Central metabolism of Salmonella in the inflamed gut

项目总结 -- 肠道沙门氏菌感染鼠伤寒沙门氏菌 结果急性炎症性腹泻。结核分枝杆菌侵袭肠道上皮细胞 在组织吞噬细胞中复制，触发强烈的粘膜炎症反应 旨在清除入侵的细菌。耐人寻味的是，肠道炎症会导致 肠腔内S.TM菌群的扩张。分子机制 S.TM在本土微生物区系上的生长在很大程度上仍然 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 使S.TM生长超过竞争共生微生物的环境。我们会 通过追求以下具体目标来测试我们的假设的关键方面：1)测定 电子供体甲酸盐对肠炎肠杆菌生长的影响 并测试炎症扰乱合并症的工作假说 甲酸盐产生菌和消耗菌之间的关系，使S.TM能够 在发炎的肠道中生长期间进入甲酸池。2.)确定主机如何- 衍生电子受体改变TCA循环的调节和探索电位 后果。成功完成工作有很大的潜力对 胃肠炎的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)和微生物区系的代谢物 (发酵最终产物)。我们设想，更好地理解这些机制 在炎症过程中，S.TM通过生长超过竞争对手的微生物将有助于 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.