Effects of UVR exposure on the gut microbiota of mice and humans.

Many alterations to the skin microbiome by exposure to UV radiation (UVR) have been postulated and may contribute to the ability of UVR phototherapy to regulate skin inflammatory diseases. Very recently, an effect of sub-erythemal narrowband UVB radiation (311 nm) on the gut microbiome of healthy individuals was reported. The relative abundance of Firmicutes and Proteobacteria increased in faecal samples of those receiving three exposures to narrowband UVB radiation; the Bacteroidetes phyla were reduced by UVB. In mice chronically exposed to sub-erythemal broadband UVR, similar faecal changes in Firmicutes and Bacteroidetes have been reported. Murine studies have allowed a further dissection of the relative ability of UVR and dietary vitamin D to modulate the gut microbiome by analysis of relative bacterial abundance in mice with similar 25-hydroxy vitamin D levels obtained by UVR exposure or from their diet, respectively. The studies of mice recovering from colitis suggested that dietary vitamin D could stimulate greater faecal abundance of Rikenellaceae, whilst exposure to UVR was necessary for changes to the abundance of Lachnospiraceae and Desulfovibrionaceae. Both human and murine studies report that multiple exposures to sub-erythemal UVR can increase the diversity of the gut microbiome, which in turn may be beneficial to the health of the host.

Vitamin D metabolites are lower with active Crohn's disease and spontaneously recover with development of remission.

BACKGROUND: Vitamin D deficiency is associated with active Crohn's disease (CD). However, it remains unclear if lower 25-hydroxyvitamin D [25(OH)D] concentration is the cause, or consequence, of intestinal inflammation. Existing literature has focused on circulating 25(OH)D rather than the active metabolite 1,25(OH)2D, or its breakdown product, 24,25(OH)2D. We aimed to characterise vitamin D metabolism in a cohort of patients with active and inactive CD. METHODS: Fifty-four patients with CD and not on corticosteroids or vitamin D supplements, were enrolled in a 6-month prospective cohort study. Sera were collected on enrolment and at 6 months and tested for 25(OH)D, 1,25(OH)2D, 24,25(OH)2D using liquid chromatography tandem mass spectroscopy as well as vitamin-D-binding protein. RESULTS: There were no differences in 25(OH)D or 1,25(OH)2D levels between participants with active versus inactive disease. Levels of 24,25(OH)2D were significantly lower in those with active compared with inactive disease (mean 3.9 versus 6.0 µmol/l; p = 0.007) and therefore the ratio of 25(OH)D:24,25(OH)2D was higher (mean 17.3 versus 11.1; p = 0.001). In those patients with active disease who achieved remission, there was a mean increase in 25(OH)D of 32.3 nmol/l (i.e. to a level in the sufficient range) and 24,25(OH)2D of 2.1 µmol/l. These increases were not seen in patients with persistently active or inactive disease. CONCLUSION: Levels of 24,25(OH)2D, but not 25(OH)D, were lower in patients with active CD, and spontaneously increased with resolution of underlying inflammation. The utility of 24,25(OH)2D as a biomarker of disease activity and vitamin D status in CD warrants further exploration.

Vitamin D C3-epimer levels are proportionally higher with oral vitamin D supplementation compared to ultraviolet irradiation of skin in mice but not humans.

A proportion of circulating 25-hydroxy vitamin D3 (25(OH)D3)) undergoes epimerization to form C3-epi 25(OH)D3 and C3-epi 1,25(OH)2D3. These epimers have less calcaemic activity than non-epimerized metabolites and are not differentiated by many immunoassays when reporting total 25(OH)D3 levels. This study aimed to compare the effect of exposure to ultraviolet radiation (UVR) and oral vitamin D3 supplementation on vitamin D C3-epimer levels. C57Bl/6 female mice were fed either vitamin D-sufficient (vitamin D3 2000 IU/kg) or -deficient diets (no vitamin D3) for 4 weeks. Among the vitamin D-deficient group, the shaved backs of half were irradiated daily for 4 days with 1 kJ/m2 UVR, followed by twice weekly irradiation for 4 weeks. Despite similar 25(OH)D3 levels, the UV-irradiated group had a lower proportion of C3-epi 25(OH)D3 at week 7 (p < 0.05) and week 9 (p < 0.01). C3-epimer concentrations and %C3-epi 25(OH)D3 were also analysed in serum samples from two human clinical trials. These trials investigated the effect of high dose oral vitamin D3 supplementation and narrowband UVB phototherapy, respectively. Serum 25(OH)D3 and the %C3-epi 25(OH)D3 levels measured at 12 months after oral vitamin D3 supplementation were not significantly different to those measured at the time of maximal effect of phototherapy (2 months). Thus, the proportion of 25(OH)D3 that undergoes epimerization is greater with oral vitamin D3 supplementation than exposure to UVR in mice, but not in humans. This important difference between human and murine vitamin D metabolism warrants consideration when interpreting animal studies.

High Dose Vitamin D supplementation alters faecal microbiome and predisposes mice to more severe colitis.

Vitamin D has been suggested as a possible adjunctive treatment to ameliorate disease severity in human inflammatory bowel disease. In this study, the effects of diets containing high (D++, 10,000 IU/kg), moderate (D+, 2,280 IU/kg) or no vitamin D (D-) on the severity of dextran sodium sulphate (DSS) colitis in female C57Bl/6 mice were investigated. The group on high dose vitamin D (D++) developed the most severe colitis as measured by blinded endoscopic (p < 0.001) and histologic (p < 0.05) assessment, weight loss (p < 0.001), drop in serum albumin (p = 0.05) and increased expression of colonic TNF-α (p < 0.05). Microbiota analysis of faecal DNA showed that the microbial composition of D++ control mice was more similar to that of DSS mice. Serum 25(OH)D3 levels reduced by 63% in the D++ group and 23% in the D+ group after 6 days of DSS treatment. Thus, high dose vitamin D supplementation is associated with a shift to a more inflammatory faecal microbiome and increased susceptibility to colitis, with a fall in circulating vitamin D occurring as a secondary event in response to the inflammatory process.

The role of vitamin D in gastrointestinal inflammation.

The emerging role of vitamin D as a regulator of both innate and adaptive immune responses has encouraged the investigation of its role in the pathogenesis of a variety of autoimmune conditions including the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Animal models consistently demonstrate that vitamin D significantly impacts on the modulation of astrointestinal inflammation, while epidemiological and observational data show an inverse relationship between vitamin D status and the onset/progression of Crohn's disease as well as the development of colorectal cancer. As vitamin D supplementation is readily available, at low cost, it is a very attractive potential therapeutic option. The biological plausibility for a role for vitamin D in inflammation modulation, the potential genetic links associated with vitamin D metabolism and the clinical aspects for it in IBD will be discussed.