Lactate metabolism during Salmonella infection

项目总结 -- 鼠伤寒沙门氏菌肠道致病菌 在肠粘膜中引起急性炎症反应，从而产生 比微生物区系更有利于病原体生长的营养生态位。这个 适应这一特殊生态位的代谢途径很差 明白了。在这一应用中，我们建议分析代谢相互作用 宿主、肠道微生物区系和肠道病原体，特别是乳酸盐 新陈代谢。我们的中心假设是肠道微生物区系在 S.TM感染导致宿主新陈代谢的变化，最终导致 乳酸的生产。S.TM利用宿主衍生的乳酸来增强 肠腔。我们将通过执行以下操作来测试我们的假设的关键方面 具体目标：1.)测定上皮性乳酸脱氢酶对 S.TM感染过程中乳酸的产生。我们将测试工作假设，即在 发炎时，乳酸是肠道上皮代谢的最终产物。2.) 确定如何触发上皮细胞向乳酸发酵的代谢切换 在S.TM感染期间。我们将测试工作假说，即细菌的生物失调， 特别是丁酸盐生产商的枯竭，导致肠道丁酸盐的减少 级别。丁酸的缺乏导致了从β氧化到乳酸发酵的转变。 成功完成有很大潜力对胃肠炎有很高的影响 通过提供一个新的概念进行研究，即宿主的新陈代谢， 微生物区系和肠道病原体高度相连，并识别关键代谢物 对于这种宿主和微生物的相互作用。我们设想，更好地了解寄主- 肠道病原体感染过程中的微生物相互作用将有助于 新的和创新的治疗方法。

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.