The genetic determinants of symbiotic host-microbial interaction in the human gut

描述（由申请人提供）：本申请描述了在哺乳动物宿主内建立人类共生体的遗传需求的第一次大规模分析。微生物构成了人体90%的细胞。它们大多数生活在胃肠道中，在肠道发育、免疫成熟和能量收集中起着关键作用。哺乳动物肠道微生物群的组成与肥胖的发展动态相关，但在正常或病理条件下控制人类肠道共生体定植和建立的机制知之甚少。本文提出的实验验证了这样一个假设，即人类共生体具有专门的机制，可以在持续灌注、激烈的资源竞争和免疫监视下进行定植。将一种新型转座子诱变系统（Aim 1a）应用于一个重要的人类肠道共生体，并在无菌小鼠（Aim 1b）中监测该诱变群体中每个成员的相对适合度，将确定这些遗传决定因素。微生物群落复杂性和宿主生理状态的调控（通过遗传和饮食诱导的肥胖，Aim 2）将肥胖依赖的肠道微生物群重组与确定肥胖或瘦肠道共生体适应性的机制联系起来。确定这些机制将有助于制定策略，以优化胃肠道微生物群对人类健康的贡献。公共卫生相关性：存在于每个人胃肠道中的微生物群落介导了我们热量摄入的很大一部分，并且该群落的组成与肥胖的发展动态相关。该应用程序使用遗传和饮食诱导的肥胖小鼠模型来识别和表征哺乳动物肠道中人类微生物共生体所采用的适应机制。在单种和多种肠道微生物群落中确定这些共生的遗传决定因素将有助于以增加人类健康的方式操纵这些群落。

DESCRIPTION (provided by applicant): This application describes the first large-scale analysis of the genetic requirements for establishment of a human symbiont within a mammalian host. Microbes constitute -90 percent of the cells in the human body. The majority live in the gastrointestinal tract, where they play critical roles in gut development, immune maturation, and energy harvest. The composition of the mammalian gut microbiota is dynamically linked to the development of obesity, but little is known about the mechanisms that control colonization and establishment of human gut symbionts under normal or pathological conditions. The experiments proposed here test the hypothesis that human symbionts possess dedicated mechanisms that allow colonization despite continuous perfusion, intense resource competition, and immune surveillance. Applying a novel transposon mutagenesis system (Aim 1a) to a prominent human gut symbiont and monitoring the relative fitness of each member of this mutagenized population in germfree mice (Aim 1b) will identify these genetic determinants. Manipulation of microbial community complexity and host physiologic status (through genetic and diet-induced obesity, Aim 2) will connect the obesity-dependent restructuring of the gut microbiota with the mechanisms that determine fitness for symbionts in the obese or lean gut. Identification of these mechanisms will help establish strategies to optimize the contribution of the gastrointestinal microbiota to human health. PUBLIC HEALTH RELEVANCE: The microbial community that resides in the gastrointestinal tract of every human mediates a significant proportion of our caloric intake, and the composition of this community is dynamically linked to the development of obesity. This application uses genetic and diet-induced mouse models of obesity to identify and characterize the adaptive mechanisms employed by human microbial symbionts in the mammalian gut. Identifying these genetic determinants of symbiosis in single- and multi-species gut microbial communities will facilitate efforts to manipulate these communities in ways that increase human health.