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: 10616518
• 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/10616518
• 关键词: Acute; Antineoplastic Agents; Beta-glucuronidase; Biological Models; Chemicals; Data; Diarrhea; Diclofenac; Dose Limiting; Drug Controls; 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; Life; Link; Liver; Mediating; Metabolic; Metagenomics; Mus; Non-Steroidal Anti-Inflammatory Agents; Patients; Perforation; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Process; Proteins; Proteomics; Role; Sampling; Small Intestines; Structure; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment-related toxicity; Ulcer; Work; Xenobiotics; anti-cancer; 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.

项目概要 药物代谢中涉及的人为因素已广为人知，但发挥作用的微生物酶 这一过程中的重要作用在很大程度上仍不为人所知。在这里，我们寻求通过以下方式填补这一知识空白： 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 通过人类 II 期药物代谢 UDP- 放置在多种药物和异生素上的部分 肝脏和其他关键代谢组织中的葡萄糖醛酸基转移酶蛋白。葡萄糖醛酸苷的结合 外源性生物素或药物几乎总是使其失活，并且经常将其标记为通过 胃肠 (GI) 道。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 肠；因此，它们是重要的药物代谢酶。药物葡萄糖醛酸苷的再激活 已知肠道会引起治疗药物的剂量限制性胃肠道毒性，并被怀疑会产生间 药物反应的个体差异。在过去的几年里，我的团队已经开始揭示多样性， 肠道微生物 GUS 酶的功能和结构，并开发了初步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 到达肠道的异生素和药物葡萄糖苷酸。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。 每一种都通过葡萄糖醛酸化作用灭活并被送到胃肠道排泄，每一种在体内重新激活 胃肠道内腔受到肠道微生物 GUS 酶的影响，每种重新激活的药物都会导致肠道剂量限制 毒性。重要的是，我们开发了针对微生物组的抑制剂，可以减少但不能消除 这些药物的肠道毒性。要实现这一新产品的潜在前景，还有相当多的工作要做 通过针对肠道微生物组来改善人类健康的方法。为了使我们在这些方面取得成功 经过努力，我们开发了一种新的基于活性的探针蛋白质组学管道来识别肠道微生物 GUS 酶存在于小鼠和人类粪便中。我们将使用这项新技术来了解 蛋白质水平 GUS 酶在药物治疗或靶向抑制后如何变化。我们的首要任务 假设肠道微生物 GUS 酶重新激活一系列结构不同的药物葡萄糖苷酸 结合物并引起胃肠道毒性，并且可以抑制这些蛋白质以防止肠道损伤。我们将 通过完成三个重点体外、蛋白质组学和体内目标来检验这一假设。综合起来， 我们收集的数据将显着扩大我们对肠道微生物群药物代谢的理解，并将 可能会产生改善人类健康的新疗法。