Host STING signaling is associated with gut microbiota, bile acid metabolism, and mucosal immune defense during Salmonella infection

The gut microbiota and its metabolites are important regulators of mucosal immunity against enteric pathogens. However, the host pathways that coordinate intestinal microbial ecology, bile acid metabolism, and antibacterial defense remain incompletely understood. STING is a key adaptor in nucleic acid sensing, but its role in shaping the intestinal microbial-metabolic environment during bacterial infection is unclear. Wild-type and STING-deficient mice were compared in an oral Salmonella enterica serovar Typhimurium infection model. Disease severity was assessed by survival, body weight change, histopathology, bacterial burden, serum cytokines, and flow cytometry. The microbiota and metabolite profiles of colonic luminal contents, together with host transcriptional responses in distal colon tissue, were analyzed using 16 S rRNA gene sequencing, untargeted LC-MS/MS metabolomics, RNA sequencing, and integrative multi-omics analyses. STING-deficient mice showed increased susceptibility to Salmonella infection, including reduced survival, greater body weight loss, higher bacterial burdens, more severe intestinal pathology, along with impaired intestinal barrier integrity, and increased inflammatory cytokine production. STING deficiency was associated with reduced microbial diversity and altered gut microbial composition, including enrichment of infection-associated taxa such as Parabacteroides and depletion of commensal genera such as Turicibacter and Lactobacillus . Metabolomic profiling revealed remodeling of the intestinal metabolic landscape, with prominent alterations in bile acid- and lipid-related metabolites. Host transcriptomic analysis showed reduced expression of genes and pathways related to MHC class II antigen presentation and T cell activation. Cross-omics correlation analyses linked altered microbial taxa and bile acid metabolites with impaired mucosal immune gene expression. These findings identify STING as a host factor associated with intestinal microbial and bile acid metabolic homeostasis during Salmonella infection. STING deficiency is associated with coordinated alterations in gut microbial composition, bile acid metabolism, mucosal immune transcriptional programs, and host susceptibility to enteric infection.