Central metabolism of Salmonella in the inflamed gut

 描述(申请人提供)：感染肠道沙门氏菌血清型鼠伤寒沙门氏菌(S.TM)可导致急性炎症性腹泻。S.TM侵入肠道上皮并在组织吞噬细胞中复制，引发旨在清除入侵细菌的强大的粘膜炎症反应。耐人寻味的是，肠道炎症导致肠腔内S.TM数量的增加。S.TM在本土微生物区系中生长的分子机制在很大程度上仍不清楚。我们的中心假设是，发炎的肠道构成了一种特殊的营养环境，使S.TM能够成长为超越竞争共生微生物的环境。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)确定电子供体甲酸盐对发炎肠腔中S.TM生长的贡献，并测试炎症扰乱甲酸盐产生微生物和消费微生物之间的合养关系，使S.TM在炎症肠道中生长期间访问甲酸盐池的工作假说。2.)确定宿主衍生的电子受体如何改变TCA循环的调节，并探索潜在的后果。成功的完成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(发酵最终产物)的代谢物，因此有可能对胃肠炎的研究产生很大影响。我们预计，更好地了解S.TM在炎症过程中生长超过竞争微生物的机制将有助于开发新的创新治疗方法。

 DESCRIPTION (provided by applicant): 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.