Microbiota outgrowth by Salmonella

项目摘要 我们的肠道是一个复杂的微生物群落的宿主，肠道微生物群，由专性微生物占主导地位。 属于梭菌属和拟杆菌属的厌氧细菌。众所周知， 通过抗生素处理的肠道微生物群导致兼性厌氧肠杆菌科的扩增， 包括病原体，如沙门氏菌（Salmonella enterica serovar Typhimurium）（S.鼠伤寒沙门氏菌），然而， 基本的机制才刚刚开始研究。重要的是，目前还不知道S。 在不存在抗生素的情况下，鼠伤寒扩大和/或触发微生物群组成的变化 治疗我们的长期目标是阐明控制蛋白质之间平衡的分子机制。 病原体、宿主及其肠道微生物群。本申请的目的是研究 使病原体在肠道炎症期间获得对竞争细菌的优势。我们的中央 假设在没有抗生素治疗的情况下，S.鼠伤寒毒力因子触发宿主 导致肠道相关微生物中产生丁酸盐的梭菌耗尽的反应 群落，这反过来又增加了结肠细胞的氧合，从而驱动细胞色素bd-II氧化酶- 依赖病原体在肠腔中的扩张。我们将测试我们假设的不同方面， 使用以下概述的逻辑和创新方法来实现本申请的目标 具体目标：具体目标1：确定S。鼠伤寒沙门氏菌在结肠炎期间消耗梭菌。具体目标二： 确定梭菌消耗如何驱动S。结肠炎期间鼠伤寒杆菌的生长。具体目标3：确定 呼吸是否驱动S.鼠伤寒传播。我们期望， 拟议中的实验将在理解这些机制方面带来重要的概念性进展 潜在的病原体在S. Typhimurium引起的胃肠炎。这种范式转换工作将 因为它将在对微生物发病机理感兴趣的研究人员中具有广泛的吸引力， 宿主相关微生物群落对健康和疾病的贡献。

Project Summary Our intestine is host to a complex microbial community, the gut microbiota, which is dominated by obligate anaerobic bacteria belonging to the classes Clostridia and Bacteroidia. It is well established that a disruption of the gut microbiota by antibiotic treatment leads to an expansion of facultative anaerobic Enterobacteriaceae, including pathogens, such as Salmonella enterica serovar Typhimurium (S. Typhimurium), however, the underlying mechanisms are just beginning to be worked out. Importantly, it is not known whether S. Typhimurium expands and/or triggers changes in the microbiota composition in the absence of antibiotic treatment. Our long-range goal is to elucidate molecular mechanisms that control the balance between the pathogen, the host and its gut microbiota. The objectives of this application are to study the mechanisms that enable the pathogen to gain an edge over competing bacteria during intestinal inflammation. Our central hypothesis is that in the absence of antibiotic treatment, S. Typhimurium virulence factors trigger host responses that lead to a depletion of butyrate-producing Clostridia from the gut-associated microbial community, which in turn increases oxygenation of colonocytes, thereby driving a cytochrome bd-II oxidase- dependent pathogen expansion in the gut lumen. We will test different aspects of our hypothesis and accomplish the objectives of this application using the logical and innovative approach outlined in the following specific aims: Specific Aim 1: Determine how S. Typhimurium depletes Clostridia during colitis. Specific Aim 2: Determine how Clostridia depletion drives S. Typhimurium growth during colitis. Specific Aim 3: Determine whether respiration drives S. Typhimurium transmission. It is our expectation that successful completion of the proposed experiments will usher in important conceptual advances in understanding the mechanisms underlying pathogen expansion during S. Typhimurium-induced gastroenteritis. This paradigm-shifting work will be significant because it will have wide appeal among researchers interested in microbial pathogenesis and the contribution of host-associated microbial communities to health and disease.