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

• 批准号: 10668579
• 负责人: Peter James Turnbaugh
• 金额: $ 7.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10668579
• 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

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一个未被充分认识的贡献者， 在人类队列中的相关性、临床前模型中的对照研究以及高通量的 体外筛选。然而，尽管最近在这一新兴研究领域取得了相当大的进展， 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 药理学Turnbaugh实验室过去5年的研究（由1 R 01 HL 122593 - 01 A1支持） 专注于了解流行的人类肠道放线杆菌Eggerthella lenta在药物中的作用， 代谢和处置。当我们开始关注心脏药物的肠道细菌灭活时， 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研究一起， 文献进一步暗示E.作为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E. Lenta可以很容易地扩展到其他遗传上难以处理的肠道细菌物种。在 在未来的几年里，我们将继续利用E。lenta作为一个测试案例，重点是两个一般性的挑战， 微生物组研究和药理学的接口。在目标1中，我们将研究肠道的内源性底物， 参与药物代谢的细菌酶，建立在令人惊讶的观察基础上， 负责地高辛代谢也是必要的，足以激活促炎性Th 17细胞， 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抑制关键肠道药物外排转运蛋白P-糖蛋白的活性， 更全面地了解微生物组在药物处置中的作用的第一步， 解释了吸收、分布、代谢和消除中的微生物组依赖性变化。我们一起努力， 这些研究强调假设驱动的机制研究的实用性和可行性， 补充了来自大规模临床队列研究和高通量筛选的丰富数据。我们 研究结果已经提供了多种见解，既为我们的模型提供了信息，也使我们的模型复杂化， 微生物组影响药物，强调了在转化这项工作之前面临的众多挑战 来实现我们基于微生物组的精准医疗的长期目标。