We previously showed that vitamin D receptor (VDR) plays a crucial role in acute inflammatory bowel disease and that intestinal fibrosis is a common complication of Crohn’s disease (CD). Epithelial-to-mesenchymal transition (EMT) is an important hallmark of fibrogenesis through which epithelial cells lose their epithelial phenotype and transform into mesenchymal cells. It is known that VDR plays an essential role in epithelial integrity and mitochondrial function, but its role in intestinal fibrosis remains unknown. Here, we investigated whether VDR is involved in epithelial mitochondrial dysfunction that results in EMT in intestinal fibrosis. Using human CD samples, intestinal-specific VDR-knockout (VDR) mice, and fibroblast cellular models, we showed that the expression of VDR was significantly lower in intestinal stenotic areas than in nonstenotic areas in patients with chronic Crohn’s disease. Genetic deletion of VDR in the intestinal epithelium exacerbated intestinal fibrosis in mice administered with DSS or TNBS, two experimental colitis inducers. Additionally, we found that vitamin D dietary intervention regulated intestinal fibrosis by modulating the intestinal expression of VDR. Mechanistically, knocking down VDR in both CCD-18Co cells and human primary colonic fibroblasts promoted fibroblast activation, while VDR overexpression or VDR agonist administration inhibited fibroblast activation. Further analysis illustrated that VDR inhibited EMT in the HT29 cell model and that mitochondrial dysfunction mediated epithelial integrity and barrier function in VDR-deficient epithelial cells. Together, our data for the first time demonstrate that VDR activation alleviates intestinal fibrosis by inhibiting fibroblast activation and epithelial mitochondria-mediated EMT.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
About The Expert
Mengli Yu
Hao Wu
Jinhai Wang
Xueyang Chen
Jiaqi Pan
Peihao Liu
Jie Zhang
Yishu Chen
Wei Zhu
Chenxi Tang
Qi Jin
Chunxiao Li
Chao Lu
Hang Zeng
Chaohui Yu
Jing Sun
References
PubMed