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   肠道病原体肠道沙门氏菌血清型鼠伤寒（S。鼠伤寒） 在肠粘膜中诱导急性炎症反应，从而产生 营养生态位，有利于病原体的生长超过微生物群。的 适应这种特殊生态位的代谢途径很差， 明白在这个应用中，我们提出分析代谢之间的相互作用， 宿主、肠道微生物群和肠道病原体，特别关注乳酸盐 新陈代谢.我们的中心假设是，在肠道微生物群的扰动， S. Tm感染导致宿主代谢的代谢变化，最终导致 乳酸盐的生产。S. Tm利用宿主来源的乳酸盐来增强 肠腔我们将通过以下方式来测试我们假设的关键方面 具体目标：1.）确定上皮乳酸脱氢酶对 乳酸产生量;感染。我们将测试工作假设，即在 在炎症中，乳酸盐是肠上皮代谢的终产物。2.）的情况。 确定上皮细胞中乳酸发酵的代谢转换是如何触发的 在S.感染。我们将测试细菌生态失调的工作假设， 特别是丁酸生产者的消耗，导致肠道丁酸的减少 程度.丁酸盐的缺乏诱导从β-氧化到乳酸盐发酵的转变。 成功完成有很强的潜力有很高的影响肠胃炎 研究提供了一个新的概念，即宿主的代谢， 微生物群和肠道病原体高度相关，并确定关键代谢物 宿主和微生物之间的相互作用我们认为，更好地了解主机- 肠道病原体感染期间的微生物相互作用将有助于 创新的治疗方法。