Illuminating the Role of Vitamin A in Skin Innate Immunity and the Skin Microbiome: A Narrative Review

Vitamin A is a fat-soluble vitamin that plays an important role in skin immunity. Deficiencies in Vitamin A have been linked to impaired immune response and increased susceptibility to skin infections and inflammatory skin disease. This narrative review summarizes recent primary evidence that elucidates the role of vitamin A and its derivatives on innate immune regulators through mechanisms that promote skin immunity and sustain the skin microbiome.     

Vitamin A as an anti-inflammatory agent

Vitamin A is necessary for normal differentiation of epithelial tissues, the visual process and reproduction, and is vital for the optimal maintenance and functioning of the innate and adaptive immune system. Vitamin A deficiency is one of the most profuse nutritional deficiencies worldwide. It is associated with increased susceptibility to infectious diseases in both man and animal models. Vitamin A also has a role as an anti-inflammatory agent. Supplementation with vitamin A has been found to be beneficial in a number of inflammatory conditions, including skin disorders such as acne vulgaris, broncho-pulmonary dysplasia and some forms of precancerous and cancer states. The present review suggests that vitamin A deficiency induces inflammation and aggravates existing inflammatory states. Supplementation with vitamin A in selected cases could ameliorate inflammation. The two main mechanisms which appear to be involved in the prevention of disease are the effects of vitamin A on the immune system and the effect on epithelial integrity.     

Vitamin D and Crohn's Disease in the Adult Patient

Crohn's disease (CD) is characterized as a chronic immune‐mediated inflammatory disorder of the gastrointestinal tract. Current consensus surrounding the cause of the disease suggests a complex interplay between genetic susceptibility, the intestinal microbiome and environmental factors, leading to the aberrant Th1 and Th17 immune cell mediated response. Vitamin D deficiency is common in CD patients, and long‐standing deficiency has been associated with reduced bone mineral density (BMD). Accumulating evidence now suggests that in addition to maintaining skeletal integrity, vitamin D also plays an integral role in regulating the general immune response, a function employed via its genomic actions on the vitamin D receptor (VDR). The VDR is expressed in all immune cells and both directly and indirectly targeted by the bioactive form of vitamin D, 1,25‐Dihydroxyvitamin D (1,25[OH]₂D). Impaired regulation or deficiency of the vitamin has been linked to the promotion of self‐reactive T cell development, loss of immune tolerance to self‐structures, and experimental colitis in animal models, whereas the subsequent administration of the vitamin in these models resulted in the improvement of immune‐mediated symptoms. In addition, low vitamin D has been associated with disease activity in CD patients, and supplementation appears to be beneficial in improving clinical scores and reducing inflammation. Therefore, the primary aims of this article were to review the molecular evidence supporting the immunoregulatory roles of vitamin D and its supplementation in the CD patient, based on existing literature. The physiological processes, accepted serum concentration values, and its well‐recognized role in bone health were also summarized.     

Retinoid repletion of vitamin A-deficient mice restores IgG responses.

Vitamin A-deficient (A-) mice produce poor IgG antibody responses due to a helper T cell dysfunction. We performed retinoid repletion studies to determine the minimum dietary retinyl acetate dose and the most active retinoid for supporting immune function. Dietary retinyl acetate repletion at 2 (R2 group) or 4 (R4 group) microgram/g diet restored serum retinol in A- mice to vitamin A-sufficient (A+) control levels within 24 h. However, in R4 mice, liver retinyl palmitate was restored about twofold faster than in R2 mice; liver retinyl palmitate reached A+ control levels by d 30 in R4 mice but not in R2 mice. We challenged the mice with antigen 24 h post repletion; the R4 mice gave an IgG1 response equal to that of A+ controls, but the R2 mice were comparable with the A- controls. We also compared four retinoids for IgG1 response restoration in vitro; 1 nmol/L retinoic acid fully repleted A- cell IgG1 responses and helper T cell frequencies to the unsupplemented A+ control levels. Retinoic acid was at least 10-fold more active than retinyl acetate or retinaldehyde, and 100-fold more active than retinol. Collectively, our results suggest that retinoic acid is probably the physiologically important metabolite for sustaining IgG immune responses in vivo. We discuss the possible relationship between liver retinyl palmitate levels and availability of retinoic acid to support immune function.     

