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Understanding and Controlling Drug Metabolism by the Gut Microbiota to Improve Human Health

了解和控制肠道微生物群的药物代谢以改善人类健康

基本信息

批准号：
10401799
负责人：
Matthew R Redinbo
金额：
$ 30.47万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401799
关键词：
Acute Antineoplastic Agents Beta-glucuronidase Biological Models Chemicals Data Diarrhea Diclofenac Dose-Limiting Drug Targeting Drug Tolerance Drug toxicity Enzymes Excretory function Feces Gastrointestinal tract structure Generations Glucuronic Acids Glucuronidase Inhibitor Glucuronides Glucuronosyltransferase Goals Health Hemorrhage Human In Vitro Indomethacin Intestines Investigation Knowledge Lead Life Link Liver Mediating Metabolic Metagenomics Mus Non-Steroidal Anti-Inflammatory Agents Patients Perforation Pharmaceutical Preparations Pharmacotherapy Phase Play Process Proteins Proteomics Reactive Inhibition Role Sampling Small Intestines Structure Testing Therapeutic Tissues Toxic effect Treatment-related toxicity Ulcer Work Xenobiotics base drug efficacy drug metabolism gastrointestinal gut microbiome gut microbiota improved in vivo in vivo Model individual response inhibitor inter-individual variation irinotecan medication safety microbial microbiome mouse model new technology novel strategies novel therapeutic intervention novel therapeutics prevent response success sugar therapy outcome

项目摘要

PROJECT SUMMARY The human factors involved in drug metabolism are well understood, but the microbial enzymes that play important roles in this process remain largely uncharacterized. Here we seek to fill this knowledge gap by focusing on the gut microbial β-glucuronidase (GUS) proteins. GUS enzymes remove the glucuronic acid moiety that is placed on a wide range of drugs and xenobiotics by human phase II drug metabolizing UDP- glucuronosyltransferase proteins in the liver and other key metabolic tissues. The conjugation of a glucuronide to a xenobiotic or drug nearly always inactivates it and very often marks it for elimination via the gastrointestinal (GI) tract. Gut microbial GUS enzymes can reverse this process and reactivate drugs in the intestines; as such, they are important drug metabolism enzymes. The reactivation of drug-glucuronides in the intestines is known to cause the dose-limiting GI toxicity of therapeutics and is suspected to produce inter- individual variabilities in drug responses. In the last few years, my group has begun to unravel the diversity, function, and structure of gut microbial GUS enzymes and has developed initial microbiome-targeted inhibitors. Through these efforts, we are beginning to elucidate the crucial roles these enzymes play in responding to the xenobiotic- and drug-glucuronides that reach the gut. This proposal focuses on three drugs: the anticancer chemotherapeutic irinotecan and two non-steroidal anti-inflammatory drugs, diclofenac and indomethacin. Each is inactivated by glucuronidation and sent to the GI tract for excretion, each is reactivated within the lumen of the GI tract by gut microbial GUS enzymes, and each reactivated drug causes dose-limiting gut toxicities. Importantly, we have developed microbiome-targeted inhibitors that reduce, but do not eliminate, the gut toxicity of these drugs. Considerably more work remains to realize the potential promise of this new approach to improve human health through targeting the gut microbiome. To enable our success in these efforts, we have developed a new activity-based probe-enabled proteomics pipeline to identify the gut microbial GUS enzymes present in mouse and human fecal material. We will use this novel technology to understand at the protein level how GUS enzymes change upon drug treatment or targeted inhibition. Our overarching hypothesis is that gut microbial GUS enzymes reactivate a range of structurally distinct drug glucuronide conjugates and cause GI toxicity, and that these proteins can be inhibited to prevent intestinal damage. We will test this hypothesis by completing three focused in vitro, proteomics, and in vivo aims. Taken together, the data we collect will significantly expand our understanding of drug metabolism by the gut microbiota, and will potentially lead to novel therapeutics to improve human health.

项目总结