Periodontitis Exacerbates Insulin Resistance via Gut Barrier Dysfunction and TLR4/NF-κB Activation

Introduction and aims Periodontitis and type 2 diabetes mellitus (T2DM) are interrelated, potentially linked through intestinal barrier dysfunction. Yet, whether their comorbidity is associated with worsened barrier integrity and how this relates to insulin resistance remain unclear. This study examined associations between periodontitis, gut barrier disruption, Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) activation, and metabolic parameters in a T2DM mouse model.Methods Twenty-four C57BL/6 mice were randomised into 4 groups (n = 6): healthy control, chronic periodontitis, T2DM without periodontitis (DNP), and T2DM with periodontitis (DP). Glucose homeostasis was assessed by measuring fasting blood glucose and the area under the curve of oral glucose tolerance tests and insulin tolerance tests. The colonic barrier's biological, chemical, physical, and immune properties were evaluated using 16S ribosomal RNA sequencing, haematoxylin and eosin staining, transmission electron microscopy, reverse transcription polymerase chain reaction, Western blotting, and flow cytometry. Furthermore, serum insulin and inflammatory cytokines were quantified by enzyme-linked immunosorbent assay.Results The composition of both the periodontal and faecal microbiota in the DP group was markedly different from that in the DNP group. In the DP group, transmission electron microscopy revealed severe damage to colonic mucosal ultrastructure; messenger RNA and protein expression levels of MUC2 and tight junctions (including occludin, claudin-1, and ZO-1) were significantly decreased; the proportion of regulatory T cells diminished, while Th17 cells increased, resulting in an imbalanced regulatory T-cell/Th17 ratio. Proinflammatory cytokines in intestinal tissues and serum were raised, whereas anti-inflammatory cytokines were decreased. Moreover, in the DP group, activation of the TLR4/NF-κB pathway was observed in intestinal tissue. Notably, levels of fasting blood glucose, serum insulin, and area under the curve for oral glucose tolerance tests and insulin tolerance tests were all higher in the DP group than in the DNP group.Conclusions Periodontitis is related to intestinal barrier disruption, TLR4/NF-κB signalling activation, and worsened metabolic parameters in T2DM mice.Clinical relevance These findings may establish periodontitis as a potent driver of gut barrier dysfunction, systemic inflammation, and insulin resistance, highlighting its profound impact on metabolic health.