Periodontal pathogen Fusobacterium nucleatum promotes ulcerative colitis by ferroptosis-mediated gut barrier disruption

Periodontitis and ulcerative colitis (UC), both inflammatory diseases caused by microecological dysregulation and host immune-inflammatory responses, are epidemiologically related and may be interlinked through the “gum-gut” axis. However, the specific mechanisms underlying this association are not fully understood. Fusobacterium nucleatum , one of the major pathogens of periodontitis and a causative agent of the gastrointestinal tract, may be responsible for the link between this comorbidity. This study aimed to investigate the role and possible mechanisms of the periodontal pathogen F. nucleatum in the pathogenesis of UC by constructing a model of UC induced by dextrose sodium sulfate and a model of periodontitis induced by F. nucleatum ATCC 25586 periodontal infection. Our findings showed that F. nucleatum induced periodontal inflammation, alveolar bone loss, and disrupted intestinal barrier thus promoting UC progression in mice. 16S rRNA sequence and LC-MS analyses of mouse colonic content indicated that ferroptosis was involved. F. nucleatum induced ferroptosis in the mouse colon and the normal colonic epithelial cell CCD841 (ATCC CRL-1790), as evidenced by elevated levels of Fe ²⁺ and malondialdehyde, decreased glutathione, altered key ferroptosis regulators GPX4, FTH1, and ACSL4, reduced mitochondrial membrane potential, and intracellular reactive oxygen species aggregation. Application of ferroptosis inhibitor Ferrostatin-1 in vivo greatly alleviated UC and rescued intestinal barrier dysfunction by decreasing intestinal permeability, protecting the mucus layer, and upregulating tight junctions Zona occludens 1 and Occludin-1 expression. In conclusion, periodontal pathogen F. nucleatum promotes UC by inducing ferroptosis in intestinal epithelial cells thus disrupting the gut barrier. This study provided new insights into the mechanisms linking periodontitis and UC from the perspective of symbiont F. nucleatum and suggested that ferroptosis may be a potential therapeutic target.