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

人类肠道共生宿主-微生物相互作用的遗传决定因素

基本信息

批准号：
7922734
负责人：
Andrew L Goodman
金额：
$ 5.01万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

项目摘要

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.

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要求的第一次大规模分析。微生物构成了人体细胞的90%。大多数人生活在胃肠道，在肠道发育、免疫成熟和能量获取方面发挥着关键作用。哺乳动物肠道微生物区系的组成与肥胖的发展动态相关，但对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。这里提出的实验验证了这样的假设，即人类共生体拥有专门的机制，允许在持续灌流、激烈的资源竞争和免疫监视的情况下进行定植。将一种新的转座子突变系统(AIM 1a)应用于一个突出的人类肠道共生体，并监测该突变群体中每个成员在无菌小鼠中的相对适合度(AIM 1b)，将识别这些遗传决定因素。操纵微生物群落的复杂性和宿主的生理状态(通过遗传和饮食诱导的肥胖，目标2)将把依赖肥胖的肠道微生物区系的重组与确定肥胖者或瘦肉者肠道中共生体的适合性的机制联系起来。确定这些机制将有助于制定战略，以优化胃肠道微生物区系对人类健康的贡献。与公共健康相关：每个人胃肠道中的微生物群落调节着我们卡路里摄入量的很大一部分，而这个群落的组成与肥胖的发展动态地联系在一起。这项应用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。确定在单一和多物种肠道微生物群落中共生的这些遗传决定因素将有助于以提高人类健康的方式操纵这些群落的努力。