The role of the Western diet in increasing severity of Clostridium difficile infection

项目摘要 饮食是微生物区系组成和功能的关键调节器。西式饮食， 它富含脂肪和简单的宿主可获得的糖，被用来模拟饮食诱导的肥胖。许多 研究表明，西方饮食会改变微生物区系和免疫系统的组成。 艰难梭状芽胞杆菌是感染性医院腹泻的主要原因。主要风险因素 艰难梭菌感染(CDI)包括抗生素暴露、年龄和质子泵抑制剂的使用，最近 数据还表明肥胖是一个风险因素。决定急性CDI预后的宿主因素包括肠道 微生物区系和免疫反应。我们实验室最近的研究表明，抗生素诱导的变化 肠道微生物区系导致2型免疫力下降，这是由于上皮细胞的IL-25和IL-33减少所致。 在这项提案中，我们将探讨西方饮食如何改变微生物区系和免疫系统的组成 系统，以增加对CDI的敏感性。我发现西式饮食会增加CDI的严重程度。 此外，我发现IL-33是一种2型免疫协调器，在野生动物的肠道中受到抑制。 类型的小鼠喂食西方饮食，同时Ly6G+中性粒细胞水平增加。另外，我发现 从喂食对照饮食的小鼠身上转移微生物区系可以保护西方饮食的小鼠免受严重疾病的侵袭。 这些数据表明：i)高脂肪和简单碳水化合物的饮食改变了微生物区系 导致(Ii)免疫稳态和肠道代谢的改变(Iii)导致CDI的严重程度增加。 这一假设将通过一系列综合的具体目标来检验。具体目标1：确定 西式饮食通过改变结肠免疫功能增加CDI的严重程度。具体目标2：确定 可保护暴露于镉微生物区系的WD喂养小鼠免受严重CDI的代谢物和微生物。 成功完成这项研究将确定高脂肪饮食成分对肠道的影响 微生物组和粘膜免疫反应，特别是其下游对CDI的影响 敏感度。

Project Summary Diet is critical modulator of both the composition and function of the microbiota. The Western diet, which is high in both fat and simple host-accessible sugars is used to model diet-induced obesity. Many studies have shown that the Western diet alters the composition of the microbiota and the immune system. Clostridioides (Clostridium) difficile is the leading cause of infectious nosocomial diarrhea. Primary risk factors for C. difficile infection (CDI) include antibiotic exposure, age, and proton pump inhibitor use, with more recent data also implicating obesity as a risk factor. Host factors determining the outcome of acute CDI include the gut microbiota and immune response. Recent work from our lab demonstrated that antibiotic-induced changes to the gut microbiota results in decreased type 2 immunity due to decreased epithelial ‘alarmins’ IL-25 and IL-33. In this proposal will explore how the Western diet alters the composition of the microbiota and the immune system to increase susceptibility to CDI. I have discovered that a Western diet increases severity of CDI. Additionally, I found that IL-33, which is an orchestrator of type 2 immunity, is suppressed in the gut of wild- type mice fed a Western diet while levels of Ly6G+ neutrophils are increased. Additionally, I found that transfer of microbiota from mice fed a control diet protects mice on the Western diet from severe disease. Together these data suggest that i) a diet high in dietary fats and simple carbohydrates alters the microbiota leading to (ii) alterations in immune homeostasis and gut metabolism (iii) resulting in increased severity of CDI. This hypothesis will be tested through a series of integrated specific aims. Specific aim 1: determine if the Western diet increases severity of CDI via alteration of colonic immunity. Specific aim 2: identify the metabolites and microbes which protect from severe CDI in WD-fed mice exposed to CD-microbiota. Successful completion of this fellowship will determine the impact of high-fat dietary components on the gut microbiome and mucosal immune response, specifically in their downstream ramifications for CDI susceptibility.