SUMMARY Non-typhoidal Salmonella (NTS) causes 100 million infections per year worldwide. The pathogen infects the gastrointestinal tract, where it triggers intestinal inflammation. Essential to NTS pathogenesis is the ability to evade host responses and compete with the gut microbiota. Research in my laboratory has contributed to elucidating the duality of the mucosal response to Salmonella enterica serovar Typhimurium (STm), a highly prevalent NTS serovar. Particularly, we have shown that STm evades sequestration of essential metal nutrients, a process known as “nutritional immunity”, to thrive in the inflamed gut and compete with the microbiota. We discovered: (i) key host factors that modulate nutritional immunity in the inflamed gut, including the cytokine interleukin-22 (IL-22) and the antimicrobial proteins lipocalin-2 and calprotectin; (ii) several mechanisms and virulence factors that enable STm to overcome metal nutrient sequestration in the inflamed gut. We also discovered that, during colitis, the probiotic bacterium Escherichia coli Nissle 1917 (EcN) competes with STm for iron and zinc via multiple mechanisms, including expression of high affinity iron and zinc acquisition systems, and secretion of small antimicrobial molecules termed microcins. Building on this prior work, the primary objective of this application is to continue to investigate host-microbe and microbe-microbe interaction in the inflamed gut, a complex environment with unique nutritional challenges for both pathogens and the microbiota. We will continue to investigate the role of microcins and zinc acquisition systems in the inflamed gut, and we will expand to elucidating the role of secondary bile acids, including newly discovered microbial conjugated bile acids, in modulating nutritional immunity. Our central hypothesis is that the host inflammatory response changes the nutritional and metabolic landscape of the gut, triggering an environment that favors the bloom of Enterobacteriaceae and promotes microbial competition. In Aim 1, we will elucidate mechanisms of competition for metal nutrients in the inflamed gut between Salmonella, E. coli Nissle, and the gut microbiota. In Aim 2, we will evaluate the impact of Salmonella infection on bile acid pool composition, and the impact of these changes on nutritional immunity. Understanding the host and microbial factors that modulate host immunity, together with the mechanisms by which STm thrives in this environment, is essential for developing new approaches to limit STm replication in the inflamed gut.