Effect of vitamin A deficiency on the immune response in obesity

Obesity has been associated with low-grade systemic inflammation and with micronutrient deficiencies. Obese individuals have been found to have lower vitamin A levels and lower vitamin A intake compared with normal-weight individuals. Vitamin A plays a major role in the immune function, including innate immunity, cell-mediated immunity and humoral antibody immunity. It has also been recognised recently that vitamin A has important regulatory functions. Vitamin A status has an important effect on the chronic inflammatory response. Vitamin A deficiency increases a T-helper type 1 (Th1) response, elevates levels of pro-inflammatory cytokines, increases the expression of leptin, resistin and uncoupling proteins (UCP) and promotes adipogenesis. The effect of vitamin A deficiency on obesity might be increasing the risk of fat deposition and also the risk of chronic inflammation associated with obesity. Supplementation with vitamin A in vitro and in animal models has been found to reduce concentrations of adipocytokines, such as leptin and resistin. In conclusion, vitamin A deficiency increases a Th1 response in the presence of obesity and thus, increases the inflammatory process involved in chronic inflammation and fat deposition. The metabolism of leptin and other adipocytokines may play a critical role in the effect of vitamin A deficiency in the inflammatory response observed in obesity.     

Vitamin A/Retinol and Maintenance of Pluripotency of Stem Cells

Retinol, the alcohol form of vitamin A is a key dietary component that plays a critical role in vertebrate development, cell differentiation, reproduction, vision and immune system. Natural and synthetic analogs of retinol, called retinoids, have generally been associated with the cell differentiation via retinoic acid which is the most potent metabolite of retinol. However, a direct function of retinol has not been fully investigated. New evidence has now emerged that retinol supports the self-renewal of stem cells including embryonic stem cells (ESCs), germ line stem cells (GSCs) and cancer stem cells (CSCs) by activating the endogenous machinery for self-renewal by a retinoic acid independent mechanism. The studies have also revealed that stem cells do not contain enzymes that are responsible for metabolizing retinol into retinoic acid. This new function of retinol may have important implications for stem cell biology which can be exploited for quantitative production of pure population of pluripotent stem cells for regenerative medicine as well as clinical applications for cancer therapeutics.     

维生素A缺乏与儿童感染性疾病

维生素A是人体生长发育重要的营养素之一,不仅参与机体新陈代谢,维持人体正常视觉反应,也维持黏膜上皮完整性,在肠道感染和呼吸道感染中发挥辅助抗感染作用。本文将对维生素A缺乏与儿童感染性疾病的相关性进行简要概述。     

Vitamin D and the Athlete: Risks,Recommendations, and Benefits

Vitamin D is well known for its role in calcium regulation and bone health, but emerging literature tells of vitamin D’s central role in other vital body processes, such as: signaling gene response, protein synthesis, hormone synthesis, immune response, plus, cell turnover and regeneration. The discovery of the vitamin D receptor within the muscle suggested a significant role for vitamin D in muscle tissue function. This discovery led researchers to question the impact that vitamin D deficiency could have on athletic performance and injury. With over 77% of the general population considered vitamin D insufficient, it’s likely that many athletes fall into the same category. Research has suggested vitamin D to have a significant effect on muscle weakness, pain, balance, and fractures in the aging population; still, the athletic population is yet to be fully examined. There are few studies to date that have examined the relationship between vitamin D status and performance, therefore, this review will focus on the bodily roles of vitamin D, recommended 25(OH)D levels, vitamin D intake guidelines and risk factors for vitamin D insufficiency in athletes. In addition, the preliminary findings regarding vitamin D’s impact on athletic performance will be examined.     

