The study investigates the role of epithelial-derived interleukin 23 (IL-23) in oral mucosal immunopathology, specifically in periodontitis. Epithelial cells, which form a barrier at mucosal surfaces, can trigger inflammatory responses that contribute to disease. The research demonstrates that epithelial cell-intrinsic production of IL-23 triggers an inflammatory loop in periodontitis, a common oral disease. This IL-23 induction is localized near the disease-associated microbiome and is evident in both experimental models and patients with common and genetic forms of periodontitis. Mechanistically, flagellated microbial species of the periodontitis microbiome trigger epithelial IL-23 induction through a TLR5 receptor-dependent pathway. Unlike other Th17-driven diseases, non-hematopoietic cell-derived IL-23 serves as an initiator of pathogenic inflammation in periodontitis. Further analysis of publicly available datasets reveals that epithelial IL-23 expression is also observed in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human diseases. The study highlights the importance of the barrier epithelium in inducing IL-23-mediated inflammation and provides insights into the potential therapeutic targets for periodontitis and other mucosal diseases.The study investigates the role of epithelial-derived interleukin 23 (IL-23) in oral mucosal immunopathology, specifically in periodontitis. Epithelial cells, which form a barrier at mucosal surfaces, can trigger inflammatory responses that contribute to disease. The research demonstrates that epithelial cell-intrinsic production of IL-23 triggers an inflammatory loop in periodontitis, a common oral disease. This IL-23 induction is localized near the disease-associated microbiome and is evident in both experimental models and patients with common and genetic forms of periodontitis. Mechanistically, flagellated microbial species of the periodontitis microbiome trigger epithelial IL-23 induction through a TLR5 receptor-dependent pathway. Unlike other Th17-driven diseases, non-hematopoietic cell-derived IL-23 serves as an initiator of pathogenic inflammation in periodontitis. Further analysis of publicly available datasets reveals that epithelial IL-23 expression is also observed in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human diseases. The study highlights the importance of the barrier epithelium in inducing IL-23-mediated inflammation and provides insights into the potential therapeutic targets for periodontitis and other mucosal diseases.