Repurposing misoprostol for Clostridium difficile colitis as identified by PheWAS

PheWAS 确定米索前列醇重新用于治疗艰难梭菌结肠炎

• 批准号: 9336367
• 负责人: David M Aronoff
• 金额: $ 27.65万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336367
• 关键词: Address; Antibiotics; Arachidonic Acids; Bacteria; Binding; Biological Markers; Body Weight decreased; Cessation of life; Clinical Data; Clinical Research; Clinical Trials; Clostridium difficile; Code; Colitis; Colon; Communicable Diseases; Computational algorithm; Data; Data Set; Development; Diarrhea; Dinoprostone; Disease; Dose; Drug usage; Exposure to; FDA approved; Feces; Fever; Gastric ulcer; Gene Targeting; Generations; Genetic; Genotype; Goals; Health; Histologic; Hospitals; ICD-9; Infection; Inflammation; Lead; Link; Lipids; Misoprostol; Modeling; Mus; Non-Steroidal Anti-Inflammatory Agents; Nosocomial Infections; Oral Administration; Pain; Patient risk; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Predisposition; Prevention; Probiotics; Prostaglandin E Receptor; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Publishing; Quality of life; Recurrence; Relapse; Research; Risk; Running; Sepsis; Severities; Severity of illness; Synthetic Prostaglandins; Tissues; Toxic Megacolon; Toxin; Ulcer; Variant; analog; base; cohort; cost effective; eicosanoid metabolism; epidemiologic data; experimental study; fecal transplantation; gastrointestinal; gut microbiome; lipid mediator; metabolome; mouse model; novel; phenome; pre-clinical; preclinical study; prevent; receptor; success

PROJECT SUMMARY: Clostridium difficile infection (CDI) is a leading nosocomial infection and the primary identifiable cause of antibiotic-associated diarrhea. It can lead to multiple CDI recurrences, sepsis, toxic megacolon, and death. Recurrent CDI complicates 20% of primary episodes of disease and is associated with an increased risk of death and a poor quality of life. While probiotics or fecal transplantation have met with some success in breaking the cycle of recurrent CDI, there remains a need for simple, safe, and cost-effective solutions to this problem. Prostaglandins (PGs) are lipid molecules involved in many aspects of health and disease. The PGs, especially the molecule PGE2, are important to gastrointestinal health and medications that block their synthesis, known as nonsteroidal anti-inflammatory drugs (NSAIDs), can cause gastrointestinal problems such as stomach ulcers. In fact, misoprostol, a PGE analogue, is FDA approved to prevent ulcers in patients taking NSAIDs. We recently applied a published and publicly available computational algorithm to perform a phenome-wide association study (PheWAS) based on ICD-9 billing code data in a disease-agnostic cohort of ~40,000 patients to identify potential novel genotype-phenotype associations related to sequence variations in the genes for the targets of misoprostol (PGE2 receptors). This analysis predicted a possible new indication for misoprostol to treat (or prevent) C. difficile colitis. Given emerging epidemiological data suggesting that NSAID use increases the risk for CDI and our new preliminary data in a mouse CDI model showing that exposure to NSAIDs worsens CDI severity while misoprostol alleviates the disease, we hypothesize that misoprostol can be repurposed to prevent recurrent C. difficile colitis. We envision a clinical study using misoprostol to prevent recurrent CDI but there are unanswered questions that must be addressed before any such clinical trial. These relate particularly to the timing and dose of the drug. We therefore propose two Aims to (1) define the optimal dose and timing of administration of oral misoprostol in a mouse model of relapsing CDI and (2) determine the correlates of protection by misoprostol in a mouse model of relapsing CDI. These studies will examine the impact of misoprostol on factors known to govern susceptibility to CDI, including changes to the gut microbiome and metabolome, tissue inflammation, and the generation of biomarkers of colitis. These studies are a critical first step in moving toward clinical studies of CDI treatment and/or prevention that exploit the beneficial effects of PGE2 on colon health. The successful completion of these studies will have immediate impact on new clinical studies of CDI and may provide evidence for more rationale use of NSAIDs or prostaglandin analogues in high CDI-risk patients.

项目概要： 艰难梭菌感染 (CDI) 是一种主要的医院感染，也是导致该病的主要原因 抗生素相关性腹泻。它可导致多次 CDI 复发、败血症、中毒性巨结肠和死亡。 复发性 CDI 使 20% 的原发性疾病变得复杂，并且与以下风险增加相关： 死亡和生活质量差。虽然益生菌或粪便移植在以下方面取得了一些成功 打破复发性 CDI 的循环，仍然需要简单、安全且具有成本效益的解决方案 问题。 前列腺素 (PG) 是涉及健康和疾病许多方面的脂质分子。 PG们， 尤其是 PGE2 分子，对胃肠道健康非常重要，并且可以使用阻断其作用的药物 合成，称为非甾体抗炎药（NSAID），可引起胃肠道问题，例如 如胃溃疡。事实上，米索前列醇（一种 PGE 类似物）已被 FDA 批准用于预防服用药物的患者发生溃疡 非甾体抗炎药。我们最近应用了一种已发布且公开可用的计算算法来执行 基于 ICD-9 帐单代码数据的全表型关联研究 (PheWAS)，涉及疾病不可知队列 约 40,000 名患者识别与序列变异相关的潜在新型基因型-表型关联 米索前列醇靶标基因（PGE2 受体）。该分析预测了可能的新迹象 米索前列醇治疗（或预防）艰难梭菌结肠炎。鉴于新出现的流行病学数据表明 NSAID 使用会增加 CDI 的风险，我们在小鼠 CDI 模型中的新初步数据表明，接触 NSAIDs 会加重 CDI 的严重程度，而米索前列醇可缓解该疾病，我们假设米索前列醇可以 重新用于预防复发性艰难梭菌结肠炎。 我们设想进行一项使用米索前列醇预防复发性 CDI 的临床研究，但尚无答案 在任何此类临床试验之前必须解决的问题。这些特别与时间和剂量有关 的药物。因此，我们提出两个目标：（1）确定口服药物的最佳剂量和时间 (2) 确定米索前列醇在复发性 CDI 小鼠模型中的保护作用的相关性 复发性 CDI 小鼠模型。这些研究将探讨米索前列醇对已知因素的影响 控制对 CDI 的易感性，包括肠道微生物组和代谢组的变化、组织炎症、 以及结肠炎生物标志物的产生。 这些研究是迈向 CDI 治疗和/或临床研究的关键第一步 利用 PGE2 对结肠健康的有益作用进行预防。这些工作的顺利完成 研究将对 CDI 的新临床研究产生直接影响，并可能为更多理由提供证据 在高 CDI 风险患者中使用 NSAID 或前列腺素类似物。