Vitamin D₃ ameliorates hyperglycemia by modulating gut microbiota and metabolites in prediabetic KKay mice

Prediabetes represents a pivotal stage in the development and pathogenesis of diabetes, during which notable alterations in the gut microbiota can be observed. Vitamin D (VD) showed anti-diabetic properties, but it is unknown whether the improvement of VD on hyperglycemia is associated with gut microbiota. Thus, our objective was to investigate and verify the effects of VD₃ on glucose metabolism in prediabetes, as well as to elucidate the underlying mechanisms. In this study, different concentrations of VD₃ were intraperitoneally administered to prediabetic mice induced by high fat diet for 16 weeks. Biochemical analyses, oral glucose tolerance test, 16S rRNA and untargeted metabolomics were used, the mechanism was explored. Then, fecal suspensions collected from the above donors were transplanted into KKay mice for 6 weeks, and the relevant indicators were measured. The results showed that VD₃ intervention alleviated glucose metabolism in KKay mice. It increased the protein expression of colon tight junction proteins, alleviated metabolic endotoxemia and inflammation, so that reduced tumor necrosis factor alpha (TNFα) induced toll-like receptor 4/nuclear factor kappa-B (TLR4/NFκB) and improvement of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) insulin signaling pathway. VD₃ affected the structure of gut microbiota and metabolites, and functional prediction analysis suggested that VD₃ may affect carbohydrate. Besides, the effect of VD₃ could be delivered by fecal microbiota transplantation (FMT). Consequently, VD₃ ameliorate glucose metabolism by modulating gut microbiota and metabolites in KKay mice, and this ability could be transferred by FMT.