Periodontitis-associated Fusobacterium nucleatum promotes ulcerative colitis by ferroptosis-mediated gut barrier disruption

Periodontitis and ulcerative colitis (UC) are inflammatory diseases linked through the “gum-gut” axis. Fusobacterium nucleatum, an important periodontitis-associated pathobiont and gastrointestinal opportunist, may mediate their comorbidity. This study investigated the role of F. nucleatum in UC using dextran sulfate sodium-induced UC and F. nucleatum-induced periodontitis models. F. nucleatum exacerbated inflammatory alveolar bone loss and intestinal barrier dysfunction, accelerating UC severity. Integrated 16S rRNA gene sequence and LC-MS metabolomics revealed ferroptosis activation, characterized by elevated Fe2+ and malondialdehyde, glutathione depletion, dysregulated GPX4, FTH1, and ACSL4 expression, reduced mitochondrial membrane potential, and reactive oxygen species aggregation in the mouse colon and colonic epithelial cell CCD841. Administration of ferroptosis inhibitor Ferrostatin-1 attenuated UC by restoring intestinal permeability, preserving mucin layers, and enhancing tight junction proteins ZO-1 and CLDN-1. These findings establish F. nucleatum as a key mediator of periodontitis-UC comorbidity through ferroptosis-mediated gut barrier disruption, providing mechanistic insights into microbial-driven inflammatory cross-talk.