Salmonella re-engineers the intestinal environment to break colonization resistance in the presence of a compositionally intact microbiota.

The gut microbiota prevents harmful microbes from entering the body, a function known as colonization resistance. The enteric pathogen Salmonella enterica serovar (S.) Typhimurium uses its virulence factors to break colonization resistance through unknown mechanisms. Using metabolite profiling and genetic analysis, we show that the initial rise in luminal pathogen abundance was powered by a combination of aerobic respiration and mixed acid fermentation of simple sugars, such as glucose, which resulted in their depletion from the metabolome. The initial rise in the abundance of the pathogen in the feces coincided with a reduction in the cecal concentrations of acetate and butyrate and an increase in epithelial oxygenation. Notably, these changes in the host environment preceded changes in the microbiota composition. We conclude that changes in the host environment can weaken colonization resistance even in the absence of overt compositional changes in the gut microbiota. [Display omitted] • Glucose fuels virulence factor-driven growth of Salmonella in the murine cecum • Colonization resistance becomes impaired when microbiota is compositionally intact • Colonization resistance is compromised when inflammation disrupts epithelial hypoxia • Aerobic respiration and fermentation of sugars support Salmonella outgrowth Rogers et al. show that Salmonella overcomes colonization resistance when the microbiota is compositionally intact by disrupting epithelial hypoxia. Pathogen outgrowth is fueled by catabolizing simple sugars, such as glucose, using a combination of aerobic respiration and mixed acid fermentation. [ABSTRACT FROM AUTHOR]