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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：
10411509
负责人：
Sebastian E Winter
金额：
$ 4.94万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-24 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411509
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.

项目总结