Vitamin A status modulates intestinal adaptation after partial small bowel resection

BACKGROUND: Intestinal adaptation after loss of functional small bowel surface area is characterized by cellular hyperplasia and increased absorptive function. Interventions to enhance the adaptive response are needed to decrease the morbidity and mortality associated with short bowel syndrome. Retinoic acid was shown to stimulate crypt cell proliferation in the adapting remnant rat ileum by 6 hours after resection. Thus, vitamin A, which is required for normal epithelial cell proliferation and differentiation and which can modulate programmed cell death, may play an important role in the adapting intestine. On the basis of these observations, the effects of vitamin A deficiency on intestinal morphology, epithelial cell proliferation, and apoptosis in the adapting intestine after resection were investigated. METHODS: Weanling male Sprague-Dawley rats fed either a vitamin A-deficient or -sufficient diet for 58 days underwent 70% proximal small bowel resection. The deficient rats were divided into cohorts that were either maintained on the experimental diet after surgery or replenished with vitamin A 20 hours before surgery and switched to the control diet after surgery. RESULTS: Ten days after resection, vitamin A-deficient rats exhibited a markedly blunted adaptive response. The adaptive increase in villus height and crypt depth was absent in the deficient rats. However, adaptive increases in crypt cell proliferation were not attenuated by vitamin A deficiency, and there were no differences in apoptotic indices. CONCLUSIONS: Vitamin A deficiency inhibits the adaptive response to partial small bowel resection, supporting a role for vitamin A in the adaptive process. Changes in cellular proliferation or programmed cell death are not sufficient to account for this inhibition. This model system will be useful for examining the role of other mechanisms, such as changes in cell-cell and cell-extracellular matrix interactions, and rates of epithelial cell migration and cell extrusion.     

The effect of vitamin A on epithelial integrity.

Vitamin A is the generic term for a variety of fat-soluble substances including retinol, retinyl palmitate and the provitamin A carotenoids such as all-trans-beta-carotene. Vitamin A is commonly known as the anti-infective vitamin and has an essential role in vision and cellular differentiation, the latter providing a unique core mechanism helping to explain the influence of vitamin A on epithelial barriers. Alterations in the epithelial lining of vital organs occur early in deficiency, suggesting a potentially important role for the barrier function. Vitamin A deficiency (VAD) is most commonly recognized in the eye. The conjunctival-impression cytology test detects the presence of larger irregular keratinized cells and the absence of mucous-secreting goblet cells, indicative of VAD. The method is simple, quick and sensitive in populations where VAD is present. In the respiratory tract, observational studies all show an association with VAD, although vitamin A supplementation studies appear to have little effect on respiratory disease. Organ-specific targeting may improve success rates. The dual-sugar intestinal-permeability test allows the effect of vitamin A supplementation to be monitored on the gastrointestinal tract. Two vitamin A supplementation studies were carried out recently in Orissa State, India. Healthy infants of weaning age were administered orally eight weekly doses of 5.0 mg retinol equivalents and hospitalized infants received one large oral dose 60 mg retinol equivalents in the form of retinyl palmitate. Improvements in gut integrity and haematological status were observed in both studies. In summary, the response of the eye to vitamin A supplementation is well established; the present review highlights some of the more recent observations examining the effects of vitamin A.     

Effects of retinoic acid on hepatic cytochrome P-450 dependent enzymes in rats under different vitamin A status

The temporal effects of retinoic acid supplementation on hepatic cytochrome P-450-dependent enzymes were studied on the rat. Four groups of male weanling rats were fed semi synthetic diets: two groups containing 0 or 4.4 mg retinol equivalents per kg diet as retinyl palmitate (A- RA- and A+ RA- groups) and two similar groups supplemented with all trans retinoic acid (12 mg/kg diet) (A- RA+ and A+ RA+ groups). After five or ten weeks of feeding, the rats were killed, liver microsomes were prepared and assayed for aniline hydroxylase, aminopyrine N demethylase activities and cytochrome P-450 levels. Whereas no change was observed between the four groups after 5 weeks, the following modifications appeared after 10 weeks: Vitamin A deficiency decreased hepatic drug metabolism by phase I enzymes (hydroxylase and N demethylase) but only when liver storage pool was not detectable. Vitamin A concentration as low as 4 micrograms/g is sufficient to avoid any perturbation of these enzymes. Parallel to a sparing effect on liver reserves of vitamin A, retinoic acid maintained a normal activity of enzymes of xenobiotic metabolism. However, retinoic acid treatment produced an alteration of phase I enzymes in vitamin A supplemented group (A+ RA+). As this was accompanied by a doubling of vitamin A liver reserves, compared to A+ RA- group, it is suggested that this might result from a liver vitamin A overloading, leading to membrane damage perturbing microsomal enzymes. These results indicate the need for a more careful use of retinoids as a therapeutic agent.     

