Microbial ecology of the inflamed intestine

项目概要 沙门氏菌病是影响人类和农业的最重要的食源性疾病之一。沙门氏菌 肠菌会引起宿主肠道炎症，从而破坏正常的微生物群。沙门氏菌 然后依靠微生物群未消耗的营养物质而茁壮成长。沙门氏菌的营养来源包括1,2- 丙二醇，是微生物群的产物；乙醇胺，来自受损细胞； 葡萄糖二酸和半乳二酸，源自Nos2介导的葡萄糖和半乳糖氧化；和 果糖天冬酰胺 (F-Asn) 来自饮食。 F-Asn利用系统提供了 有趣的治疗目标，因为抑制 FraB 酶会通过代谢使细菌中毒 中间。我们的主要目标是使用系统级方法来确定主要营养源 随着时间的推移，沙门氏菌在发炎的肠道中利用并识别出竞争这些微生物的微生物 营养素。我们假设其中一些营养获取系统将为以下疾病提供治疗靶点： 沙门氏菌和潜在的其他肠杆菌科细菌，包括耐碳青霉烯类肠杆菌科细菌 (CRE) 被 CDC 报告列为“紧急”威胁，“美国的抗生素耐药性威胁” 国”。在其他情况下，我们假设竞争微生物可以用作益生菌或 所利用的营养素可用作益生元。我们建议实现我们的目标并检验我们的假设 具有以下两个目标：1）确定沙门氏菌介导的化学和生物指标 随着时间的推移出现炎症； 2）表征沙门氏菌与其竞争者之间的代谢交换 肠道。这些目标的实现将极大地扩展我们对微生物生态学的理解。 沙门氏菌病，可能与其他病原体或相关炎症性疾病广泛相关。

Project Summary Salmonellosis is one of the most significant food-borne diseases affecting humans and agriculture. Salmonella enterica induces inflammation of the host intestinal tract, which disrupts the normal microbiota. Salmonella then thrives on the nutrients that are not consumed by the microbiota. Salmonella nutrient sources include 1,2- propanediol, which is a product of the microbiota; ethanolamine, which is derived from damaged cells; glucarate and galactarate which are derived from Nos2-mediated oxidation of glucose and galactose; and fructose-asparagine (F-Asn) which is derived from the diet. The F-Asn utilization system provides an interesting therapeutic target as inhibition of the FraB enzyme intoxicates the bacterium with a metabolic intermediate. Our primary objectives are to use a systems-level approach to identify the major nutrient sources utilized by Salmonella over time in the inflamed gut and to identify the microbes that compete for those nutrients. We hypothesize that some of these nutrient acquisition systems will provide therapeutic targets for Salmonella and potentially other Enterobacteriaceae, including the carbapenem-resistant Enterobacteriaceae (CRE) that are classified as an “urgent” threat by the CDC report, “Antibiotic resistance threats in the United States”. In other cases, we hypothesize that the competing microbes could be utilized as probiotics or the nutrients utilized could be utilized as prebiotics. We propose to fulfill our objectives and test our hypotheses with the following two aims: 1) Identify the chemical and biological indicators of Salmonella-mediated inflammation over time; 2) characterize metabolic exchanges between Salmonella and its competitors in the gut. The fulfillment of these aims will greatly expand our understanding of the microbial ecology of salmonellosis and may be broadly relevant to other pathogens or related inflammatory disorders.