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：
10461860
负责人：
Peter James Turnbaugh
金额：
$ 65万
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/10461860
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 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 insight interdisciplinary approach interest intestinal epithelium large scale data metabolomics microbial microbiome microbiome research mouse model murine colitis 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.

项目摘要人类微生物组是药物处置和治疗结果的不足的贡献，在人类人群中的协会，临床前模型中的对照研究和高通量的支持下体外屏幕。但是，尽管最近在这一新兴领域取得了很大进展，但仍有关于人类肠道微生物影响的基本机制知识的主要差距药理。在过去5年中，Turnbaugh实验室的研究（由1R01HL122593-01A1支持）专注于了解普遍的人肠肠杆菌在药物中的作用代谢和性格。当我们开始专注于心脏药物的肠道细菌失活地高辛，用于治疗心力衰竭和心脏芳烃，我们的结果与更广泛的科学文献进一步牵涉到伦塔（E. lenta）作为多种药物代谢的关键细菌物种，膳食小分子和宿主代谢产物。我们建立了一个可靠的比较基因组学工具包研究Lenta，可以很容易地扩展到其他遗传上棘手的肠道细菌。在未来几年，我们将继续利用E. Lenta作为测试案例，重点是在微生物组研究与药理学的界面。在AIM 1中，我们将研究肠内的内源性底物与药物代谢有关的细菌酶，基于令人惊讶的观察结果，即相同的酶负责地高辛代谢也足以激活促炎性Th17细胞鼠肠，加剧结肠炎的小鼠模型。然后，在AIM 2中，我们将确定机制 E. lenta抑制关键肠道药物外排运动蛋白p-糖蛋白的活性对微生物组在药物处置中的作用进行更全面看法的第一步占微生物组的吸收，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理研究的效用和可行性，该研究旨在补充来自大型临床队列研究和高通量屏幕的大量数据。我们的结果已经提供了多种见解，这些见解都使我们的模型了解并使我们的模型变得复杂微生物组会影响药物，强调翻译这项工作之前面临的众多挑战为了实现我们基于微生物组的精确药物的长期目标。