Repurposing misoprostol for Clostridium difficile colitis as identified by PheWAS

项目概要： 艰难梭菌感染（CDI）是一种主要的医院感染，并且是导致严重的呼吸道感染的主要可识别原因。 腹泻相关性腹泻。可导致多发性CDI复发、败血症、中毒性巨结肠和死亡。 复发性CDI使20%的原发性疾病发作复杂化，并且与以下风险增加相关： 死亡和低质量的生活。虽然益生菌或粪便移植在某些方面取得了一些成功， 为了打破CDI的循环，仍然需要简单、安全和具有成本效益的解决方案 问题. 前列腺素（PGs）是一种脂质分子，参与健康和疾病的许多方面。PG们， 特别是PGE 2分子，对胃肠道健康和阻断其功能的药物很重要。 非甾体类抗炎药（NSAIDs）可能导致胃肠道问题， 胃溃疡事实上，米索前列醇，一种PGE类似物，被FDA批准用于预防服用 非甾体抗炎药。我们最近应用了一种公开发表的计算算法来执行一个 一项基于ICD-9计费代码数据的全表型关联研究（PheWAS），在一个疾病不可知队列中， 约40，000例患者，以确定与序列变异相关的潜在新型基因型-表型关联， 米索前列醇的靶基因（PGE 2受体）。这项分析预测了一个可能的新迹象， 米索前列醇治疗（或预防）C.艰难性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显示， NSAID降低了CDI的严重程度，而米索前列醇降低了疾病的严重程度，我们假设米索前列醇可以 重新利用以防止复发C.艰难性结肠炎 我们设想了一项使用米索前列醇预防复发性CDI的临床研究， 这些问题必须在任何此类临床试验之前得到解决。这些特别涉及到时间和剂量 的药物。因此，我们提出两个目的：（1）确定口服给药的最佳剂量和时间 在复发性CDI的小鼠模型中测定米索前列醇和（2）测定米索前列醇的保护作用的相关性 复发性CDI的小鼠模型。这些研究将检查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/或治疗的临床研究的关键的第一步。 利用PGE 2对结肠健康的有益作用进行预防。成功完成这些 研究将对CDI的新临床研究产生直接影响，并可能为更多的合理性提供证据 在高CDI风险患者中使用NSAID或前列腺素类似物。

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.