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Glutarate metabolism in Salmonella

沙门氏菌中的戊二酸代谢

基本信息

批准号：
10351526
负责人：
Sebastian E Winter
金额：
$ 8.16万
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：
2021-09-22 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10351526
关键词：
Acute Affect Anaerobic Bacteria Animal Disease Models Bacteria Bacterial Model Biological Assay Carbon Carboxylic Acids Cell physiology Colitis Degradation Pathway Development Diarrhea Dicarboxylic Acids Energy Metabolism Ensure Environment Enzymes Gastroenteritis Genetic Glucose Glutarates Goals Growth Hypochlorite Immunocompetent In Situ In Vitro Infection Inflammation Inflammatory Inflammatory Response Intervention Intestinal Content Intestines Laboratories Medical Care Costs Metabolism Modeling Molecular Mus Nature Nitric Oxide Nitrogen Nucleic Acids Nutrient Nutritional Organism Oxides Oxygen Pathogenesis Patients Population Productivity Proteins Reaction Research Role Salmonella Salmonella enterica Salmonella typhimurium Serotyping Shapes Source Testing Tissues Toxin United States Virulence Factors Work antimicrobial bacterial genetics bacterial metabolism commensal bacteria cost diarrheal disease enteric infection enteric pathogen experimental study glutaric acid gut colonization host-microbe interactions improved inflammatory disease of the intestine metabolic abnormality assessment metabolomics microbiota mouse model mutant non-typhoidal Salmonella oxidation oxidized lipid pathogen pathogenic bacteria sugar transmission process

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. In this application, we will investigate how inflammatory reactive oxygen and nitrogen species are generating a diverse array of inflammation-associated small metabolites. We hypothesize that reactive oxygen and nitrogen species oxidize sugars to smaller mono- and dicarboxylic acids such as glutarate, which serve as nutrients for S. Tm to support gut colonization. We will test key aspects of our hypothesis in mouse models of infection and in vitro. We will pursue the following specific aims: 1.) Determine whether glutarate and other carboxylic acids are generated as byproducts of RNS metabolism, and 2. Investigate S. Tm glutarate metabolism in the context of infection. 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. These studies are also expected to advance our understanding of how reactive oxygen and nitrogen species participate in diversity-generating reactions that shape the metabolite landscape during gut inflammation.

项目总结肠道沙门氏菌感染鼠伤寒沙门氏菌是炎症性腹泻的常见原因。耐人寻味的是，肠道炎症肠腔内S.TM菌群的扩张。其分子机制是支持S.TM在肠道的定植仍然不完全清楚。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。这使得S.TM的生长超过了专性厌氧共生菌。在这应用，我们将调查炎症性活性氧和氮物种正在产生一系列不同的炎症相关小代谢物。我们假设活性氧和氮物种将糖氧化成较小的单核糖. 以及二元酸，如戊二酸，它们是S.TM支持的营养物质肠道殖民。我们将在小鼠感染模型中测试我们假设的关键方面。而且是在体外。我们将追求以下具体目标：1.确定戊二酸是否和其他羧酸作为RNS代谢的副产物而产生，以及2. 在感染的情况下研究S.TM的戊二酸代谢。这项工作将会取得进展我们对肠道病原体，如S.TM，如何适应它们的碳和在哺乳动物肠道中定居的能量代谢。这些研究也是有望促进我们对活性氧和氮物种如何参与产生多样性的反应，在此期间塑造代谢物格局肠道发炎。