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

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，当来自肥胖者的粪便微生物群 (Ob)将来自不一致对（未进行代谢表型分析）的瘦型（Ln）双胞胎移植到无菌的 在小鼠中，Ob微生物群传递伴随人胰岛素的肥胖和代谢特征增加- 抗性状态（例如，血清支链氨基酸的循环水平增加）。此外，联合国- 将携带Ob共双胞胎微生物群的小鼠与含有移植的Ln微生物群的小鼠一起圈养， 这些身体组成和代谢表型的发展在Ob cagglutinus：预防是 与细菌分类群从Ln到Ob cagulus肠道群落的单向入侵有关， 表明Ob微生物群中未填充的小生境可以被占据，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饮食下未观察到）。 结果与之前发现的Ob个体微生物群多样性降低一致， 这表明，将不和谐双胞胎的粪便移植到gnotobiotic小鼠身上可能有助于指导 用于恢复微生物群供体的肠道微生物群的治疗策略（基于微生物或饮食） 将人群恢复到肥胖前或代谢健康状态。办法：为了更好地界定联合国系统的贡献， 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- 针对治疗或预防的干预措施，我们将确定，从一个年轻的成年女性大面板， 异卵双胞胎对，三个信息组：对双重不一致的肥胖和代谢 健康/不健康（MH/MUN：通过高胰岛素/正葡萄糖钳夹[HEC]索引）， 肥胖，以及代谢健康的单独不一致对（LnMH/ObMUN，LnMH/ObMH和ObMH/ObMUN对， Ln=BMI 18.5-24.9 kg/m2，Ob=BMI 30-44.9）。对将进行HEC和身体成分分析，以量化 胰岛素抵抗和确认分组。配对将提供粪便、尿液和血液（血清）样本 在自由饮食下（1周），每天记录饮食摄入量，然后完成家庭交叉对照 饮食研究，以随机顺序进食受控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液样品。人对人 小鼠粪便移植实验（项目1），使用在LoSF-HiFV与HiSF- LoFV饮食条件将用于表征供体表型的遗传性，其对饮食的敏感性 以及通过与Ln共住房可实现的对传播的ObMUN和ObMH表型的预防程度 小鼠（作为细菌侵入模式和饮食类型的函数）。代谢组学分析（核心A）将用于 测试在喂食与人类饮食组成相似的饮食的小鼠中观察到的代谢表型， 代表了人类身上的那些。增加双胞胎的招募将确保足够的权力。

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.