Clinical Evaluation of Vitamin A Supplementation on Disease Development, Progression and Treatment of Multiple Sclerosis: Current Evidence and Future Perspectives

Research Article

Austin J Nutri Food Sci. 2022; 10(1): 1163.

Clinical Evaluation of Vitamin A Supplementation on Disease Development, Progression and Treatment of Multiple Sclerosis: Current Evidence and Future Perspectives

Tryfonos C1*, Mantzorou M1, Fotiou D2, Serdari A3, Pavlidou E1, Karampinaki M1, Vadikolias K4 and Giaginis C1*

1Department of Food Science and Nutrition, University of the Aegean, Myrina, Lemnos, Greece

2Department of Neurology, School of Medicine, Aristotelian University of Thessaloniki, Thessaloniki, Greece

3Department of Psychiatry, Faculty of Health Sciences, Department of Medicine, Democritus University of Thrace, Alexandroupoli, Greece

4Department of Neurology, School of Medicine, Democritus University of Thrace, Alexandroupoli, Greece

*Corresponding author: Christina Tryfonos, Department of Food Science and Nutrition, School of the Environment, University of the Aegean, Lemnos, GR 81400, Greece

Constantinos Giaginis, Associate Professor of Human Nutrition, Wellness and Health, Department of Food Science and Nutrition School of the Environment, University of the Aegean, Lemnos, GR 81400, Greece

Received: February 21, 2022; Accepted: March 19, 2022; Published: March 26, 2022


Vitamin A constitutes an essential nutrient with important actions in immunological responses and the Central Nervous System (CNS). Neuroimmunological functions of vitamin A are mediated through its active metabolite, Retinoic Acid (RA). RA contributes to the regeneration and plasticity of the CNS, exerting also a key role in enhancing tolerance and reducing inflammatory responses by regulating T- and B- cells, as well dendritic cells’ populations. Several important studies have documented low plasma vitamin A levels in patients suffering from Multiple Sclerosis (MS). Vitamin A deficiency also leads to dysregulation of immune tolerance and pathogenic immune cell production in MS.

In view of the above, the present review aims to critically summarize and discuss the currently available clinical studies, focusing on the potential beneficial effects of vitamin A on controlling MS pathophysiology.

Cochrane Register of Controlled Trials (CENTRAL), BioMed Central, and MEDLINE databases database was thoroughly searched, using relative keywords, in order to identify clinical trials published in English. According to the existing clinical studies, the role of vitamin A in MS could be dual: it may decrease inflammation, while, at the same time, it may increase autoimmunity tolerance, also contributing to brain protection of MS patients. However, it must be stated that, at the present time, there is no clear clinical indication for using vitamin A as a complimentary treatment for MS.

Further clinical trials with vitamin A supplementation as a potential cotreatment agent or as an add-on option are strongly recommended.

Keywords: Vitamin A; Multiple sclerosis; Inflammation; Immunological response; Central nervous system


Vitamin A is a lipid soluble vitamin that cannot be synthesized by mammals and must be obtained from the diet, as either pre-formed vitamin A (e.g. liver) or carotenoid-containing fruits and vegetables [1]. Retinoid homeostasis is a tightly regulated process with a number of specific carrier proteins and enzymes, being involved in transportation, storage, metabolism and clearance. Vitamin A (and pro-vitamin A in the form of carotenoids) is absorbed via the mucosal cells of the small intestine [2,3] and can either be transported to target tissues or stored in the liver [4]. Through binding to Retinoic Acid Receptors (RARs) and Retinoid X Receptors (RXRs), this ligand regulates target gene transcription [5,6]. Retinoic acid can enhance or decrease expression of more than 500 genes depending on the target cell type and the physiological state of the organism [6,7].

Multiple Sclerosis (MS) is a demyelinating disease, in which the insulating covers of nerve cells in the brain and the spinal cord are damaged [8]. MS constitutes a chronic inflammatory disease that leads to degeneration of the brain and spinal tissue. Imbalance of CD4+ T-cells, their secreted cytokines and their relative gene expression are all-important aspects of MS immune-pathogenesis [9]. MS usually appears in adults in their late twenties or early thirties, whereas it rarely starts in childhood or after 50 years of age [10]. Similar to many other autoimmune disorders, MS is more common in women, and this trend prevalence is expected to in-crease in the future [8]. As of 2008, it is about two times more common in women than in men globally [10].

