Project 1 - Determining the contributions of the gut microbiota to the physiologi

总结 项目1将使用转化研究管道进行人类肠道微生物导向的诊断， 我们开发的治疗方法是基于携带从三种类型的 肥胖和/或其相关代谢异常不一致的成年双胞胎[瘦代谢健康-肥胖 代谢不健康（LnMH/ObMUN）、LnMH/ObMH、ObMH/ObMUN]。它的目标是（i）建立肠道的因果作用 肥胖症和相关代谢表型中的微生物群，（ii）获得关于 饮食与产生这些表型的肠道微生物群成员之间的相互作用，（iii）进行测试 操纵饮食和细菌分类群对ObMUN微生物群传播的表型的影响。项目1 有四个目标。(1)确定微生物群的影响，从双胞胎对收集在他们的两个结束 在家庭饮食期间，对给予 与收集供体微生物群时消耗的饮食同源的饮食或双胞胎的其他饮食 将消耗（交叉饮食组）。对内、双胞胎对间比较和跨不一致 将执行对类型比较。(2)具有完整的未培养微生物群的共同圈养无菌小鼠 以确定（i）来自LnMH供体的微生物群是否阻止或改善了 肥胖和肥胖相关的代谢功能障碍的小鼠与ObMH或ObMUN共双胞胎的殖民 微生物群，以及预防/改善如何与来自微生物群的细菌分类群的入侵相关。 一个笼舍到另一个笼舍，以及后来涉及ObMH和ObMUN小鼠的可比较的共饲养实验。（三） 确定由目标2中表征的微生物群样品制备的细菌培养物集合是否也转移 不一致的供体表型，以gnotobiotic小鼠;进行共同饲养实验，以确定侵入性培养 与不同饮食环境中表型拯救相关的分类群。(4)执行一个测试矩阵， 将来自代表性的ObMUN或ObMH共双胞胎的收集物引入不同的致菌小鼠组 喂食高饱和脂肪和低水果蔬菜的代表性美国饮食，单独或与铅一起 益生菌联合体（从AIMS 2、3中鉴定的侵入性分类群），或先导益生元（从体外筛选中鉴定）， 或两者的组合（合生元铅）。治疗电极导线将在以下时间给药： 在培养物收集时定殖（预防组）或初始定殖后2周（治疗组）。 将使用核心A进行代谢特征分析。将使用现有工具分析多组学数据集， 用于生成项目3和核心B的新分析策略。

SUMMARY Project 1 will use a translational research pipeline for human gut microbiota-directed diagnostics and therapeutics we developed based on gnotobiotic mice harboring microbiota transplanted from three types of adult twin pairs discordant for obesity and/or its associated metabolic abnormalities [LeanMetabolicallyHealthy-Obese Metabolically Unhealthy (LnMH/ObMUN), LnMH/ObMH, ObMH/ObMUN]. Its goal is to (i) establish a causal role of the gut microbiota in obesity and associated metabolic phenotypes, (ii) obtain mechanistic insights about the interactions between diet and members of the gut microbiota that produce these phenotypes, (iii) conduct tests of the effects of manipulating diet and bacterial taxa on phenotypes transmitted by ObMUN microbiota. Project 1 has 4 aims. (1) Determine the effects of microbiota, collected from twin pairs at the end of the each of their two in-home diet periods, on body composition/metabolic phenotypes of recipient adult gnotobiotic mice given a diet homologous to that consumed at the time the donor's microbiota was collected or the other diet that twins will have consumed (cross-over diet group). Within-pair, between-twin pair comparisons and across discordant pair type comparisons will be performed. (2) Co-house gnotobiotic mice harboring intact uncultured microbiota from discordant pairs to determine if (i) microbiota from the LnMH donor prevents or ameliorates development of obesity- and obesity-associated metabolic dysfunction in mice colonized with the ObMH or ObMUN co-twin's microbiota, and how prevention/amelioration correlates with invasion of bacterial taxa from the microbiota of one cagemate to the other, and later comparable co-housing experiments involving ObMH and ObMUN mice. (3) Determine if bacterial culture collections prepared from microbiota samples characterized in Aim 2 also transfer discordant donor phenotypes to gnotobiotic mice; perform co-housing experiments to identify invasive cultured taxa associated with phenotypic rescue in different diet contexts. (4) Execute a testing matrix in which a culture collection from a representative ObMUN or ObMH co-twin are introduced to separate groups of gnotobiotic mice fed a representative USA diet high in saturated fats and low in fruits and vegetables, alone or with a lead probiotic consortium (invasive taxa identified from aims 2, 3), or a lead prebiotic (identified from in vitro screen), or a combination of the two (synbiotic lead). The therapeutic lead will be administered at the time of colonization with the culture collection (prevention arm) or 2 weeks after initial colonization (treatment arm). Metabolic profiling will be performed with Core A. Multi-omics datasets will be analyzed with existing tools and used to generate new analysis strategies with Project 3 and Core B.