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. 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 down-regulates expressions of ATG16L1 and lysozyme, and impairs anti-microbial 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 IBD patients. 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.

The effect of polymeric formula on enterocyte differentiation

“…Both are shown mediate an increase in Caco-2 differentiation through the VDR [33] and to increase its expression [56] with butyrate shown to be more potent [33].…”

“…Vitamin D deficiency is commonly seen in IBD [51,[55][56], and VDR knockout mice have a significant reduction in the ATG16L1 protein, one of the main risk genes for CD [56]. Most individuals get almost their entire required daily intake through a reaction between UV and vitamin D precursors in the skin [32].…”

“…Almost all known actions of vitamin D are mediated through the VDR [33,56]. Caco-2 cells, like normal enterocytes, have a functional VDR at all stages of differentiation [30].…”

Vitamin D and population health; a nephrology viewpoint

“…Sunlight plays a vital role in absorbing vitamin D in the body, then vitamin D should be converted to 25-hydroxyvitamin D, or calcidiol that is converted to calcitriol in the kidneys (3). Vitamin D helps calcium absorption in the intestine and provides sufficient concentration of calcium and phosphate for bone formation and prevention of tetanus due to hypocalcemia (4). Vitamin D is also essential to grow and regenerate bones by osteoblasts and osteoclasts (5).…”

“…Today, bone fracture due to osteoporotic state is a health problem around the world that poses a risk to 40% of women and 13% of men over the age of 50 years. Vitamin D is essential for the absorption of calcium from the intestine (3,4,14). Calcium is one of the essential factors for homeostasis.…”