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（由应用提供）：现代医学的最重要局限性之一是患者对治疗的反应时之间的实质且通常是不可预测的。现在已经很好地确定，人类基因组的变异，尤其是在肠道和肝脏中表达的酶和转运蛋白，对循环中药物水平有重大影响。但是这些研究忽略了我们的“第二个基因组”的遗传变异 - 在人体和人体上繁衍生息的微生物（微生物组）的数万亿微生物中。迄今为止，研究表明，跨越许多最棘手的慢性疾病的肠道微生物组可以代谢40种药物：癌症，心脏病和炎症性肠病。然而，由于对负责的微生物酶以及饮食摄入等环境因素如何影响其活性的环境因素如何，取得了很少的进展来翻译这些发现。作为初始证明，我们选择专注于心力衰竭和不规则心跳的心脏DRU地高辛。地高辛是理想的测试案例，原因有多种：（i）单一反应，由肠道细菌独特地催化，使药物失活；（ii）由于其狭窄的治疗范围，对药物水平的微小变化在临床上是相关的；（iii）eggerthella lenta是唯一已证明可以催化这种反应的肠道细菌。我们最近确定了导致地高辛还原的细菌酶（Haiser等，科学， 2013年），为肠道微生物组的个体间差异如何促进药物水平的差异提供了第一个机械解释。我们的初步结果表明，两个因素在控制肠道细菌对地高辛的失活的两个因素中很重要：伦塔大肠杆菌种群的应变水平变化和宿主饮食摄入。我们将系统地剖析这两个因素，确定它们如何以及为什么影响药物水平。这些研究将提供基本的生物学见解，以对研究不足但临床上的细菌物种进行，同时通过配对基于微生物组的诊断测试和营养准则，朝着我们的长期目标迈向优化治疗结果。