Activated vitamin D3 improves the microbiota and intestinal barrier in type 2 diabetic mice via modulating AMPK activation

The association between vitamin D and type 2 diabetes mellitus (T2DM) pathogenesis, particularly through gut microbial interactions, requires further elucidation. This study investigates vitamin D-microbial interactions in T2DM pathogenesis, targeting their modulation of inflammatory cascades and redox imbalance. After successfully establishing a T2DM mouse model using a high-fat diet (HFD)/streptozotocin (STZ), the mice were treated with activated Vitamin D₃ (1,25(OH)₂D₃) for 4 weeks. Systemic parameters including glycemic control (FBG, GHbA1c, insulin), oxidative stress biomarkers (ROS, MDA, T-AOC, CAT), proinflammatory cytokines (TNF-α, TNF-β), and lipopolysaccharide (LPS) levels were measured. Microbial community profiling via 16 S rRNA sequencing, while colonic redox status (MDA/SOD), barrier integrity (ZO-1/Occludin), and metabolic signaling (SIRT1, p-AMPK) were analyzed. T2DM mice exhibited gut microbial dysbiosis, marked by significant enrichment of Enterococcus and Enterobacter, whose abundances correlated positively with hyperglycemia, inflammation, and oxidative stress. Histopathological analyses concurrently demonstrated compromised intestinal barrier integrity, characterized by reduced ZO-1/Occludin protein expression and SOD activity. Notably, treatment with 1,25(OH)₂D₃ effectively mitigated these pathological changes and concurrently enhanced AMPK phosphorylation in the colon. These findings position vitamin D-AMPK axis modulation as a promising therapeutic strategy for microbiota-metabolism crosstalk in T2DM, highlighting its translational potential for clinical validation.