Central metabolism of Salmonella in the inflamed gut

发炎肠道中沙门氏菌的中枢代谢

基本信息

批准号：
10411509
负责人：
Sebastian E Winter
金额：
$ 4.94万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-24 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411509
关键词：
Acids Acute Address Anaerobic Bacteria Animal Disease Models Animal Model Bacterial Model Biochemical Carbon Cell physiology Citric Acid Cycle Colitis Dental Calculus Development Diarrhea Disease Energy Metabolism Environment Epithelial Equilibrium Fumarates Gastroenteritis Genes Genetic Goals Growth Gut Mucosa Immune response Immunocompetent In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Intervention Intestines Isomerism Large Intestine Lead Medical Care Costs Metabolic Metabolism Methods Microbe Modeling Molecular Mucous Membrane Nature Nitrogen Nutritional Operon Organism Oxidants Oxides Oxygen Pathogenesis Pathway interactions Phase Population Productivity Regulation Research Respiration Salmonella Salmonella enterica Salmonella typhimurium Serotyping Symptoms Tartrates Testing Time Toxin United States Variant Virulence Virulence Factors Work bacterial metabolism base commensal bacteria cost diarrheal disease enteric pathogen gut colonization gut inflammation gut microbiota in vivo innovation metabolic abnormality assessment microbial microbiota murine colitis neutrophil non-typhoidal Salmonella novel oxidation pathogen pathogenic bacteria pathogenic microbe rational design sugar

项目摘要

PROJECT SUMMARY Infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Tm) is a common cause of inflammatory diarrhea. Intriguingly, intestinal inflammation drives an expansion of the S. Tm population in the gut lumen. The molecular mechanisms that support S. Tm colonization of the intestinal tract remain incompletely understood. Our central hypothesis is that the inflamed gut constitutes a peculiar nutritional environment that enables S. Tm to outgrow obligate anaerobic commensal bacteria. We have recently demonstrated that during the acute phase of the infection, neutrophil-derived electron acceptors facilitate an oxidative central metabolism in S. Tm. In this application, we hypothesize that S. Tm relies on a branched TCA cycle for initial gut colonization. In particular, tartaric acid, produced through oxidation of microbiota-liberated sugars, supports fumarate reduction in the branched TCA cycle. We will test key aspects of our hypothesis by pursuing the following specific aims: 1.) determine how utilization of D- and L-tartrate contributes to growth of S. Tm in the lumen of the mammalian large intestine, 2.) determine the origin of tartrate during S. Tm infection, and 3.) investigate the regulation of tartrate utilization genes in vitro and in vivo. This work will advance our understanding of how intestinal pathogens, such as S. Tm, adapt their carbon and energy metabolism to colonize the mammalian intestinal tract. We envision that a better understanding of the mechanisms by which S. Tm outgrows competing microbes during inflammation will aid the development of new and innovative approaches for treatment.

项目概要细菌病原体伤寒沙门氏菌 (S.Tm) 感染是导致以下疾病的常见原因：炎症性腹泻。有趣的是，肠道炎症会导致 S.Tm 群体的扩张。肠腔。支持 S.Tm 肠道定植的分子机制仍然存在不完全理解。我们的中心假设是发炎的肠道构成了一种特殊的营养物质使 S.Tm 能够生长超过专性厌氧共生菌的环境。我们最近有证明在感染的急性期，中性粒细胞衍生的电子受体促进 S. Tm 中的氧化中枢代谢。在此应用中，我们假设 S.Tm 依赖于支链 TCA 初始肠道定植的周期。特别是，通过微生物群释放的氧化产生的酒石酸糖，支持支链 TCA 循环中的富马酸还原。我们将通过以下方式检验我们假设的关键方面：追求以下具体目标：1.) 确定 D- 和 L- 酒石酸盐的利用如何促进哺乳动物大肠腔中的S.Tm，2.)确定S.Tm感染期间酒石酸盐的来源， 3.) 研究酒石酸利用基因的体外和体内调控。这项工作将推动我们了解肠道病原体（例如 S. Tm）如何调整其碳和能量代谢以适应定植于哺乳动物肠道。我们希望更好地理解其机制 S.Tm 在炎症过程中的生长速度超过了竞争微生物，这将有助于新的和创新的开发治疗方法。