Impact of Amino Acids on Host Susceptibility to the Colonization and Expansion of Salmonella enterica serovar Typhimurium

Abstract

Salmonella Typhimurium represents one of the four leading causes of foodborne illnesses worldwide. While studied for many decades as a model intracellular pathogen, there exists a gap in knowledge on the role of the gut microenvironment in influencing Salmonella colonization and expansion in the inflamed gut. One major factor influencing pathogen success is the resident collection of commensal organisms, known as the gut microbiota. The microbiota hinders Salmonella through several protective mechanisms, like sequestration of nutrients, i.e., amino acids (colonization resistance). However, which amino acids are important for Salmonella in the mammalian gut remained unknown. Using bacterial mutagenesis in combination with in vitro and in vivo studies leveraging conventional and germ-free animals, we identify and characterize the critical role of two S. Tm aspartate interconverting enzymes, AspA and AspC. We find that aspartate enables Salmonella to overcome microbiota-mediated colonization resistance by fueling anaerobic respiration during gut inflammation. Additionally, we develop a novel model for the study of colonization resistance against Salmonella in the terminal ileum, through the manipulation of dietary amino acids, overcoming host genetics-based resistance to severe disease and mortality. Lastly, we identify and characterize key alterations in pathogen metabolism that support colonization and expansion within the ileal lumen. Altogether, this work highlights the importance of amino acids in dictating Salmonella colonization, expansion, and the resultant disease severity.