Central metabolism of Salmonella in the inflamed gut

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） 导致急性炎症性腹泻。S. Tm侵入肠上皮， 在组织吞噬细胞中复制，引发强有力的粘膜炎症反应 旨在清除入侵的细菌有趣的是，肠道炎症会导致 S.肠腔中的Tm群体。的分子机制 S.对本地微生物的Tm仍然主要是 未知我们的中心假设是，发炎的肠道构成了一种特殊的营养物质， 环境使S。它的生长速度超过了与之竞争的微生物。我们将 通过追求以下具体目标来测试我们假设的关键方面：1.）确定 电子给体甲酸盐对S.在发炎的肠道里 管腔和测试的工作假设，炎症干扰互养 之间的关系甲酸生产和消费微生物，使S。Tm到 在发炎的肠道中生长期间进入甲酸池。2.）的情况。确定主机如何- 衍生的电子受体改变TCA循环的调节， 后果成功完成具有强大的潜力，对 胃肠炎研究提供了一个新的概念，即肠道病原体 利用宿主（电子受体）和微生物群的代谢物 （发酵终产物）。我们设想，更好地了解这些机制， 其中S.在炎症过程中，TM的生长超过了竞争的微生物， 开发新的和创新的治疗方法。

PROJECT SUMMARY   Infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Tm) results in acute inflammatory diarrhea. S. Tm invades the intestinal epithelium and replicates in the tissue phagocytes, triggering a potent mucosal inflammatory response aimed at clearing the invading bacteria. Intriguingly, intestinal inflammation results in an expansion of the S. Tm population in the gut lumen. The molecular mechanisms underlying the outgrowth of S. Tm over the indigenous microbiota remains largely unknown. Our central hypothesis is that the inflamed gut constitutes a peculiar nutritional environment that enables S. Tm to outgrow competing commensal microbes. We will test key aspects of our hypothesis by pursuing the following specific aims: 1.) Determine the contribution of the electron donor formate to growth of S. Tm in the inflamed gut lumen and test the working hypothesis that inflammation perturbs syntrophic relationships between formate-producing and -consuming microbes, allowing S. Tm to access the formate pool during growth in the inflamed gut. 2.) Determine how host- derived electron acceptors alter regulation of the TCA cycle and explore potential consequences. Successful completion has a strong potential to have a high impact on gastroenteritis research by providing a novel concept, i.e. that an enteric pathogen exploits metabolites from both, the host (electron acceptors) and the microbiota (fermentation end products). 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.