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.
