Periodontitis aggravates high-fat diet-induced MASLD via gut microbiota dysbiosis and metabolic dysfunction in mice

Periodontitis has been recognized as a contributing factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise mechanisms through which periodontitis influences the pathogenesis of MASLD remain unclear. This study aimed to investigate the association between experimental periodontitis and MASLD severity and to explore the potential underlying mechanisms using a ligature-induced periodontitis model under low-fat diet (LFD) and high-fat diet (HFD) conditions. A total of 40 mice were divided into four groups: low-fat diet control group (LFD-Ctrl), low-fat diet with periodontitis group (LFD-Perio), high-fat diet control group (HFD-Ctrl), and high-fat diet with periodontitis group (HFD-Perio), with 10 mice initially assigned to each group. Mice were fed an HFD for 12 weeks to establish the MASLD model, followed by ligature-induced periodontitis for 4 weeks. Periodontal inflammation and alveolar bone loss were assessed using micro-computed tomography (Micro-CT), hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining, while MASLD severity was evaluated via hepatic H&E staining, Oil Red O staining, periodic acid-Schiff (PAS) staining, Masson's Trichrome staining, nonalcoholic fatty liver disease activity score (NAS), alpha-smooth muscle actin (α-SMA) expression, pericellular fibrosis, and serum lipid and liver enzyme measurements. Compared with HFD-Ctrl mice, HFD-Perio mice exhibited aggravated MASLD-related phenotypes, including elevated fasting blood glucose, significantly increased homeostatic model assessment for insulin resistance (HOMA-IR) (2.89 ± 0.67 vs. 1.93 ± 0.26, P < 0.0001), higher nonalcoholic fatty liver disease activity score (NAS) (4.57 ± 0.71 vs. 2.30 ± 0.33, P < 0.01), and more pronounced pericellular fibrosis. Gut microbiota analysis showed that the Firmicutes/Bacteroidota ratio was further increased in HFD-Perio mice compared with HFD-Ctrl mice (9.39 ± 2.82 vs. 5.48 ± 1.98, P < 0.05), accompanied by enrichment of the genus Helicobacter. These findings indicate that experimental periodontitis aggravates HFD-induced MASLD phenotypes, potentially via metabolic dysregulation, liver inflammation and fibrosis, and gut microbiota dysbiosis, highlighting the need for further studies to clarify whether periodontal health influences MASLD progression.