ABSTRACT Our intestine is host to a complex microbial community, the gut microbiota, which is dominated by obligate anaerobic bacteria belonging to the classes Clostridia and Bacteroidia. This community provides benefit to the host by contributing to nutrition, immune education and niche protection against enteric pathogens (colonization resistance). However, Salmonella enterica serovar (S.) Typhimurium can use its virulence factors to overcome colonization resistance by triggering intestinal inflammation. The host inflammatory response remodels the intestinal environment, which fuels growth of the pathogen, but also causes an imbalance in the microbiota (dysbiosis). The question of how intestinal inflammation drives changes in the microbiota composition and how these changes affect host physiology and pathogen expansion represents a high-impact topic that will be addressed in this application. The objectives of this application are to study the mechanisms that enable the pathogen to gain an edge over competing Enterobacterales during intestinal inflammation. Our central hypothesis is that S. Typhimurium virulence factors trigger host responses that remodel the intestinal environment to generate resources that fuel pathogen growth while at the same time enabling it to edge out competing Enterobacterales. To test this hypothesis, we will determine in Specific Aim 1 whether S. Typhimurium benefits from intestinal inflammation because this host response increases the availability of polyols. In Specific Aim 2 we will determine whether S. Typhimurium depletes a neurotransmitter to compete with Enterobacterales for iron. Finally, our third specific aim will determine whether sulfide production by S. Typhimurium provides a benefit during competition with endogenous Enterobacterales. It is our expectation that successful completion of the proposed experiments will usher in important conceptual advances in understanding the mechanisms underlying pathogen expansion during S. Typhimurium-induced gastroenteritis.

PUBLIC HEALTH RELEVANCE STATEMENT Non-typhoidal Salmonella serotypes are the single most common cause of death from diarrheal disease associated with viruses, parasites or bacteria and the leading cause of foodborne disease outbreaks in the United States, producing between $0.5 billion to $2.3 billion in annual costs for medical care and lost productivity. The most common human clinical isolate is Salmonella enterica serotypes Typhimurium (S. Typhimurium). Research proposed in this application will support pioneering studies on molecular mechanisms that control the balance between the pathogen, the host and its microbiota. The proposed studies will drive knowledge about Salmonella gastroenteritis to a higher level by providing critical new insights into pathogenesis and mechanisms that enable the pathogen to overcome colonization resistance mediated by the gut microbiota.