Predicting and preventing drug metabolism by the human gut microbiome

项目摘要-未更改上级拨款 人类微生物群对药物处置和治疗结果的贡献被低估了， 由人类队列中的关联、临床前模型中的对照研究和 试管筛查。然而，尽管最近在这一新兴研究领域取得了相当大的进展，但仍有 关于人体肠道微生物影响的基本机制的主要知识空白 药理学。特恩堡实验室过去5年的研究(由1R01HL122593-01A1支持)是 重点了解流行的人体肠道放线杆菌在药物中的作用 新陈代谢和性情。虽然我们开始关注心脏药物的肠道细菌灭活 地高辛，用于治疗心力衰竭和心律失常，我们的结果与更广泛的科学 文献进一步表明，兰氏乳杆菌是多种药物代谢的关键细菌物种， 饮食小分子和宿主代谢物。我们建立了一个强大的比较基因组学工具包 研究可以很容易地推广到其他遗传上难以处理的肠道细菌物种的乳杆菌。在 未来几年，我们将继续利用E.lenta作为测试案例，重点放在 微生物组研究与药理学的接口。在目标1中，我们将研究肠道的内源底物 细菌酶参与药物代谢，建立在令人惊讶的观察基础上，相同的酶 负责地高辛代谢也是激活促炎Th17细胞的必要条件和充分条件 小鼠肠道，加重小鼠结肠炎模型。然后，在目标2中，我们将确定机制 通过它抑制关键的肠道药物外排转运体P-糖蛋白的活性，提供 为了更全面地了解微生物组在药物处置中的作用，第一步是 说明了微生物组在吸收、分布、代谢和消除方面的变化。一起， 这些研究强调假设驱动的机械论研究的实用性和可行性，意在 补充来自大规模临床队列研究和高通量筛查的丰富数据。我们的 结果已经提供了多种洞察力，这些洞察力既提供了信息，也使我们的模型复杂化 微生物组影响药物，强调在翻译这项工作之前面临的众多挑战 以实现我们基于微生物组的精准医学的长期目标。

PROJECT SUMMARY – NO CHANGES FROM PARENT GRANT The human microbiome is an underappreciated contributor to drug disposition and treatment outcomes, supported by associations in human cohorts, controlled studies in preclinical models, and high-throughput in vitro screens. However, despite considerable recent progress in this emerging area of study there are still major gaps in knowledge regarding the fundamental mechanisms through which human gut microbes impact pharmacology. Research in the Turnbaugh lab over the past 5 years (supported by 1R01HL122593-01A1) was focused on understanding the role of the prevalent human gut Actinobacterium Eggerthella lenta in drug metabolism and disposition. While we began by focusing on the gut bacterial inactivation of the cardiac drug digoxin, used to treat heart failure and cardiac arrythmias, our results together with the broader scientific literature have further implicated E. lenta as a key bacterial species for the metabolism of diverse drugs, dietary small molecules, and host metabolites. We established a robust comparative genomics toolkit for studying E. lenta that could be readily extended to other genetically intractable gut bacterial species. In the coming years we will continue to leverage E. lenta as a test case, with a focus on two general challenges at the interface of microbiome research and pharmacology. In Aim 1, we will study the endogenous substrates for gut bacterial enzymes involved in drug metabolism, building on the surprising observation that the same enzyme responsible for digoxin metabolism is also necessary and sufficient to activate pro-inflammatory Th17 cells in the murine gut, exacerbating mouse models of colitis. Then, in Aim 2, we will determine the mechanism through which E. lenta inhibits the activity of the key intestinal drug efflux transporter P-glycoprotein, providing the first step towards a more comprehensive view of the role of the microbiome in drug disposition that accounts for microbiome-dependent changes in absorption, distribution, metabolism, and elimination. Together, these studies emphasize the utility and feasibility of hypothesis-driven mechanistic studies, meant to complement the wealth of data from large-scale clinical cohort studies and high-throughput screens. Our results have already provided multiple insights that both inform and complicate our model of how the microbiome impacts drugs, emphasizing the numerous challenges that lie ahead prior to translating this work to achieve our long-term goal of microbiome-based precision medicine.