Hyperglycemia impairs the expression of inflammatory mediators in rat intestine: an implication for intestinal inflammation and inflammatory bowel disease

Diabetes mellitus and inflammatory bowel disease are chronic inflammatory disorders characterized by immune dysregulation and rising global prevalence. Epidemiological studies increasingly suggest a bidirectional association between the two conditions, linked through shared mechanisms of intestinal barrier dysfunction, microbial dysbiosis, and sustained innate immune activation. Activated macrophages play a central role in driving mucosal inflammation through polarization toward a pro-inflammatory M1 phenotype, accompanied by increased production of inflammatory cytokines. These mediators disrupt tight junctions, induce epithelial apoptosis, and perpetuate cycles of immune activation and tissue injury. This macrophage-cytokine axis not only amplifies local inflammation but also sustains chronic barrier dysfunction, creating a pathogenic overlap between diabetes mellitus-associated intestinal injury and intestinal bowel disease. In this study, we used a low dose streptozotocin and high-fat diet-induced diabetic Sprague-Dawley rat model in both sexes to investigate the effects of chronic hyperglycemia on intestinal inflammation, with particular emphasis on macrophage activation and pro-inflammatory cytokine responses. We found inflammation in both small and large intestines with mucosal injury and barrier disruption, and immune activation involving macrophages and enhanced expression of CD68, iNOS, TNF-α, and IL-6. Female rats were more susceptible to gut-related inflammatory changes due to diabetes. These findings suggest a complex interplay between epithelial stress, immune signaling, and microbial factors supporting the role of intestinal inflammation in the immune-metabolic interaction in diabetes-associated intestinal changes, which may contribute to the pathogenesis of inflammatory bowel disease.