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.

项目摘要众所周知，药物代谢所涉及的人为因素，但是发挥的微生物酶在此过程中的重要作用在很大程度上仍然没有特征。在这里，我们试图通过专注于肠道微生物β-葡萄糖醛酸酶（GUS）蛋白。 GUS酶去除葡萄糖酸由人类II期药物代谢UDP-放置在广泛的药物和异种生物上的部分肝和其他关键代谢组织中的葡萄糖醛酸转移酶蛋白。葡萄糖醛酸酯的结合对于异生元或药物，几乎总是会使它失活，并且经常将其标记为消除胃肠道（GI）。肠道微生物GUS酶可以扭转这一过程并重新激活药物肠；因此，它们是重要的药物代谢酶。在已知肠引起理论的剂量限制性GI毒性，并被怀疑会产生药物反应中的个体变异性。在过去的几年中，我的小组已经开始揭示多样性，肠道微生物GUS酶的功能和结构，并开发了初始微生物组靶向抑制剂。通过这些努力，我们开始阐明这些酶在回应该酶中所起的关键作用到达肠道的异生元和药物 - 葡萄糖醛酸苷。该提议重点介绍三种药物：抗癌化学治疗性虹膜素和两种非甾体类抗炎药，双氯芬酸和吲哚美辛。每个人都被谷化灭活并发送到胃肠道以进行排泄，每种都被重新激活肠道微生物GUS酶的胃肠道腔，每种重新激活的药物会导致剂量限制肠毒性。重要的是，我们开发了靶向微生物组的抑制剂，以减少但不会消除，这些药物的肠道毒性。还有更多的工作要实现这一新的潜在希望通过靶向肠道微生物组来改善人类健康的方法。为了使我们成功努力，我们开发了一种新的基于活动的探针蛋白质组学管道来识别肠道微生物小鼠和人类粪便中存在的GUS酶。我们将使用这种新颖的技术来理解蛋白质水平在药物治疗或靶向抑制后如何变化GUS酶。我们的总体假设是肠道微生物GUS酶重新激活一系列结构上不同的药物糖苷结合并引起胃肠道毒性，并且可以抑制这些蛋白质以防止肠道损伤。我们将通过完成三个重点在体外，蛋白质组学和体内目标来检验这一假设。总的来说，我们收集的数据将大大扩展我们对肠道菌群对药物代谢的理解，并将有可能导致新的治疗以改善人类健康。