Rationale: The prevalence of vitamin D deficiency is increasing and has been linked to obstructive lung diseases including asthma and chronic obstructive pulmonary disease. Recent studies suggest that vitamin D deficiency is associated with reduced lung function. The relationship between vitamin D deficiency and lung function is confounded by the association between physical activity levels and vitamin D status. Thus, causal data confirming a relationship between vitamin D and lung function are lacking. Objectives: To determine if vitamin D deficiency alters lung structure and function. Methods: A physiologically relevant BALB/c mouse model of vitamin D deficiency was developed by dietary manipulation. Offspring from deficient and replete colonies of mice were studied for somatic growth, lung function, and lung structure at 2 weeks of age. Measurements and Main Results: Lung volume and function were measured by plethysmography and the forced oscillation technique, respectively. Lung structure was assessed histologically. Vitamin D deficiency did not alter somatic growth but decreased lung volume. There were corresponding deficits in lung function that could not be entirely explained by lung volume. The volume dependence of lung mechanics was altered by deficiency suggesting altered tissue structure. However, the primary histologic difference between groups was lung size rather than an alteration in architecture. Conclusions: Vitamin D deficiency causes deficits in lung function that are primarily explained by differences in lung volume. This study is the first to provide direct mechanistic evidence linking vitamin D deficiency and lung development, which may explain the association between obstructive lung disease and vitamin D status.

The immunomodulatory effects of vitamin D have been described following chronic oral administration to mice or supplementation of cell cultures with 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), the active form of vitamin D. In this study, topically applied 1,25(OH)₂D₃, enhanced the suppressive capacity of CD4⁺CD25⁺ cells from the draining lymph nodes. The effects of topical 1,25(OH)₂D₃ were compared with those of UVB irradiation, which is the environmental factor required for 1,25(OH)₂D₃ production in skin. CD4⁺ cells from the skin-draining lymph nodes (SDLN) of either 1,25(OH)₂D₃-treated or UVB-irradiated mice had reduced capacity to proliferate to Ags presented in vitro, and could suppress Ag-specific immune responses upon adoptive transfer into naive mice. This regulation was lost upon removal of CD4⁺CD25⁺ cells. Furthermore, purified CD4⁺CD25⁺ cells from the SDLN of 1,25(OH)₂D₃-treated or UVB-irradiated mice compared with equal numbers of CD4⁺CD25⁺ cells from control mice had increased capacity to suppress immune responses in both in vitro and in vivo assay systems. Following the sensitization of recipient mice with OVA, the proportion of CD4⁺Foxp3⁺ cells of donor origin significantly increased in recipients of CD4⁺CD25⁺ cells from the SDLN of 1,25(OH)₂D₃-treated mice, indicating that these regulatory T cells can expand in vivo with antigenic stimulation. These studies suggest that 1,25(OH)₂D₃ may be an important mediator by which UVB-irradiation exerts some of its immunomodulatory effects.

The role of vitamin D in curtailing the development of obesity and comorbidities such as the metabolic syndrome (MetS) and type 2 diabetes has received much attention recently. However, clinical trials have failed to conclusively demonstrate the benefits of vitamin D supplementation. In most studies, serum 25-hydroxyvitamin D [25(OH)D] decreases with increasing BMI above normal weight. These low 25(OH)D levels may also be a proxy for reduced exposure to sunlight-derived ultraviolet radiation (UVR). Here we investigate whether UVR and/or vitamin D supplementation modifies the development of obesity and type 2 diabetes in a murine model of obesity. Long-term suberythemal and erythemal UVR significantly suppressed weight gain, glucose intolerance, insulin resistance, nonalcoholic fatty liver disease measures; and serum levels of fasting insulin, glucose, and cholesterol in C57BL/6 male mice fed a high-fat diet. However, many of the benefits of UVR were not reproduced by vitamin D supplementation. In further mechanistic studies, skin induction of the UVR-induced mediator nitric oxide (NO) reproduced many of the effects of UVR. These studies suggest that UVR (sunlight exposure) may be an effective means of suppressing the development of obesity and MetS, through mechanisms that are independent of vitamin D but dependent on other UVR-induced mediators such as NO.

Altered composition of gut bacteria and changes to the production of their bioactive metabolites, the short-chain fatty acids (SCFAs), have been implicated in the development of multiple sclerosis (MS). However, the immunomodulatory actions of SCFAs and intermediaries in their ability to influence MS pathogenesis are uncertain. In this study, levels of serum SCFAs were correlated with immune cell abundance and phenotype as well as with other relevant serum factors in blood samples taken at first presentation of Clinically Isolated Syndrome (CIS; an early form of MS) or MS and compared to healthy controls. There was a small but significant reduction in propionate levels in the serum of patients with CIS or MS compared with healthy controls. The frequencies of circulating T follicular regulatory cells and T follicular helper cells were significantly positively correlated with serum levels of propionate. Levels of butyrate associated positively with frequencies of IL-10-producing B-cells and negatively with frequencies of class-switched memory B-cells. TNF production by polyclonally-activated B-cells correlated negatively with acetate levels. Levels of serum SCFAs associated with changes in circulating immune cells and biomarkers implicated in the development of MS.