Predicting and preventing drug metabolism by the human gut microbiome

项目摘要/摘要 现代医学最重要的局限性之一是巨大的、往往是不可预测的变化 患者对治疗的反应不同。现在已经确定的是，人类基因组的变异， 尤其是在肠道和肝脏中表达的酶和转运蛋白，对药物有重大影响 血液循环中的水平。但这些研究忽略了我们“第二基因组”--数万亿个基因组中的遗传变异。 指在人体内和人体上茁壮成长的微生物(微生物群)。 到目前为止，研究表明&gt；40药物可以通过肠道微生物群代谢，这些微生物群跨越许多 最难治的慢性病：癌症、心脏病和炎症性肠病。但却很少 由于缺乏对微生物酶的了解，翻译这些发现取得了进展 以及饮食摄入量等环境因素如何影响他们的活动。 作为最初的原则证明，我们选择专注于心脏药物地高辛，它是治疗心力衰竭和 心跳不规律。地高辛是一种理想的测试用例，原因有很多：(I)唯一催化的单一反应 由肠道细菌引起的，使药物失去活性；(2)药物水平的微小变化具有临床意义，因为它的范围很窄 治疗范围；及(Iii)兰氏Eggerthella lenta是唯一已被证明催化这种作用的肠道细菌 反应。我们最近确定了导致地高辛还原的细菌酶(Haiser等人，《科学》 2013)，为肠道微生物群的个体间差异提供了第一个机械解释 导致药物水平的变化。 我们的初步结果表明，有两个因素在控制肠道中地高辛的失活方面起着重要作用。 细菌：香菇种群和宿主饮食摄入量中菌株水平的变化。我们将系统地剖析 这两个因素决定了它们如何以及为什么影响药物水平。这些研究将提供基本的生物学基础 对研究不足但与临床相关的细菌物种的洞察，同时朝着我们的长期目标前进 通过将基于微生物组的诊断测试和营养指南配对来优化治疗结果。

PROJECT SUMMARY/ABSTRACT 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 drug 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.