Host inflammation-derived citrate enhances Salmonella Typhimurium pathogenesis by fueling growth and activating...

Salmonella enterica serovar Typhimurium (STm) infection triggers robust intestinal inflammatory responses during host colonization. Although host inflammatory responses typically function as defense mechanisms, STm subverts these processes by co-opting inflammation-derived metabolites to increase both bacterial proliferation and intestinal colonization. Here, we demonstrate that STm-induced intestinal inflammation results in the significant accumulation of luminal citrate, which plays dual roles in STm pathogenesis, serving as both an anaerobic fermentation substrate to support bacterial growth and a virulence-activating signaling molecule. Mechanistically, the CitAB two-component system detects elevated citrate concentrations in the inflamed intestine, initiating the transcriptional activation of citrate fermentation genes to facilitate STm luminal proliferation. Moreover, CitAB-mediated citrate sensing directly upregulates hilD, which encodes the master regulator of Salmonella Pathogenicity Island 1, thereby enhancing type III secretion system-dependent epithelial invasion. Genetic disruption of either citrate anaerobic fermentation pathway or citrate-mediated virulence-regulating pathway severely compromises both intestinal colonization and invasive capacity of STm. These findings underscore citrate-responsive pathways as promising therapeutic targets for simultaneously disrupting STm metabolic adaptability and virulence.