Central metabolism of Salmonella in the inflamed gut

发炎肠道中沙门氏菌的中枢代谢

基本信息

批准号：
10677940
负责人：
Sebastian E Winter
金额：
$ 2.29万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-11 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10677940
关键词：
Acids Acute Address Anaerobic Bacteria Animal Disease Models Animal Model Bacterial Model Biochemical Carbon Cell physiology Citric Acid Cycle Colitis Dental Calculus Development Diarrhea Disease Energy Metabolism Environment Epithelial Equilibrium Fumarates Gastroenteritis Genes Genetic Goals Growth Gut Mucosa Immune response Immunocompetent In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Intervention Intestines Isomerism Large Intestine Lead Medical Care Costs Metabolic Metabolism Methods Microbe Modeling Molecular Mucous Membrane Nature Nitrogen Nutritional Operon Organism Oxidants Oxides Oxygen Pathogenesis Pathway interactions Phase Population Productivity Regulation Research Respiration Salmonella Salmonella enterica Salmonella typhimurium Serotyping Symptoms Tartrates Testing Time Toxin United States Variant Virulence Virulence Factors Work bacterial metabolism base commensal bacteria cost diarrheal disease enteric pathogen gut colonization gut inflammation gut microbiota in vivo innovation metabolic abnormality assessment microbial microbiota murine colitis neutrophil non-typhoidal Salmonella novel oxidation pathogen pathogenic bacteria pathogenic microbe rational design sugar

项目摘要

PROJECT SUMMARY Infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Tm) is a common cause of inflammatory diarrhea. Intriguingly, intestinal inflammation drives an expansion of the S. Tm population in the gut lumen. The molecular mechanisms that support S. Tm colonization of the intestinal tract remain incompletely understood. Our central hypothesis is that the inflamed gut constitutes a peculiar nutritional environment that enables S. Tm to outgrow obligate anaerobic commensal bacteria. We have recently demonstrated that during the acute phase of the infection, neutrophil-derived electron acceptors facilitate an oxidative central metabolism in S. Tm. In this application, we hypothesize that S. Tm relies on a branched TCA cycle for initial gut colonization. In particular, tartaric acid, produced through oxidation of microbiota-liberated sugars, supports fumarate reduction in the branched TCA cycle. We will test key aspects of our hypothesis by pursuing the following specific aims: 1.) determine how utilization of D- and L-tartrate contributes to growth of S. Tm in the lumen of the mammalian large intestine, 2.) determine the origin of tartrate during S. Tm infection, and 3.) investigate the regulation of tartrate utilization genes in vitro and in vivo. This work will advance our understanding of how intestinal pathogens, such as S. Tm, adapt their carbon and energy metabolism to colonize the mammalian intestinal tract. 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.

项目摘要细菌病原体沙门氏菌血清鼠伤寒（S. tm）的感染是炎症性腹泻。有趣的是，肠道炎症推动了S. tm种群的扩张肠腔。支持S. tm肠道的分子机制保留不完全理解。我们的中心假设是发炎的肠道构成了特殊的营养使S. TM能够超越厌氧共生细菌的环境。我们最近有证明在感染的急性阶段，中性粒细胞衍生的电子受体有助于 S. tm中的氧化中心代谢。在此应用程序中，我们假设S. tm依赖于分支的TCA 初始肠道定植的循环。特别是，通过氧化微生物蛋白蛋白酶产生的tart酸糖，支持分支TCA周期的富马酸盐减少。我们将通过追求以下具体目的：1。）确定D-和L tartrate的利用如何有助于增长 S. tm在哺乳动物大肠的腔内，2。）确定th感染期间的tartrate的起源，和3.）研究体外和体内降水酸盐利用基因的调节。这项工作将推动我们的了解肠道病原体（例如S. tm）如何使其碳和能量代谢适应定植哺乳动物肠道。我们设想，更好地理解 S. tm在炎症期间竞争微生物的长大将有助于开发新的和创新的治疗方法。