Vitamin D 3 Spatially Regulates Gut Homeostasis in Obese Mice: Segmental Epithelial Integrity and Microbial Ecology

Obesity is closely linked to vitamin D3 (VD3) deficiency and intestinal homeostasis disruption, underscoring a VD3-gut homeostasis-obesity triad. This study investigates how VD₃ spatially regulates gut epithelial homeostasis and microbiota in high-fat diet (HFD)-induced obese mice, highlighting its significance for obesity nutritional management. Mice fed with a standard HFD served as models of diet-induced obesity and were administrated VD3. Epithelial oxidative stress/inflammation, barrier function, and microbiota were assessed across intestinal segments to evaluate VD3’s spatially specific role in intestinal homeostasis regulation under obese physiology. It was found that VD3 supplementation could suppress HFD-induced weight gain. Comparative analysis of duodenal, jejunal, ileal, and colonic epithelia revealed that VD3 preferentially alleviated oxidative stress, inflammation, and barrier dysfunction in the ileum and colon: colonic pro-inflammatory cytokines decreased by 29.26–47.90%, markedly higher than in the ileum (8.68–34.18%); VD3 upregulated ileal tight junction proteins mRNA and protein expression levels (73.26-197.62% and 66.63-199.89%) and mucin (8.68%), while balancing colonic pro-inflammatory macrophage (M1)/anti-inflammatory macrophage (M2) polarization. Gut microbiota analysis demonstrated VD3 enriched Lactobacillus in the ileum and Lachnospiraceae in the colon, while suppressing Faecalibaculum and Romboutsia. VD₃ exhibits segment-specific gut homeostasis regulation in obesity through antioxidant, anti-inflammatory, barrier repair, and microbiota remodeling mechanisms, validating the necessity of micronutrient supplementation for obesity management.