个信息丰富的群体：在肥胖和代谢方面双重不一致的配对 健康/不健康（MH/MUN：由高胰岛素/正常血糖钳 [HEC] 索引），单独不一致的配对 肥胖，以及代谢健康方面单独不一致的配对（LnMH/ObMUN、LnMH/ObMH 和 ObMH/ObMUN 配对， Ln=BMI 18.5-24.9 kg/m2，Ob=BMI 30-44.9）。配对将接受 HEC 和身体成分分析以量化 胰岛素抵抗并确认分组。两人将提供粪便、尿液和血液（血清）样本 自由饮食（1周），每天记录饮食摄入量，然后完成家庭交叉控制 饮食研究，随机饮食受控 HiSF-LoFV 饮食（2 周）和受控更健康饮食 （LoSF-HiFV，2 周），持续提供粪便、尿液和饮食结束时的血样。人与人之间 小鼠粪便移植实验（项目 1），使用 LoSF-HiFV 与 HiSF- 下收集的供体粪便 LoFV 饮食条件将用于表征供体表型的遗传性及其对饮食的敏感性 以及与 Ln 共同居住可实现的预防 ObMUN 和 ObMH 表型传播的程度 小鼠（作为细菌入侵模式和饮食类型的函数）。代谢组学分析（核心 A）将用于 测试在喂养与人类饮食成分相似的饮食的小鼠中是否观察到代谢表型， 代表存在于人类中的那些。增加双胞胎的招募将确保充足的电力。