Causes and consequences of interpersonal microbial variation

 描述(由申请人提供)：药物反应的个体差异很大。人类胃肠道中的微生物在多个层面上影响药物代谢，但我们目前无法预测一个人的肠道微生物群落(微生物区系)是否使他们倾向于几乎任何药物的高效或低效代谢。这项研究计划的长期目标是了解在人类肠道微生物群落中造成人际差异的机制，并测量这种差异如何影响药物代谢。我们描述了将揭示三种一般机制(直接细菌相互作用、小分子交换和微生物区系的宿主调制)如何决定微生物组动态的实验。首先，野生型和基因操纵的人类肠道共生体将在体外和灵知生菌小鼠模型中进行研究。下一步，将使用基因组分析和流行病学建模来将从遗传上易受影响的人类肠道厌氧菌的实验结果与整个微生物组联系起来。然后，将在体外和灵知生菌小鼠身上检查确定的人类肠道微生物集合，以检验从实验和计算数据中做出的预测。同时，我们还将应用这些方法来剖析微生物群变化对5-氨基水杨酸盐(5-ASA)代谢的影响，5-ASA是一种治疗溃疡性结肠炎的一线药物，直接由细菌酶修饰。这项建议提出了一项计划，将患者开始或目前服用5-ASA的药物反应结果与他们的微生物群对5-ASA代谢的体外和生理学动物研究相结合。总之，这些研究将提供关键的机制见解，这些见解对于以可预测和稳定的方式添加或移除人类肠道微生物群中的物种至关重要；对于操纵个人的微生物群以改进医学治疗，以及衡量微生物群对个人药物反应的贡献至关重要。

 DESCRIPTION (provided by applicant): Individuals vary widely in drug response. Microbes in the human gastrointestinal tract influence drug metabolism at multiple levels, but we cannot currently predict whether an individual's gut microbial community (microbiota) predisposes them towards efficient or inefficient metabolism of almost any drug. The long-term goals of this research program are to understand the mechanisms that create interpersonal variation in human gut microbial communities and to measure how this variation impacts drug metabolism. We describe experiments that will uncover how three general mechanisms (direct bacterial interaction, small molecule exchange, and host modulation of the microbiota) determine microbiome dynamics. First, wildtype and genetically manipulated human gut symbionts will be studied in vitro and in gnotobiotic mouse models. Next, genomic analyses and epidemiological modeling will be used to connect experimental results from genetically tractable human gut anaerobes to the entire microbiome. Defined assemblies of human gut microbes will then be examined in vitro and in gnotobiotic mice in order to test predictions from the experimental and computational data. In parallel, we will also apply these approaches to dissect the consequences of microbiome variation on metabolism of 5-aminosalicylate (5-ASA), a front-line drug for ulcerative colitis that is directly modified by bacterial enzymes. This proposal presents plan to integrate drug responsiveness results from patients initiating or currently taking 5-ASA with in vitro and gnotobiotic animal studies of 5-ASA metabolism by their microbiomes. Together, these studies will provide key mechanistic insights critical for adding or removing species in human gut microbiomes in a predictable and stable manner; for manipulating individuals' microbiomes in order to improve medical therapy, and for measuring the contribution of the microbiome to individual drug responses.