Vitamin D inhibits the development of colorectal cancer cells by regulating the gut microbiota and immune microenvironment using JAKSTAT signaling pathway

Objective To investigate whether vitamin D modulates gut microbiota and the colorectal cancer (CRC) immune microenvironment through the vitamin D receptor (VDR)-JAK-STAT signaling pathway.Methods Thirty male SD rats were randomly divided into the control group (CG), model group (MG), and vitamin D intervention group (VDG). Protein expression levels of VDR-JAK-STAT pathway (VDR, p-JAK2/JAK2, p-STAT3/STAT3), gut microbiota composition (via 16S rRNA sequencing), and immune markers (CD4+/CD8+ T cells, regulatory T cells (Treg), interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α were compared across the groups.Results Compared to the CG, the MG exhibited a significant reduction in VDR expression (p < 0.05) and a marked increase in the p-JAK2/JAK2 and p-STAT3/STAT3 ratios (p < 0.05). The gut microbiota α-diversity (Shannon/Chao1 indices) was significantly reduced (p < 0.05), and microbial composition was abnormal, with a decrease in Bacteroidetes and an increase in Firmicutes/Proteobacteria (p < 0.05). Immune microenvironment imbalance was characterized by a reduction in CD4+ T cells (p < 0.05), an increase in Treg cells (p < 0.05), elevated pro-inflammatory cytokines IL-6/TNF-α, and decreased anti-inflammatory cytokine IL-10 (p < 0.05). Vitamin D intervention significantly reversed these abnormalities (all p < 0.05). The MG also showed a significant increase in macrophage proportion and M2 polarization, and a significant decrease in dendritic cell proportion and M1 macrophage polarization (all p < 0.01). Vitamin D intervention reversed the polarization imbalance, reducing total macrophages, increasing M1 polarization, and decreasing M2 polarization (all p < 0.05).Conclusion Vitamin D inhibits excessive activation of the JAK-STAT pathway through VDR activation, ameliorates gut microbiota dysbiosis, restores butyrate metabolism, and rebalances macrophage polarization.