Bacterial strains used in this study.

Salmonella enterica serovar Typhimurium (S. Tm) employs type III secretion system 1 and 2 (TTSS-1 and TTSS-2) to infect host tissues. In orogastric infections, both TTSSs manipulate host responses, increasing mucosal pathogen loads and eliciting inflammation. However, we still do not fully understand how virulence and inflammatory enteropathy are interconnected. Here, we investigate whether TTSS-2–dependent virulence contributes to epithelial barrier disruption and delineate its role in shaping inflammatory response profiles in the mouse gut. Using wild-type and TTSS-2 mutant S. Tm strains in antibiotic-pretreated mouse models, we demonstrate that intestinal epithelial destruction is promoted by TTSS-2 virulence. This effect is observed in both wild-type and immune-deficient C57BL/6J mice. Transcriptomic profiling together with immunofluorescence microscopy analysis reveals that wild-type S. Tm triggers a distinct, yet amplified immune response compared to a TTSS-2 mutant which is characterized by enhanced phagocyte recruitment and a unique transcriptional signature. These findings underscore the role of TTSS-2–mediated virulence in S. Tm gut infection, shaping distinct inflammatory microenvironments with potential implications for host-pathogen interaction studies.