Causes and consequences of interpersonal microbial variation

人际微生物变异的原因和后果

• 批准号: 9294121
• 负责人: Andrew L Goodman
• 金额: $ 4.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294121
• 关键词: Aminosalicylate; Anaerobic Bacteria; Animals; Bacteria; Communities; Data; Enzymes; Gastrointestinal tract structure; Genomics; Gnotobiotic; Goals; Health; Human; In Vitro; Individual; Measures; Medical; Metabolism; Microbe; Mus; Patients; Pharmaceutical Preparations; Research; Shapes; Testing; Ulcerative Colitis; Variant; drug metabolism; epidemiological model; experimental study; gut microbiome; improved; insight; microbial; microbial community; microbiome; microbiota; mouse model; programs; public health relevance; response; small molecule

 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.

 描述（适用提供）：个体在药物反应中的差异很大。人类胃肠道中的微生物在多个层次上影响药物代谢，但是我们目前无法预测一个人的肠道微生物群落（微生物群）是否会使它们偏爱几乎任何药物的有效或效率低下的代谢。该研究计划的长期目标是了解在人肠道微生物群落中产生人际变化的机制，并衡量这种变异如何影响药物代谢。我们描述了将发现三种通用机制（直接细菌相互作用，小分子交换和微生物群的宿主调制）如何确定微生物组动力学的实验。首先，野生型和遗传操纵的人肠符号将在体外和gnotobiotic小鼠模型中进行研究。接下来，将使用基因组分析和流行病学建模将遗传处理的人肠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，我们还将采用这些方法来剖析微生物组变异对5-氨基水杨酸盐​​代谢（5-ASA）的后果，这是一种溃疡性结肠炎的前线药物，该药物直接通过细菌酶修饰。该提案提出了计划，计划将启动或目前服用5-ASA的患者与其微生物组5-ASA代谢的体外和gnotobiotic动物研究相结合。总之，这些研究将提供关键的机械见解，对于以可预测且稳定的方式添加或去除人类肠道微生物中的物种至关重要。为了操纵个体的微生物组，以改善医疗疗法，并衡量微生物组对单个药物反应的贡献。