Vitamin D and influenza

Vitamin D has become increasingly recognized in the literature for its extra-skeletal roles, including an effect on inflammation and the immune response to infection. Our goal was to describe the role of vitamin D in the immune response and implications for the risk of influenza infection in humans. In this review, we first consider literature that provides molecular and genetic support to the idea that vitamin D is related to the adaptive and innate immune responses to influenza infection in vitro and in animal models. We then discuss observational studies and randomized controlled trials of vitamin D supplementation in humans. Finally, we consider some of the knowledge gaps surrounding vitamin D and immune response that must be filled.     

All-trans retinoic acid biases immune response induced by DNA vaccine in a Th2 direction

Vitamin A deficiency diminishes Th2-mediated Ab responses. Providing Vitamin A or its active metabolites reverses this defect. All-trans retinoic acid (ATRA), an acid derivation of Vitamin A, regulates the balance of immune response induced by TR421-hCGbeta DNA vaccine. Compared to DNA vaccine alone or treatment with vehicle, significantly higher level of antibody against the protein encoded by DNA vaccine was observed in mice 6 weeks after the first immunization. The IgG2a/IgG1 ratio was lower in mice treated with ATRA. We also found that treatment with ATRA also diminishes specific cellular immune response induced by gene immunization by measuring the marker of cellular immune response. We conclude that ATRA biases the immune response to Th2 direction induced by DNA vaccine and acts as a candidate adjuvant and immunomodulatory molecule.     

维生素D与儿童感染性疾病相关性及其抗感染机制研究

维生素D是类固醇类激素超家族中的一员,除调节钙磷代谢,维持儿童骨骼健康的经典作用外,维生素D还具有重要的免疫调节作用。近年来多项研究表明,维生素D低水平与儿童多种感染性疾病的发生、进展相关,维生素D增补被用于治疗与预防多种儿童感染性疾病。本文就维生素D营养状况与儿童感染性疾病的相关性及其抗感染机制进行简要综述。     

Vitamin A-not for your eyes only: requirement for heart formation begins early in embryogenesis

Vitamin A insufficiency has profound adverse effects on embryonic development. Major advances in understanding the role of vitamin A in vertebrate heart formation have been made since the discovery that the vitamin A active form, all-trans-retinoic acid, regulates many genes, including developmental genes. Among the experimental models used, the vitamin A-deficient avian embryo has been an important tool to study the function of vitamin A during early heart formation. A cluster of retinoic acid-regulated developmental genes have been identified that participate in building the heart. In the absence of retinoic acid the embryonic heart develops abnormally leading to embryolethality.     

The Function Of Retinol And Retinoic Acid In The Testes

Vitamin A-deficient rats have lowered testosterone levels which can be restored by retinoic acid. Since retinoic acid cannot restore the germinal epithelium in vitamin A-deficient rats, these results indicate a role for retinoic acid in testosterone synthesis.     

Vitamin B6 and Immune Function in the Elderly and HIV-seropositive Subjects

Vitamin B₆ plays an important role in immune response. A recent investigation of healthy elderly subjects in a vitamin B₆ depletion-repletion study indicates that B₆ deficiency impairs interleukin-2 production and lymphocyte proliferation. Another study in HIV-1-infected patients found impaired immune responsiveness in patients with compromised vitamin B₆ status.