Lactate metabolism during Salmonella infection

沙门氏菌感染期间的乳酸代谢

• 批准号: 9225982
• 负责人: Sebastian E Winter
• 金额: $ 20.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225982
• 关键词: Acute; Animal Disease Models; Bacterial Model; Butyrates; Carbon; Cell physiology; Colitis; Data; Development; Diet; Disease; Disease model; Energy-Generating Resources; Environment; Epithelial; Epithelium; Equilibrium; Fermentation; Gastroenteritis; Genes; Goals; Growth; Immunocompetent; Infection; Inflammation; Inflammatory Response; Inflammatory disease of the intestine; Intervention; Intestinal Mucosa; Intestines; Lactate Dehydrogenase; Medical Care Costs; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Nutritional; Organism; Pathogenesis; Patients; Population; Production; Productivity; Research; Salmonella; Salmonella enterica; Salmonella infections; Salmonella typhimurium; Science; Serotyping; Source; Symptoms; Testing; Toxin; United States; Virulence; Virulence Factors; Work; bacterial metabolism; base; cost; enteric pathogen; expectation; experimental study; fitness; gut microbiota; host-microbe interactions; innovation; intestinal epithelium; lactate dehydrogenase 5; metabolic abnormality assessment; microbial; microbiota; mouse model; novel; oxidation; pathogen; pathogenic bacteria; respiratory

PROJECT SUMMARY   The enteric pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) induces an acute inflammatory response in the intestinal mucosa, thus creating a nutritional niche that favors the growth of the pathogen over the microbiota. The metabolic pathways underlying the adaptation to this peculiar niche are poorly understood. In this application, we propose to analyze metabolic interactions between the host, the gut microbiota, and the enteric pathogen with a particular focus on lactate metabolism. Our central hypothesis is that the perturbation of the gut microbiota during S. Tm infection leads to metabolic changes in host metabolism, ultimately resulting the production of lactate. S. Tm utilizes host-derived lactate to enhance colonization of the intestinal lumen. We will test key aspects of our hypothesis by pursuing the following specific aims: 1.) Determine the contribution of epithelial lactate dehydrogenase to lactate production during S. Tm infection. We will test the working hypothesis that during inflammation, lactate is an end product of the metabolism of the intestinal epithelium. 2.) Determine how the metabolic switch to lactate fermentation in the epithelium is triggered during S. Tm infection. We will test the working hypothesis that bacterial dysbiosis, specifically a depletion of butyrate producers, leads to a decrease in intestinal butyrate levels. Lack of butyrate induces the switch from β-oxidation to lactate fermentation. Successful completion has a strong potential to have a high impact on gastroenteritis research by providing a novel concept, i.e. that the metabolism of the host, the microbiota and the enteric pathogen are highly connected and identify key metabolites for this host-microbe interaction. We envision that a better understanding of host- microbe interactions during infection with enteric pathogens will aid the development of new and innovative approaches for treatment.

项目摘要   肠道病原体沙门氏菌血清鼠伤寒（S. typhimurium） 在肠粘膜中诱导急性炎症反应，从而产生 营养利基有利于病原体在微生物群上的生长。 适应该特殊利基市场的代谢途径很差 理解。在此应用中，我们建议分析之间的代谢相互作用 宿主，肠道微生物群和促进病原体，特别关注乳酸 代谢。我们的中心假设是肠道菌群的扰动 S. tm感染导致宿主代谢的代谢变化，最终导致 生产鞋底。 S. tm利用宿主衍生的缝隙来增强定殖 肠腔。我们将通过追求以下来检验假设的关键方面 具体目的：1。）确定上皮刀酸脱氢酶对 S. tm感染期间的乳酸产生。我们将测试在此期间的工作假设 炎症，裂缝是肠上皮代谢的最终产物。 2.） 确定如何触发上皮中的代谢转换发酵 在S. tm感染期间。我们将测试细菌营养不良的工作假设， 特别是丁酸酯生产商的部署，导致肠丁酸酯的减少 水平。缺乏丁酸酯会诱导从β氧化转变为裂解发酵。 成功完成对胃肠炎产生很大影响的强大潜力 通过提供一个新颖的概念，即宿主的新陈代谢， 微生物群和肠病原体高度连接，并识别关键代谢物 对于这种宿主 - 微叶片相互作用。我们设想，对主机有更好的理解 - 与肠道病原体感染期间的微生物相互作用将有助于发展 新的和创新的治疗方法。