Inflammatory bowel disease (IBD) encompasses two main conditions: Crohn's disease and ulcerative colitis. The role of foodborne pathogens, often transmitted through contaminated food, is a subject of ongoing research regarding their potential involvement in IBD. The most common foodborne pathogens S. typhimurium usually causes intestinal inflammation in the intestines of both humans and cattle, known as enterocolitis. Phage therapy shows promise in treating Salmonella-induced colitis due to its highly specific targeting of bacteria. Here, we demonstrated the efficacy of phage therapy in a murine model of Salmonella-induced colitis. In mice, Salmonella administration exacerbated colitis severity, as evidenced by reduced colon length and elevated production of inflammatory cytokines. Comprehensive metabolomic investigations demonstrated that treatment with a Salmonella-specific novel phage FPSP6 effectively mitigated colitis induced by Salmonella. This therapeutic approach effectively reduced intestinal inflammation, increased CD4+ T-cell levels and decreased cytokine expression, demonstrating its potential efficacy and safety for treating Salmonella-induced colitis. This study, the first to verify the effectiveness and immunomodulatory mechanism of FPSP6, indicates that phage therapy targeting the gut microbiota is a viable alternative to antibiotics, connecting phage therapy, immune regulation, and microbial dynamics in the context of intestinal inflammation caused by foodborne pathogens.Copyright © 2025. Published by Elsevier Ltd.