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

该项目与项目1协同工作，将评估肠道微生物区系与肥胖之间的关系 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 来自不协调对(非代谢表型)的(Ob)和瘦(Ln)双胞胎被移植到无菌双胞胎 小鼠，Ob微生物区系传递了伴随着人类胰岛素的肥胖和代谢特征的增加- 抵抗状态(例如，循环中血清支链氨基酸水平升高)。此外，联合- 用含有移植的Ln微生物群的小鼠安置携带Ob共生微生物群的小鼠可防止 Ob cagemate的这些身体成分和代谢表型的发展：预防是 与从Ln到Ob cagemate肠道群落的细菌分类群的单向入侵有关， 表明Ob微生物区系中未填充的生态位可以被占据，但仅在特定的饮食环境下 (在低饱和脂肪/高水果蔬菜[LoSF-HiFV]饮食下观察，但在HISF-LoFV饮食下不观察)。 结果与先前发现的Ob个体微生物区系多样性降低和 提示，将不和谐双胞胎的粪便移植到诺生菌小鼠身上可以帮助指导糖尿病的发展。 恢复微生物区系供者肠道微生物区系的治疗策略(微生物或饮食为主) 使人群达到肥胖前或代谢健康状态。方法：更好地定义 微生物区系与肥胖及其相关的代谢功能障碍有关，并促进微生物区系的发展- 针对治疗或预防的定向干预，我们将从一大群年轻成年女性中确定 双卵双胞胎，三个信息组：对肥胖和代谢不一致的双胞胎 健康/不健康(MH/MUN：以高胰岛素/正血糖钳[HEC]为指标)，成对不协调 肥胖，与代谢健康有关的配对(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 胰岛素抵抗和确认分组分配。PIRS将提供粪便、尿液和血液(血清)样本 在免费饮食(1周)下，每天记录饮食摄入量，然后完成居家交叉对照 饮食研究，随机顺序饮食，对照HISF-LoFV饮食(2周)，以及对照更健康的饮食 (LoSF-HiFV，2周)，继续提供粪便、尿液和饮食结束后的血液样本。人与人之间 小鼠粪便移植实验(项目1)，使用在LoSF-HiFV和HISF-HISF下收集的供体粪便- LoFV的饮食条件，将被用来表征供体表型的遗传性，它们对饮食的敏感性 以及与Ln共住可实现的传播ObMUN和ObMH表型的预防程度 小鼠(作为细菌入侵模式和饮食类型的函数)。代谢分析(核心A)将用于 测试在喂食与人类相似的饲料的小鼠中观察到的代谢表型， 代表那些存在于人类体内的生物。增加双胞胎的招募将确保足够的力量。

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.