Central metabolism of Salmonella in the inflamed gut

发炎肠道中沙门氏菌的中枢代谢

• 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
• 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

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.

项目摘要 感染细菌病原体肠道沙门氏菌血清型鼠伤寒沙门氏菌（S。Tm）是一种常见的 炎症性腹泻有趣的是，肠道炎症驱动了S。TM人群中 肠腔支持S.肠道的Tm定殖仍然存在 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， 环境使S。Tm生长超过专性厌氧微生物。我们最近 表明，在感染的急性期，嗜中性粒细胞衍生的电子受体促进 S. TM.在本申请中，我们假设S. Tm依赖于分支TCA 初始肠道定植周期。特别是酒石酸，通过微生物的氧化产生-释放 糖，支持分支TCA循环中的富马酸盐减少。我们将测试我们的假设的关键方面， 实现以下具体目标：1.）确定D-和L-酒石酸盐的利用率如何促进 S. Tm在哺乳动物大肠的内腔中，2.）确定S. Tm感染， 和3.）在体外和体内研究酒石酸盐利用基因的调控。这项工作将促进我们的 了解肠道病原体，如S。适应它们的碳和能量代谢， 寄生在哺乳动物的肠道中我们设想，更好地了解机制， S. TM在炎症期间超过竞争微生物将有助于开发新的和创新的 治疗方法。