Dextran sodium sulfate confounds causal role of periodontitis in inflammatory bowel disease

Abstract Background Emerging evidence supports a bidirectional link between periodontitis and inflammatory bowel disease (IBD). To investigate this relationship, experimental models commonly use dextran sodium sulfate (DSS) to induce colitis. However, DSS is presumed to selectively affect the colon, and its potential off‐target effects on the oral cavity remain poorly understood. We examined whether DSS disrupts oral health, potentially confounding oral–gut axis research. Methods C57BL/6 mice received 2% DSS in drinking water for 8 days, followed by 2 days of untreated water. Colitis severity was assessed by weight loss, colon length, histopathology, and quantitative real‐time–polymerase chain reaction (qRT‐PCR). Oral health was evaluated via micro–computed tomography (micro‐CT) analysis of alveolar bone, gingival histology, cytokine expression, and 16S rRNA sequencing of the oral microbiome. Results DSS induced hallmark features of colitis, including weight loss, colon shortening, epithelial crypt damage, and mucosal inflammation. Strikingly, DSS also induced significant oral pathology, including alveolar bone loss, gingival epithelial hyperplasia, inflammatory infiltration, and upregulated gingival pro‐inflammatory cytokines (interleukin IL ‐6, IL‐17, tumor necrosis factor‐alpha TNF‐α). DSS further altered the oral microbiota causing reduced alpha‐diversity and a dysbiotic shift, with enrichment of Streptococcus danieliae and depletion of commensals such as Lactobacillus murinus and Clostridium ASF502 . These microbial changes were accompanied by upregulated pathways involved in carbohydrate metabolism, oxidative stress response, and environmental sensing. Conclusion DSS induces periodontal inflammation and oral dysbiosis, independent of colitis. These findings expose a critical confounder in oral–gut axis models and highlight the need to include DSS‐only or periodontitis‐only controls and alternative models to accurately distinguish systemic effects of DSS from true oral–gut interactions. Plain language summary This study shows that dextran sodium sulfate (DSS), a chemical used to model gut inflammation in mice, also causes gum disease‐like changes—including bone loss, inflammation, and changes in oral bacteria. These findings reveal that DSS alone can affect the mouth and may confound studies investigating links between gum disease and inflammatory bowel disease, highlighting the need for better‐controlled models.