Repurposing misoprostol for Clostridium difficile colitis as identified by PheWAS

项目总结： 艰难梭菌感染(CDI)是一种主要的医院感染，也是引起肺炎的主要原因。 抗生素相关性腹泻。它可能导致多次CDI复发、败血症、中毒性巨结肠和死亡。 复发的CDI会使20%的初始疾病发作复杂化，并与增加 死亡和低劣的生活质量。虽然益生菌或粪便移植在 打破重复的CDI循环，仍然需要简单、安全和经济有效的解决方案来解决这个问题 有问题。 前列腺素(PGs)是一种脂分子，与健康和疾病的许多方面有关。篮球队， 尤其是PGE2分子，对胃肠道健康和阻断其活性的药物都很重要。 合成，被称为非类固醇抗炎药(NSAIDs)，可导致胃肠道问题，如 作为胃溃疡。事实上，米索前列醇是一种前列腺素E类似物，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布的计算算法来执行 基于ICD-9计费代码数据的表型组范围关联研究(Phewas) 约40,000名患者，以确定与基因序列变异相关的潜在新的基因-表型关联 米索前列醇靶标基因(PGE2受体)。这一分析预测了一个可能的新迹象 米索前列醇用于治疗(或预防)艰难梭菌结肠炎。鉴于新出现的流行病学数据表明非甾体抗炎药 使用CDI增加了CDI的风险，我们在小鼠CDI模型中的新初步数据显示，暴露于 非甾体抗炎药加重CDI严重程度而米索前列醇减轻疾病，我们假设米索前列醇可以 用于预防艰难梭状芽胞杆菌结肠炎复发。 我们设想了一项使用米索前列醇预防CDI复发的临床研究，但没有得到回应 在任何这样的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。 药物的作用。因此，我们提出了两个目标：(1)确定口服的最佳剂量和时间 米索前列醇在复发性CDI小鼠模型中的作用和(2)确定米索前列醇对CDI的保护作用的相关性 复发性CDI小鼠模型的建立。这些研究将检查米索前列醇对已知的 控制对CDI的敏感性，包括肠道微生物组和代谢组的变化，组织炎症， 结肠炎生物标志物的产生。 这些研究是迈向CDI治疗和/或临床研究的关键的第一步 利用PGE2对结肠健康的有益影响进行预防。这些项目的顺利完成 研究将对CDI的新临床研究产生直接影响，并可能为更多的理论基础提供证据 非甾体抗炎药或前列腺素类似物在CDI高危患者中的应用。

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.