Consumed by millions of people to manage blood glucose and body weight, sugar substitutes may have unintended side effects. Here, we found that the ingestion of arabinose, lactulose, maltitol, erythritol, and sorbitol, which can be substituted for table sugar, reduces colonization resistance against the common food borne pathogen, Salmonella Typhimurium and promotes its virulence. In mice, consumption of these sugars upon infection led to gut colonization by the pathogen characterized by high fecal shedding, a disseminated systemic infection and enteropathy. Although the gut microbiota can utilize these sugars, it is perturbed by intestinal acidification resulting from accumulating microbiota-derived fermentation byproducts, subsequently permitting pathogen colonization. In addition, Salmonella virulence gene expression is induced, which further enhances infection and intestinal disease. Moreover, the gut environment altered by these sugar substitutes selects for fully virulent, invasive Salmonella, as avirulent mutants are highly attenuated for growth in the gut. Interestingly, the diet can alter the pathogen's tissue tropism along the intestinal tract. These findings highlight that sugar substitutes in diets may pose a risk for enteric infections and offer a new model for studying how diet influences pathogen behavior and disease outcomes.