Central metabolism of Salmonella in the inflamed gut

发炎肠道中沙门氏菌的中枢代谢

• 批准号: 9058993
• 负责人: Sebastian E Winter
• 金额: $ 40.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058993
• 关键词: Acute; Address; Animal Disease Models; Bacteria; Bacterial Model; Bacteroides; Cause of Death; Cell physiology; Citric Acid Cycle; Colitis; Data; Development; Diarrhea; Disease; Disease Outbreaks; Environment; Enzymes; Equilibrium; Fermentation; Formates; Gastroenteritis; Genetic Transcription; Goals; Growth; Health; Hospitalization; Immune response; Immunocompetent; Indigenous; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Intervention; Intestines; Invaded; Knowledge; Medical Care Costs; Metabolic; Metabolism; Microbe; Modeling; Molecular; Mucous Membrane; Mus; Nitrates; Nutritional; Organism; Oxidants; Pathogenesis; Patients; Phagocytes; Population; Productivity; Regulation; Research; Respiration; Running; Salmonella; Salmonella enterica; Science; Serotyping; Succinates; Testing; Tissues; Toxin; United States; Virulence; Virulence Factors; Work; bacterial metabolism; base; commensal microbes; electron donor; enteric pathogen; expectation; foodborne; innovation; insight; intestinal epithelium; metabolic abnormality assessment; microbiota; mouse model; neglect; novel; pathogen; pathogenic bacteria; research study; stem; transmission process

 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.

 描述（由申请方提供）：细菌病原体肠道沙门氏菌鼠伤寒血清型（S. Tm）导致急性炎性腹泻。S. Tm侵入肠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有力的粘膜炎症反应。有趣的是，肠道炎症导致S。肠腔中的Tm群体。对S. Tm对本地微生物群的影响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个特殊的营养环境，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。测定电子供体甲酸盐对S生长的贡献。Tm在发炎的肠腔和测试的工作假设，炎症扰乱之间的互养关系甲酸生产和消费的微生物，使S。Tm以在发炎的肠道中生长期间进入甲酸盐池。2.）的情况。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。成功完成具有强大的潜力，通过提供一个新的概念，即肠道病原体利用来自宿主（电子受体）和微生物群（发酵终产物）的代谢物，对胃肠炎研究产生重大影响。我们设想，更好地了解的机制，S。在炎症过程中，Tm的生长超过了竞争性微生物，这将有助于开发新的创新治疗方法。