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Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis
  1. Shaoping Wu1,
  2. Yong-guo Zhang1,
  3. Rong Lu1,
  4. Yinglin Xia2,
  5. David Zhou3,
  6. Elaine O Petrof4,
  7. Erika C Claud5,6,
  8. Di Chen1,
  9. Eugene B Chang6,
  10. Geert Carmeliet7,
  11. Jun Sun1
  1. 1Department of Biochemistry, Rush University, Chicago, Illinois, USA
  2. 2Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA
  3. 3Department of Pathology, University of Rochester, Rochester, New York, USA
  4. 4Department of Medicine, GI Diseases Research Unit and Division of Infectious Diseases, Queen's University, Kingston, Ontario, Canada
  5. 5Departments of Pediatrics, The University of Chicago Medical Center, Chicago, Illinois, USA
  6. 6Departments of Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA
  7. 7Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
  1. Correspondence to Dr Jun Sun, Department of Biochemistry, Rush University, Cohn Research Building, 1735 W. Harrison St., 506, Chicago, IL 60612, USA; jun_sun{at}


Objective Vitamin D and the vitamin D receptor (VDR) appear to be important immunological regulators of inflammatory bowel diseases (IBD). Defective autophagy has also been implicated in IBD, where interestingly, polymorphisms of genes such as ATG16L1 have been associated with increased risk. Although vitamin D, the microbiome and autophagy are all involved in pathogenesis of IBD, it remains unclear whether these processes are related or function independently.

Design We investigated the effects and mechanisms of intestinal epithelial VDR in healthy and inflamed states using cell culture models, a conditional VDR knockout mouse model (VDRΔIEC), colitis models and human samples.

Results Absence of intestinal epithelial VDR affects microbial assemblage and increases susceptibility to dextran sulfate sodium-induced colitis. Intestinal epithelial VDR downregulates expressions of ATG16L1 and lysozyme, and impairs antimicrobial function of Paneth cells. Gain and loss-of-function assays showed that VDR levels regulate ATG16L1 and lysozyme at the transcriptional and translational levels. Moreover, low levels of intestinal epithelial VDR correlated with reduced ATG16L1 and representation by intestinal Bacteroides in patients with IBD. Administration of the butyrate (a fermentation product of gut microbes) increases intestinal VDR expression and suppresses inflammation in a colitis model.

Conclusions Our study demonstrates fundamental relationship between VDR, autophagy and gut microbial assemblage that is essential for maintaining intestinal homeostasis, but also in contributing to the pathophysiology of IBD. These insights can be leveraged to define therapeutic targets for restoring VDR expression and function.

  • Inflammatory Bowel Disease
  • Vitamin D Receptor Gene
  • Epithelial Cells

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