The enteric pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) induces an acute inflammatory response in the intestinal mucosa, thus creating a nutritional niche that favors the growth of the pathogen over the microbiota. The metabolic pathways underlying the adaptation to this peculiar niche are poorly understood. In this application, we propose to analyze metabolic interactions between the host, the gut microbiota, and the enteric pathogen with a particular focus on lactate metabolism. Our central hypothesis is that the perturbation of the gut microbiota during S. Tm infection leads to metabolic changes in host metabolism, ultimately resulting the production of lactate. S. Tm utilizes host-derived lactate to enhance colonization of the intestinal lumen. We will test key aspects of our hypothesis by pursuing the following specific aims: 1.) Determine the contribution of epithelial lactate dehydrogenase to lactate production during S. Tm infection. We will test the working hypothesis that during inflammation, lactate is an end product of the metabolism of the intestinal epithelium. 2.) Determine how the metabolic switch to lactate fermentation in the epithelium is triggered during S. Tm infection. We will test the working hypothesis that bacterial dysbiosis, specifically a depletion of butyrate producers, leads to a decrease in intestinal butyrate levels. Lack of butyrate induces the switch from ?-oxidation to lactate fermentation. Successful completion has a strong potential to have a high impact on gastroenteritis research by providing a novel concept, i.e. that the metabolism of the host, the microbiota and the enteric pathogen are highly connected and identify key metabolites for this host-microbe interaction. We envision that a better understanding of host- microbe interactions during infection with enteric pathogens will aid the development of new and innovative approaches for treatment.
Non-typhoidal Salmonella serotypes are a common cause diarrheal disease in the United States, causing a cost of .5 billion to $2.3 billion per year due to lost productivity and the cost of medical care. This application will support studies on the molecular mechanisms that control bacterial colonization and disease symptoms in models of disease, which is expected to aid in the development of new intervention strategies through science.
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|Spiga, Luisella; Winter, Maria G; Furtado de Carvalho, Tatiane et al. (2017) An Oxidative Central Metabolism Enables Salmonella to Utilize Microbiota-Derived Succinate. Cell Host Microbe 22:291-301.e6|