Central metabolism of Salmonella in the inflamed gut

PROJECT SUMMARY Infection with non-typhoidal Salmonella enterica serovars is a common cause of inflammatory diarrhea. Intriguingly, intestinal inflammation drives an expansion of the Salmonella population in the gut lumen. Prior work in mouse colitis models has defined mechanisms of how inflammation-driven changes in metabolite availability support Salmonella colonization in the large intestine through a respiratory metabolism. Due to limitations of the animal models, these prior studies have focused on the large intestine, however, human disease primarily afflicts the terminal ileum. We have developed a murine model of Salmonella-induced ileitis, which recapitulates a key aspect of non-typhoidal Salmonellosis in humans, i.e., neutrophil-dominated ileitis. In this application, we hypothesize that non-typhoidal Salmonella relies on a tissue-specific, inflammation-adapted carbon and energy metabolism to facilitate colonization; conversely, we hypothesize that inhibition of this metabolism decreases gut colonization, disease, and fecal shedding. We will test key aspects of our hypothesis by pursuing the following specific aims: Aim 1: Determine the carbon and energy metabolism of Salmonella in a mouse model of ileitis, and Aim 2: Determine whether pharmacological inhibition of anaerobic respiration alleviates features of non- typhoidal Salmonellosis. This work will advance our understanding of how intestinal pathogens, such as Salmonella, adapt their carbon and energy metabolism to colonize the mammalian intestinal tract with a particular focus on the ileum. We envision that a better understanding of the mechanisms by which Salmonella outgrows competing microbes during inflammation will aid the development of new and innovative approaches for treatment, and idea we will be pioneering in this application.