Pediococcus pentosaceus JNL0053 Mitigates DSS-induced colitis in mice via the IL-22–Gut Barrier pathway

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease that imposes an increasing socioeconomic burden worldwide. Among emerging live biotherapeutics, the probiotic Pediococcus pentosaceus has shown therapeutic promise against UC, yet its molecular mode of action remains fragmentary. In this study, we isolated a novel strain P. pentosaceus JNL0053 from traditional Inner Mongolian cheese. By integrating transcriptomics, untargeted metabolomics, and 16S rRNA gene profiling, we dissected its protective efficacy in the dextran sulfate sodium (DSS)-induced murine colitis model. Mice receiving P. pentosaceus JNL0053 exhibited reduced body-weight loss, reduced disease activity index scores and attenuated histopathological damage. The treatment reshaped the gut microbiota and was accompanied by a more balanced immune microenvironment, evidenced by markedly decreased serum pro-inflammatory cytokines interleukin (IL)-6 and IL-1β and significantly elevated anti-inflammatory IL-10. N-acetylmuramate, identified as a key differential metabolite, potently promoted Th17 cell differentiation, leading to the secretion of IL-22 and IL-17F. This, in turn, increased the expression of mucin 2 and occludin, thereby protecting the intestinal barrier against intestinal pathogens. Collectively, P. pentosaceus JNL0053 orchestrated a multi-level crosstalk between host immunity and the gut microbiome to alleviate DSS-induced colitis. By activating the IL-22–MUC axis and restoring epithelial integrity, this food-borne P. pentosaceus JNL0053 established a compelling therapeutic strategy for UC.