Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis
Shaoping Wu,Yong Guo Zhang,Rong Lu,Yinglin Xia,David Zhou,Elaine O. Petrof,Erika C. Claud,Di Chen,Eugene B. Chang,Geert Carmeliet,Jun Sun +10 more
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TLDR
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 is demonstrated.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. 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 (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.read more
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Journal ArticleDOI
Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.
TL;DR: The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange, which will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications.
Journal ArticleDOI
Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease
Floris Imhann,Arnau Vich Vila,Marc Jan Bonder,Jingyuan Fu,Dirk Gevers,Marijn C. Visschedijk,Lieke M. Spekhorst,Rudi Alberts,Lude Franke,Hendrik M. van Dullemen,Rinze W. F. ter Steege,Curtis Huttenhower,Curtis Huttenhower,Gerard Dijkstra,Ramnik J. Xavier,Ramnik J. Xavier,Eleonora A. M. Festen,Cisca Wijmenga,Alexandra Zhernakova,Rinse K. Weersma +19 more
TL;DR: It is shown for the first time that genetic risk variants associated with IBD influence the gut microbiota in healthy individuals.
Journal ArticleDOI
Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut
Andrea Michielan,Renata D'Incà +1 more
TL;DR: Functional tests, such as the sugar absorption tests or the novel imaging technique using confocal laser endomicroscopy, allow an in vivo assessment of gut barrier integrity and Antitumor necrosis factor-α (TNF-α) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients.
Journal ArticleDOI
Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer
TL;DR: Evidence for the influence of the microbiome, diet, and environmental factors on CRC incidence and outcomes is reviewed and features of the intestinal microbiome might be used for CRC screening and modified for chemoprevention and treatment are modified.
Journal ArticleDOI
New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD.
TL;DR: This review describes the latest researches on the mechanisms by which dysfunctional autophagy leads to disrupted intestinal epithelial function, gut dysbiosis, defect in anti-microbial peptide secretion by Paneth cells, endoplasmic reticulum stress response and aberrant immune responses to pathogenic bacteria.
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