Causes and consequences of interpersonal microbial variation

项目摘要 人类胃肠道中含有数以万亿计的共生微生物，它们总共编码150倍。 比人类基因组更多的基因；在个体之间，微生物组的变异远远超过基因组 变种。尽管微生物组可能代表一个关键且容易修改的成分 肠道微生物区系对健康、疾病风险和治疗反应的贡献 这在很大程度上仍然是未知数。我们实验室的总体目标是了解原理、机制和 塑造肠道微生物群落与宿主之间相互作用的过程。我们的战略是 结合厌氧微生物遗传学、高通量质谱学和灵知菌(无菌和无菌) GermFree)动物模型来剖析这些相互作用。在最近的研究中，我们使用了这些方法来 测量人体肠道微生物群对药物代谢的贡献，并确定 肠道微生物群中的合作、竞争和对抗过程。我们在这些领域的进展 为今后围绕两个主题展开研究奠定了基础。我们将应用我们的新陈代谢方法 是为研究微生物群介导的药物代谢而开发的，以转化为非药物的外来化合物， 包括食物的分子成分。微生物遗传和灵知生菌方法也使 研究在微生物组调查中不容易测量的两个过程如何在宿主内进化 和表型异质性，有助于健康和不安的肠道中宿主-微生物组的相互作用 环境。如果成功，这些研究将确定宿主-微生物群相互作用的原因和后果 对人类健康有着广泛的影响。

Project Summary The human gastrointestinal tract harbors trillions of commensal microbes that collectively encode 150-fold more genes than the human genome; between individuals, microbiome variation far exceeds genome variation. Despite the possibility that the microbiome may represent a critical and readily modifiable component of human biology, the contribution of the gut microbiota to health, disease risk, and response to therapy remains largely undefined. The overall goal of our laboratory is to understand the principles, mechanisms, and processes that shape the interaction between gut microbial communities and their hosts. Our strategy is to combine anaerobic microbial genetics, high-throughput mass spectrometry, and gnotobiotic (germfree and ex- germfree) animal models to dissect these interactions. In recent studies, we have used these approaches to measure the contribution of the human gut microbiome to the metabolism of medical drugs and to define cooperative, competitive, and antagonistic processes in the gut microbiome. Our progress in these areas provides the basis for future studies centered on two themes. We will apply the metabolomic approaches we developed for studying microbiome-mediated drug metabolism to xenobiotic compounds that aren't drugs, including molecular components of food. Microbial genetic and gnotobiotic approaches also enable investigation of how two processes that are not readily measured in microbiome surveys, within-host evolution and phenotypic heterogeneity, contribute to host-microbiome interaction in the healthy and perturbed gut environment. If successful, these studies will define causes and consequences of host-microbiome interaction with broad implications for human health.