Causes and consequences of interpersonal microbial variation

项目摘要 人类胃肠道内有数万亿的肠道微生物，它们共同编码150倍于 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 变化量尽管微生物组可能是一个关键的和容易改变的组成部分， 肠道微生物群对健康的贡献，疾病风险和对治疗的反应 在很大程度上仍然不确定。我们实验室的总体目标是了解原理，机制， 这些过程塑造了肠道微生物群落及其宿主之间的相互作用。我们的策略是 联合收割机将厌氧微生物遗传学、高通量质谱和无菌（无菌和无菌）微生物生物学技术结合起来， 无菌）动物模型来剖析这些相互作用。在最近的研究中，我们使用这些方法来 测量人类肠道微生物组对医疗药物代谢的贡献，并确定 肠道微生物组中的合作、竞争和拮抗过程。我们在这些领域的进展 为今后围绕两个主题开展研究奠定了基础。我们将应用代谢组学方法， 是为了研究微生物介导的药物代谢为非药物的异生化合物而开发的， 包括食物的分子成分。微生物遗传学和细菌学方法也使 调查在微生物组调查中不容易测量的两个过程，宿主内进化 和表型异质性，有助于健康和扰动肠道中的宿主-微生物组相互作用 环境如果成功，这些研究将确定宿主-微生物组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.