Microbial ecology of the inflamed intestine

项目摘要 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 肠道引起宿主肠道的炎症，破坏正常的微生物区系。沙门氏菌 然后依靠微生物群没有消耗的营养物质茁壮成长。沙门氏菌营养来源包括1，2- 丙二醇，它是微生物区系的产物；乙醇胺，它来自受损细胞； 由NOS2介导的葡萄糖和半乳糖氧化而来的葡萄糖酸和半乳糖酸盐；以及 来自饮食的果糖-天冬酰胺(F-ASN)。F-ASN利用系统提供一种 有趣的治疗靶点，因为抑制FRAb酶使细菌陷入新陈代谢 中级的。我们的主要目标是使用系统水平的方法来确定主要的营养来源 沙门氏菌随着时间的推移在发炎的肠道中利用，并识别竞争这些细菌的微生物 营养素。我们假设其中一些营养获取系统将提供治疗靶点 沙门氏菌和其他可能的肠杆菌科，包括耐碳青霉烯的肠杆菌科 (CRE)被美国疾病控制与预防中心的报告列为“紧急”威胁，“美国的抗生素耐药性威胁” 国家“。在其他情况下，我们假设竞争的微生物可以被用作益生菌或 所利用的养分可作为益生素利用。我们建议实现我们的目标并检验我们的假设 目的有两个：1)鉴定沙门氏菌介导的化学和生物学指标 炎症随着时间的推移；2)表征沙门氏菌与其竞争对手之间的代谢交换 直觉。这些目标的实现将极大地扩大我们对微生物生态学的理解 沙门氏菌病，并可能与其他病原体或相关的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.