Causes and consequences of interpersonal microbial variation

 描述（由申请人提供）：个体在药物反应方面差异很大。人体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个体的肠道微生物群落（微生物群）是否倾向于对几乎任何药物进行有效或无效的代谢。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产生人际变异的机制，并测量这种变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群的宿主调节）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gnotobiotic小鼠模型中进行研究。接下来，基因组分析和流行病学建模将用于将遗传上易处理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gnotobiotic小鼠中检查人类肠道微生物的定义组件，以测试实验和计算数据的预测。同时，我们还将应用这些方法来剖析微生物组变异对5-氨基水杨酸（5-阿萨）代谢的影响，5-ASA是一种直接由细菌酶修饰的溃疡性结肠炎一线药物。该提案提出了将开始或正在服用5-阿萨的患者的药物反应性结果与通过其微生物组进行的5-阿萨代谢的体外和无菌动物研究相结合的计划。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去除人类肠道微生物组中的物种至关重要;操纵个体的微生物组以改善医学治疗，以及测量微生物组对个体药物反应的贡献。

 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.