Abstract

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease that imposes a growing socioeconomic burden worldwide. Among emerging live biotherapeutics, the probiotic Pediococcus pentosaceus has shown therapeutic promise against UC, yet its molecular mode of action remains poorly understood. In this study, we isolated a novel strain P. pentosaceus JNL0053 from traditional Inner Mongolian cheese. By integrating transcriptomics, untargeted metabolomics, and 16 S rRNA gene profiling, we elucidated its protective efficacy in the dextran sulfate sodium (DSS)-induced murine colitis model. Mice receiving P. pentosaceus JNL0053 exhibited reduced body-weight loss, lower disease activity index scores and attenuated histopathological damage. This treatment reshaped the gut microbiota and was accompanied by a more balanced immune microenvironment, as evidenced by markedly decreased serum levels of pro-inflammatory cytokines interleukin (IL)-6 and IL-1β, alongside 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-17 F. This, in turn, increased the expression of mucin 2 and occludin, thereby protecting the intestinal barrier against pathogens. Collectively, P. pentosaceus JNL0053 orchestrated 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-derived P. pentosaceus JNL0053 represents a compelling therapeutic strategy for UC.