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：
9233197
负责人：
Peter James Turnbaugh
金额：
$ 39.24万
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 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233197
关键词：
Actinobacteria class Adverse effects Amino Acids Antibiotics Area Arginine Arrhythmia Bacteria Biological Biological Availability Blood Circulation Cardiac Cardiac Glycosides Chronic Disease Communities Consumption Cytochromes Data Set Dependence Diagnostic tests Diet Dietary Proteins Dietary intake Digoxin Drug Prescriptions Drug usage Ecology Economics Environmental Risk Factor Enzymes Genetic Transcription Genetic Variation Genome Genomics Germ-Free Goals Growth Health Care Costs Heart Diseases Heart failure Human Human Genome Human body Individual Individual Differences Inflammatory Bowel Diseases Intestines Knowledge Link Liver Malignant Neoplasms Metabolic Metabolism Microbe Minor Modeling Modern Medicine Monitor Mus Operon Oral Outcome Oxidoreductase Patients Pattern Persons Pharmaceutical Preparations Pharmacology Pharmacotherapy Population Population Heterogeneity Publishing Reaction Risk Role Science Serum Shapes Structure Testing Therapeutic Time Transcriptional Regulation Translating Treatment outcome Variant Vitamins base clinically relevant drug efficacy drug metabolism genomic variation gut microbiome human subject improved insight microbial microbial community microbiome microorganism nutrition nutritional guideline precision medicine prevent protein intake public health relevance tool transcription factor treatment response virtual

项目摘要

DESCRIPTION (provided by applicant): 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 dru 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.

描述（由申请人提供）：现代医学最重要的限制之一是患者对治疗的反应存在显着且常常不可预测的差异，现已明确人类基因组的变异，特别是所表达的酶和转运蛋白。但这些研究忽略了我们“第二基因组”中的遗传变异。迄今为止，研究表明肠道微生物组可以代谢超过 40 种药物，涵盖许多最棘手的慢性疾病：癌症、心脏病和糖尿病。然而，由于缺乏对相关微生物酶以及饮食摄入等环境因素如何影响其活性的了解，这些发现的转化进展甚微。选择专注于治疗心力衰竭和心律不齐的心脏药物地高辛是一个理想的测试案例，原因有多种：(i) 由肠道细菌独特催化的单一反应使药物失活；(ii) 药物发生微小变化。由于其治疗范围较窄，药物水平具有临床相关性；(iii) 迟缓艾格氏菌是唯一已被证明能催化这种反应的肠道细菌。最近发现了负责地高辛还原的细菌酶（Haiser 等人，《科学》 (2013)，为肠道微生物组的个体间差异如何导致药物水平的变化提供了第一个机制解释，我们的初步结果表明，有两个因素在控制肠道细菌对地高辛的灭活方面很重要：菌株水平的变化。我们将系统地剖析这两个因素，确定它们如何以及为何影响药物水平。这些研究将为研究不足但与临床相关的细菌物种提供基本的生物学见解，同时朝着研究方向迈进。我们的长期目标是通过将基于微生物组的诊断测试和营养指南相结合来优化治疗结果。