Predicting and preventing drug metabolism by the human gut microbiome

 描述（由申请人提供）：现代医学最重要的限制之一是患者对治疗的反应存在实质性且通常不可预测的差异。现在已经确定，人类基因组的变异，特别是在肠和肝中表达的酶和转运蛋白，对循环中的药物水平有重大影响。但是这些研究忽略了我们“第二基因组”中的遗传变异-- 数以万亿计的微生物在人体内和人体上茁壮成长（微生物组）。迄今为止，研究表明，超过40种药物可以通过肠道微生物组代谢，涵盖许多最棘手的慢性疾病：癌症，心脏病和炎症性肠病。然而，由于缺乏对负责的微生物酶以及饮食摄入等环境因素如何塑造其活性的了解，这些发现的转化进展甚微。作为一个初步的原理验证，我们选择集中在心脏药物地高辛，用于心力衰竭和心律不齐。地高辛是一种理想的测试案例，原因有多个：（i）由肠道细菌独特催化的单一反应使药物失活;（ii）由于其治疗范围狭窄，药物水平的微小变化具有临床相关性;（iii）缓慢埃格特菌是唯一一种已被证明催化该反应的肠道细菌。我们 最近鉴定了负责地高辛还原的细菌酶（Haiser等人，科学 2013年），提供了第一个机制解释肠道微生物组的个体间差异如何导致药物水平的变化。我们的初步结果表明，两个因素是重要的控制地高辛的失活肠道细菌：菌株水平的变化，在大肠杆菌。lenta人口和主机的饮食摄入量。我们将系统地剖析这两个因素，确定它们如何以及为什么影响药物水平。这些研究将为研究不足但与临床相关的细菌物种提供基本的生物学见解，同时通过将基于微生物组的诊断测试和营养指南配对，实现我们优化治疗结果的长期目标。

 DESCRIPTION (provided by applicant): One of the most important limitations to modern medicine is the substantial and often unpredictable variation between patients in their response to treatment. It is now well established that variations in the human genome, in particular the enzymes and transporters expressed in the intestine and liver, have a major impact on drug levels in circulation. But these studies ignore the genetic variation in our "second genome" - that of the trillions of microorganisms that thrive in and on the human body (the microbiome). To date, studies have shown that >40 drugs can be metabolized by the gut microbiome spanning many of the most intractable chronic diseases: cancer, heart disease, and inflammatory bowel disease. Yet very little progress has been made to translate these findings due to a lack of knowledge about the microbial enzymes responsible and how environmental factors like dietary intake shape their activity. As an initial proof-of-principle, we chose to focus on the cardiac dru digoxin, prescribed for heart failure and irregular heartbeat. Digoxin is an ideal test case for multiple reasons: (i) a single reaction, uniquely catalyzed by gut bacteria, inactivates the drug; (ii) minor changes to drug levels are clinically relevant due to its narrow therapeutic range; and (iii) Eggerthella lenta is the only gut bacterium that has been shown to catalyze this reaction. We recently identified the bacterial enzymes responsible for digoxin reduction (Haiser et al., Science 2013), providing the first mechanistic explanation for how inter-individual differences in the gut microbiome contribute to variations in drug levels. Our preliminary results suggest that two factors are important in controlling the inactivation of digoxin by gut bacteria: strain-level variation in E. lenta population and host dietary intake. We will systematically dissect these two factors, determining how and why they impact drug levels. These studies will provide basic biological insights into a poorly studied but clinically-relevant bacterial species, while moving towards our long-term goal of optimizing treatment outcomes by pairing microbiome-based diagnostic tests and nutritional guidelines.