title: Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis.
abstract: 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.
  
  
  METHODS
  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 (VDR(ΔIEC)), 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.
authors: Department of Biochemistry, Rush University, Chicago, Illinois, USA.
authors: Shaoping
authors: S
authors: Wu
authors: Department of Biochemistry, Rush University, Chicago, Illinois, USA.
authors: Yong-Guo
authors: YG
authors: Zhang
authors: Department of Biochemistry, Rush University, Chicago, Illinois, USA.
authors: Rong
authors: R
authors: Lu
authors: Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA.
authors: Yinglin
authors: Y
authors: Xia
authors: Department of Pathology, University of Rochester, Rochester, New York, USA.
authors: David
authors: D
authors: Zhou
authors: Department of Medicine, GI Diseases Research Unit and Division of Infectious Diseases, Queen's University, Kingston, Ontario, Canada.
authors: Elaine O
authors: EO
authors: Petrof
authors: Departments of Pediatrics, The University of Chicago Medical Center, Chicago, Illinois, USA Departments of Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA.
authors: Erika C
authors: EC
authors: Claud
authors: Department of Biochemistry, Rush University, Chicago, Illinois, USA.
authors: Di
authors: D
authors: Chen
authors: Departments of Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA.
authors: Eugene B
authors: EB
authors: Chang
authors: Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors: Geert
authors: G
authors: Carmeliet
authors: Department of Biochemistry, Rush University, Chicago, Illinois, USA.
authors: Jun
authors: J
authors: Sun
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D003092:Colitis / Q000276:immunology / Q000503:physiopathology*; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism*; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008875:Middle Aged; D019879:Paneth Cells / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000276:immunology / Q000502:physiology*
chemical_list: D018167:Receptors, Calcitriol
keywords: Epithelial Cells; Inflammatory Bowel Disease; Vitamin D Receptor Gene