Vitamin D Regulates the Gut Microbiome and Protects Mice from Dextran Sodium Sulfate–Induced Colitis

Abstract

The active form of vitamin D [1,25-dihydroxycholecalciferol, 1,25(OH)2D3] and the vitamin D receptor (VDR) regulate susceptibility to experimental colitis. The effect of the bacterial microflora on the susceptibility of C57BL/6 mice to dextran sodium sulfate-induced colitis was determined. Mice that cannot produce 1,25(OH)2D3 [Cyp27b1 (Cyp) knockout (KO)], VDR KO as well as their wild-type littermates were used. Cyp KO and VDR KO mice had more bacteria from the Bacteroidetes and Proteobacteria phyla and fewer bacteria from the Firmicutes and Deferribacteres phyla in the feces compared with wild-type. In particular, there were more beneficial bacteria, including the Lactobacillaceae and Lachnospiraceae families, in feces from Cyp KO and VDR KO mice than in feces from wild-type. Helicobacteraceae family member numbers were elevated in Cyp KO compared with wild-type mice. Depletion of the gut bacterial flora using antibiotics protected mice from colitis. 1,25(OH)2D3 treatment (1.25 μg/100 g diet) of Cyp KO mice decreased colitis severity and reduced the numbers of Helicobacteraceae in the feces compared with the numbers in the feces of untreated Cyp KO mice. The mechanisms by which the dysbiosis occurs in VDR KO and Cyp KO mice included lower expression of E-cadherin on gut epithelial and immune cells and fewer tolerogenic dendritic cells that resulted in more gut inflammation in VDR and Cyp KO mice compared with wild-type mice. Increased host inflammation has been shown to provide pathogens with substrates to out-compete more beneficial bacterial species. Our data demonstrate that vitamin D regulates the gut microbiome and that 1,25(OH)2D3 or VDR deficiency results in dysbiosis, leading to greater susceptibility to injury in the gut.

Vitamin D as a novel therapy in inflammatory bowel disease: new hope or false dawn?

“…Relevant to IBD, there is evidence that vitamin D deficiency may compromise the gastrointestinal mucosal barrier, whereas active vitamin D appears to promotes epithelial integrity through up-regulation of tight junction proteins zonula occcludens-1 and claudin-1 (61,62) . Some reports suggest changes in the gut microbial composition in animal models (63) in response to vitamin D. Despite immense interest in the gut microbiome (64,65) this has yet to be investigated in response to vitamin D therapy in CD. Although some parallels exist, the degree to which the immune effects observed in animal models translate to human IBD is not fully understood.…”

Optimal vitamin D levels in Crohn's disease: a review

“…Evidence suggests that vitamin D increases tight junction proteins and enhances gut mucosal healing post-injury (77) . For example, following exposure to dextran sulphate sodium, a chemical which induces colitis, the VDR knock out mice were unable to maintain the integrity of the epithelial barrier (69,78) and had lower expression of tight junction proteins than in wild-type mice (77)(78)(79) . As a result of reduced tight junction proteins, vitamin D-deficient and VDR knock out mice had increased gut permeability compared with vitamin D-sufficient wild-type mice (78) .…”

“…For example, following exposure to dextran sulphate sodium, a chemical which induces colitis, the VDR knock out mice were unable to maintain the integrity of the epithelial barrier (69,78) and had lower expression of tight junction proteins than in wild-type mice (77)(78)(79) . As a result of reduced tight junction proteins, vitamin D-deficient and VDR knock out mice had increased gut permeability compared with vitamin D-sufficient wild-type mice (78) . Whilst the basic science supports a role for vitamin D in Crohn's disease as reviewed elsewhere (80) , further work is required to establish if this translates to human studies.…”

Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation

“…70 Furthermore, intake of micronutrients such as vitamins A, 59, 71, 72 C, 59, 73 and E 73 has been inversely associated with asthma, whereas vitamin D insufficiency has been associated with higher asthma disease burden 74 and lower lung function. 75,76 Although the exact mechanism through which vitamin D influences asthma in obese children is not known, vitamin D does have immunomodulatory effects 77 and may influence intestinal microflora, 78 mechanisms that have been associated with asthma pathophysiology. 79,80 There is also evidence to suggest that maternal diet may influence incident childhood asthma and obesity, an aspect that has been previously reviewed.…”