Microbiota outgrowth by Salmonella

摘要 我们的肠道是一个复杂的微生物群落的宿主，肠道微生物区系占主导地位 属于梭状芽胞杆菌和杆菌纲的专性厌氧细菌。这 社区通过营养、免疫教育和利基为宿主提供好处 对肠道病原体的保护(抗定植)。然而，肠沙门氏菌 Serovar(S.)鼠伤寒沙门氏菌可以利用其毒力因子通过 引发肠道炎症。宿主炎症反应重塑肠道 环境，这促进了病原体的生长，但也导致了微生物区系的不平衡 (生态失调)。肠道炎症如何驱动微生物区系变化的问题 构成以及这些变化如何影响寄主生理和病原体扩张代表 这是一个影响很大的主题，将在本申请中解决。此应用程序的目标是 研究使病原体获得竞争优势的机制 肠道炎症过程中的肠杆菌感染。我们的中心假设是鼠伤寒沙门氏菌 毒力因子触发宿主反应，重塑肠道环境以产生 在推动病原体增长的同时使其能够在竞争中脱颖而出的资源 肠杆菌属。为了检验这一假设，我们将在特定目标1中确定S。 小鼠从肠道炎症中受益，因为这种宿主反应增加了 多元醇的可得性。在特定目标2中，我们将确定鼠伤寒沙门氏菌是否消耗a 神经递质与肠杆菌竞争铁。最后，我们的第三个具体目标将 确定鼠伤寒沙门氏菌的硫化物生产是否在竞争中提供好处 内源性肠杆菌。我们期望这项工程能顺利完成 拟议的实验将带来重要的概念上的进展，理解 鼠伤寒沙门氏菌引起胃肠炎时病原体扩张的机制。

ABSTRACT 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. This community provides benefit to the host by contributing to nutrition, immune education and niche protection against enteric pathogens (colonization resistance). However, Salmonella enterica serovar (S.) Typhimurium can use its virulence factors to overcome colonization resistance by triggering intestinal inflammation. The host inflammatory response remodels the intestinal environment, which fuels growth of the pathogen, but also causes an imbalance in the microbiota (dysbiosis). The question of how intestinal inflammation drives changes in the microbiota composition and how these changes affect host physiology and pathogen expansion represents a high-impact topic that will be addressed in this application. The objectives of this application are to study the mechanisms that enable the pathogen to gain an edge over competing Enterobacterales during intestinal inflammation. Our central hypothesis is that S. Typhimurium virulence factors trigger host responses that remodel the intestinal environment to generate resources that fuel pathogen growth while at the same time enabling it to edge out competing Enterobacterales. To test this hypothesis, we will determine in Specific Aim 1 whether S. Typhimurium benefits from intestinal inflammation because this host response increases the availability of polyols. In Specific Aim 2 we will determine whether S. Typhimurium depletes a neurotransmitter to compete with Enterobacterales for iron. Finally, our third specific aim will determine whether sulfide production by S. Typhimurium provides a benefit during competition with endogenous Enterobacterales. 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.