Microbiota Outgrowth by Salmonella

描述（由申请人提供）：肠炎沙门氏菌血清型鼠伤寒沙门氏菌（S. Typhimurium）引起肠胃炎，是一种以急性肠道炎症为特征的腹泻性疾病。病原体利用其毒力因子侵入肠上皮并在组织巨噬细胞中存活，从而引发炎症。炎症伴随着腔内环境的变化，这使鼠伤寒沙门氏菌和常驻微生物群之间的竞争平衡向有利于病原体的方向倾斜。哪些机制导致微生物群组成的这些变化的问题代表了一个将在本应用中解决的高影响主题。我们的中心假设是炎症产生一种新的呼吸电子受体四硫酸盐，通过使病原体利用不能在肠道厌氧环境中发酵进一步分解的化合物来促进鼠伤寒沙门氏菌的腔内生长。我们将通过确定去除硫化物是否可以阻止肠道中的四硫酸盐呼吸（目的1），发炎肠道生长过程中能量导向的作用（目的2）以及鼠伤寒沙门氏菌是否在炎症期间利用特定的营养物质（目的3）来测试我们假设的不同方面。拟议的研究将通过提供对控制病原体，宿主及其微生物群之间平衡的分子机制的重要新见解（目标2和3）以及通过科学促进新的干预策略的发展（目标1），将胃肠炎的知识推向更高的水平。因此，预期拟议工作所产生的概念进展将对实地产生强有力和持续的影响。

DESCRIPTION (provided by applicant): Salmonella enterica serotype Typhimurium (S. typhimurium) causes gastroenteritis, a diarrheal illness characterized by acute intestinal inflammation. The pathogen triggers inflammation by using its virulence factors to invade the intestinal epithelium and survive in tissue macrophages. Inflammation is accompanied by changes in the luminal environment, which tip the balance in the competition between S. typhimurium and the resident microbiota in favor of the pathogen. The question of which mechanisms are responsible for these changes in the microbiota composition represents a high-impact topic that will be addressed in this application. Our central hypothesis is that inflammation generates a new respiratory electron acceptor, tetrathionate, which promotes a luminal outgrowth of S. typhimurium by enabling the pathogen to utilize compounds that cannot be further broken down by fermentation in the anaerobic environment of the gut. We will test different aspects of our hypothesis by determining whether removal of sulfide can prevent tetrathionate respiration in the gut (Aim 1), the role of energy taxis during growth in the inflamed gut (Aim 2) and whether S. typhimurium utilizes specific nutrients during inflammation (Aim 3). The proposed research will drive knowledge about gastroenteritis to a higher level by providing critical new insights into molecular mechanisms that control the balance between the pathogen, the host and its microbiota (Aims 2 and 3) and by facilitating the development of new intervention strategies through science (Aim 1). The conceptual advances resulting from the proposed work are thus expected to have a strong and sustained influence on the field.