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.

项目总结 参与药物新陈代谢的人类因素是众所周知的，但发挥作用的微生物酶 这一进程中的重要作用在很大程度上仍未确定。在这里，我们试图通过以下方式来填补这一知识空白 重点研究肠道微生物的β-葡萄糖醛酸苷酶(GUS)蛋白。GUS酶去除葡萄糖醛酸 人类第二相药物代谢UDP的部分被放置在广泛的药物和外源物质上 肝脏和其他关键代谢组织中的葡萄糖醛酸基转移酶蛋白质。葡萄糖醛酸苷的偶联反应 异物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，并重新激活药物在 肠道；因此，它们是重要的药物代谢酶。药物-葡萄糖醛酸苷在血管内皮细胞的重新激活 已知肠道会引起治疗药物的剂量限制的胃肠道毒性，并被怀疑会产生 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， 肠道微生物GUS酶的功能和结构，并已开发出最初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 异源生物--和药物--到达肠道的葡萄糖醛酸苷。这项提案集中在三种药物上：抗癌 化疗药物伊立替康和两种非类固醇抗炎药双氯芬酸和消炎痛。 每一种都被葡萄糖醛酸化作用灭活并被送到胃肠道排泄，每一种都在 肠道微生物GUS酶对胃肠道管腔的影响，每种重新激活的药物都会引起剂量限制的肠道 毒物。重要的是，我们已经开发了针对微生物组的抑制剂，可以减少但不会消除 这些药物的肠道毒性。要实现这一新的潜在前景，还有相当多的工作要做 通过针对肠道微生物群来改善人类健康的方法。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使能蛋白质组学管道来鉴定肠道微生物 GUS酶存在于老鼠和人类的排泄物中。我们将使用这项新技术在 在药物治疗或靶向抑制时GUS酶如何变化的蛋白质水平。我们最重要的是 假说是肠道微生物GUS酶重新激活一系列结构不同的药物葡萄糖醛酸苷 结合物和引起胃肠道毒性，这些蛋白质可以被抑制以防止肠道损伤。我们会 通过完成三个专注于体外、蛋白质组学和体内的目标来检验这一假设。总而言之， 我们收集的数据将极大地扩展我们对肠道微生物区系对药物代谢的理解，并将 可能会导致新的治疗方法来改善人类健康。