Predicting and preventing drug metabolism by the human gut microbiome

预测和预防人类肠道微生物组的药物代谢

基本信息

批准号：
10294892
负责人：
Peter James Turnbaugh
金额：
$ 65.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10294892
关键词：
ABCB1 gene Abbreviations Actinobacteria class Address Analytical Chemistry Area Arginine Bile Acids Biochemical Biochemistry Biological Availability Cardiac Cardiac Glycosides Cells Cellular Assay Clinical Cohort Studies Colitis Complement Complex Controlled Study Coupled Development Diagnostic tests Diet Digoxin Disease Dopamine Drug Efflux Drug Kinetics Drug Prescriptions Economics Environmental Risk Factor Enzymatic Biochemistry Enzymes Fractionation Future Genes Genetic Genomics Germ-Free Gnotobiotic Goals Health Health Care Costs Heart Diseases Heart failure Human Human Microbiome In Vitro Inflammatory Interdisciplinary Study Intestines Knockout Mice Knowledge Literature Liver Measures Medicine Metabolism Methods Modeling Mus Operon Oral Outcome Oxidoreductase Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Population Positioning Attribute Pre-Clinical Model Proteins Research Role Severities Shapes Testing Translating Treatment outcome Variant Work World Health Organization absorption base cohort comparative genomics dietary dietary supplements drug disposition drug metabolism gut bacteria gut microbes gut microbiome high throughput screening human disease immunoregulation in vitro Assay inhibitor/antagonist insight interdisciplinary approach interest intestinal epithelium large scale data metabolomics microbial microbiome microbiome research mouse model pharmacokinetic model polyphenol precision medicine prevent programs small molecule steroid hormone treatment optimization

项目摘要

PROJECT SUMMARY 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.

项目概要人类微生物组对药物处置和治疗结果的贡献被低估了，得到人类队列协会、临床前模型对照研究以及高通量研究的支持体外筛选。然而，尽管这一新兴研究领域最近取得了相当大的进展，但仍然存在一些问题。关于人类肠道微生物影响的基本机制的知识存在重大差距药理。 Turnbaugh 实验室过去 5 年的研究（由 1R01HL122593-01A1 支持）专注于了解人类肠道中普遍存在的缓慢埃格特菌放线菌在药物中的作用新陈代谢和处置。虽然我们首先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结果一起文献进一步表明 E. lenta 是多种药物代谢的关键细菌物种，膳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 E. lenta 可以很容易地扩展到其他遗传上难以控制的肠道细菌物种。在未来几年，我们将继续利用 E. lenta 作为测试用例，重点关注两个普遍挑战微生物组研究和药理学的界面。在目标 1 中，我们将研究肠道的内源性底物细菌酶参与药物代谢，基于令人惊讶的观察，即相同的酶负责地高辛代谢的物质对于激活促炎性 Th17 细胞也是必要且充分的。小鼠肠道，加剧小鼠结肠炎模型。然后，在目标 2 中，我们将确定机制 E. lenta 通过它抑制关键肠道药物流出转运蛋白 P-糖蛋白的活性，提供更全面地了解微生物组在药物处置中的作用的第一步解释微生物组依赖性吸收、分布、代谢和消除的变化。一起，这些研究强调了假设驱动的机制研究的实用性和可行性，旨在补充来自大规模临床队列研究和高通量筛选的丰富数据。我们的结果已经提供了多种见解，这些见解既为我们的模型提供了信息，又使其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实现我们基于微生物组的精准医学的长期目标。