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

西方饮食在增加艰难梭菌感染严重程度中的作用

• 批准号: 10601652
• 负责人: Jhansi Lakshmi Margaret Leslie
• 金额: $ 0.25万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601652
• 关键词: Acute; Address; Adoptive Transfer; Age; Antibiotic Resistance; Antibiotics; Antibodies; Bioinformatics; Carbohydrates; Centers for Disease Control and Prevention (U.S.); Clostridium difficile; Complex; Data; Diarrhea; Diet; Dietary Component; Dietary Fats; Disease; Environment; Environmental Risk Factor; Epithelial; Exposure to; Fatty acid glycerol esters; Fellowship; Genetic; Gut Mucosa; Homeostasis; Immune; Immune response; Immune system; Immunity; Immunology; Infection; Infectious colitis; Integration Host Factors; Leptin; Link; Mediating; Metabolic Pathway; Metabolism; Metagenomics; Microbe; Modeling; Mucosal Immune Responses; Mucositis; Mucous Membrane; Mus; Names; Neutrophil Infiltration; North America; Nosocomial Infections; Nutrient; Obesity; Outcome; Pathway interactions; Predisposition; Prevention approach; Proton Pump Inhibitors; Research; Risk Factors; Role; Sampling; Series; Severities; Severity of illness; Signal Transduction; Testing; Training; Wild Type Mouse; Work; adipokines; analysis pipeline; base; bioinformatics tool; cytokine; diet-induced obesity; dietary control; experimental study; gut microbiome; gut microbiota; innovation; investigator training; metabolomics; microbiome; microbiota; mouse model; neutrophil; prebiotics; response; sugar; western diet

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.

项目摘要 饮食是微生物群组成和功能的关键调节剂。西方饮食， 其脂肪和宿主可接近的单糖含量都很高，用于模拟饮食诱导的肥胖症。许多 研究表明，西方饮食改变了微生物群和免疫系统的组成。 艰难梭菌是医院感染性腹泻的主要原因。主要危险因素 梭艰难梭菌感染（CDI）包括抗生素暴露，年龄和质子泵抑制剂的使用，最近 数据也暗示肥胖是一个危险因素。决定急性CDI结局的宿主因素包括肠道 微生物群和免疫反应。我们实验室最近的工作表明， 肠道微生物群由于减少的上皮“alarmins”IL-25和IL-33而导致2型免疫力降低。 在这项提案中，将探讨西方饮食如何改变微生物群和免疫系统的组成。 系统增加对CDI的敏感性。我发现西方饮食会增加CDI的严重程度。 此外，我发现IL-33是2型免疫的协调者，在野生型小鼠的肠道中受到抑制。 型小鼠喂食西方饮食，同时Ly 6 G+嗜中性粒细胞的水平增加。另外，我发现， 来自喂食对照饮食的小鼠的微生物群的转移保护喂食西方饮食的小鼠免于严重疾病。 总之，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群 导致（ii）免疫稳态和肠道代谢的改变（iii）导致CDI严重程度增加。 这一假设将通过一系列综合的具体目标进行检验。具体目标1：确定 西方饮食通过改变结肠免疫增加CDI的严重程度。具体目标2：确定 在暴露于CD微生物群的WD喂养的小鼠中，这些代谢物和微生物保护免于严重的CDI。 成功完成这项奖学金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，特别是在其下游分支的CDI 易感性