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

• 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
• 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

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 参与药物代谢的人为因素已经很好地理解了，但是起作用的微生物酶 在这一进程中的重要作用基本上仍不明确。在这里，我们试图填补这一知识空白， 专注于肠道微生物β-葡萄糖醛酸酶（GUS）蛋白。GUS酶去除葡萄糖醛酸 通过人II期药物代谢UDP-1而被置于广泛的药物和外源性物质上的部分。 葡萄糖醛酸转移酶蛋白在肝脏和其他关键代谢组织。葡糖苷酸的结合 外源性物质或药物几乎总是使其失活，并经常通过 胃肠道（GI）。肠道微生物GUS酶可以逆转这一过程，并重新激活体内的药物。 因此，它们是重要的药物代谢酶。药物-葡萄糖醛酸苷在肝细胞中的再活化 已知肠引起治疗剂的剂量限制性GI毒性，并怀疑产生肠间 药物反应的个体差异。在过去的几年里，我的团队已经开始解开多样性， 功能和结构的肠道微生物GUS酶，并已开发出初始的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响应免疫应答中的关键作用。 外源性和药物性葡糖苷酸到达肠道。该提案重点关注三种药物： 化疗药物伊立替康和两种非甾体抗炎药双氯芬酸和吲哚美辛。 每一种都被葡萄糖醛酸化灭活，并被送到胃肠道排泄，每一种都在胃肠道内被重新激活。 肠道微生物GUS酶对胃肠道管腔的破坏，并且每种重新激活的药物都会导致剂量限制性肠道 毒性重要的是，我们已经开发了微生物组靶向抑制剂，可以减少，但不能消除， 这些药物的毒性。要实现这一新的承诺，还有相当多的工作要做。 通过靶向肠道微生物组改善人类健康的方法。为了使我们在这些领域取得成功， 通过努力，我们开发了一种新的基于活性的探针蛋白质组学管道，以识别肠道微生物 存在于小鼠和人类粪便材料中的GUS酶。我们将利用这项新技术来了解 GUS酶在药物处理或靶向抑制后的蛋白质水平变化。我们的总体 假设是肠道微生物GUS酶重新激活一系列结构不同药物葡糖苷酸 这些蛋白质可结合并引起GI毒性，并且这些蛋白质可被抑制以防止肠损伤。我们将 通过完成三个重点体外、蛋白质组学和体内目标来验证这一假设。总的来说， 我们收集的数据将大大扩展我们对肠道微生物群药物代谢的理解， 可能导致新的治疗方法来改善人类健康。