The formation of lesions in the CNS (also called plaques), the inflammation and the destruction of myelin sheaths of neurons are considered to be the three basic characteristics of MS. The interaction of these features to produce the breakdown of the nerve tissue and, as a result, the following disease symptoms, are very complicated and not entirely well understood, so far [8]. It is believed that the interaction of the individuals’ genetics and several currently unidentified environmental factors may lead to increased risk for MS development [11,12]. Also, MS involves the loss of oligodendrocytes, which are the responsible cells for creating and maintaining myelin, which supports the neurons to carry electrical signals [8]. When myelin is destroyed, a neuron can no longer effectively conduct electrical signals. Then, a repair process, called remyelination, takes place in early phases of the disease [13], but repeated attacks from the immune system lead to successively less effective remyelination, until a scar-like plaque is built up around the damaged axons [14]. Regardless of the underlying conditions for MS, some damage is triggered by a Cerebrospinal Fluid (CSF) unknown soluble factor, which is produced in meningeal areas and diffuses into the cortical parenchyma. This factor can destroy myelin either in a direct or indirect way through microglia activation [15].

Several disease phenotypes have been the focus of many studies. The course of MS is used by phenotypes in order to predict future disease progression. They are important not only for disease prognosis, but also for treatment decisions. In 1996, the United States National Multiple Sclerosis Society described four clinical courses [16]. In 2013, these courses were reviewed by an international panel, adding clinically isolated syndrome and radiologically isolated syndrome as phenotypes, without changing the main structure [17]. These phenotypes include Relapsing-Remitting MS (RRMS), characterised by periods of neurological relapses, followed by remissions; Secondary Progressive MS (SPMS), in which there is a gradual progression of neurological dysfunction with fewer or no relapses; Primary Progressive MS (PPMS), in which there is neurological deterioration from disease onset. It should be noted that the Progressive Relapsing MS (PRMS) entity was removed in the 2013 review [17].

Most of the currently available evidence, as far as MS aetiology is concerned, suggests that disease prevalence depends on the interaction between diet and visible sunlight exposure. The recommended diet program includes supplementation with fish oils, avoidance of saturated fats, and the associated intake of antioxidants with unsaturated fatty acids [18]. The antioxidant properties of vitamin A may lead to inhibition of leukotriene synthesis [19], increasing tolerance and decreasing inflammation [20]. Moreover, vitamin D is considered to exert an important immune function. Notably, low serum levels of 25-Hydroxyvitamin D (25OH-vitamin D) were associated with enhanced disease progression over 5 years in a large population of individuals presenting a first demyelinating episode [21]. Visible solar radiation could be of benefit due to vitamin A releasing from visual pigment rhodopsin [19]. It should be noted that 1,25 (OH)-vitamin D and RA may exert synergistic effects on the regulation of T-cells, in particular T helper 17 (Th17) cells [22]. Thus, the epidemiological observations on the prevalence of MS may be attributed to the inter-action of both factors [19].

Fragoso et al. have documented that several environmental modifiable factors may be involved in MS, such us low adherence to treatment, smoking, obesity, low levels of liposoluble vitamins A and D, high salt consumption, and a sedentary life-style [12]. A recent meta-analysis has also shown that smoking is strongly associated with increased MS prevalence [23]. Notably, smokers are in two times greater risk of developing MS compared to non-smokers [24]. MS patients who smoke also tend to have a more severe disease course and a faster disability progression rate [25]. Moreover, individuals, who were overweight or obese during childhood or adolescence, are more likely to develop MS in adulthood. It has also been reported that physical exercise may induce favorable changes in T-cells, by reducing plasma levels of both interferon gamma (INF-γ) and interleukin-17 (IL-17) [18]. The somatic-affective improvement in mood also occurs due to regular physical activities [26]. Moreover, vitamin A adequacy may ameliorate several pro-inflammatory states that enforce MS disease onset [20]. Considerable improvement in MS in-flammatory conditions could be achieved by smoking cessation, reducing over-weight or obesity, enhancing physical activities or increasing vitamin levels. The possibility of modification of these environmental risk factors could be an important approach in MS management [12]. Notably, there are more than 136 ongoing clinical trials on National MS Society website, testing different FDA approved therapeutic agents for MS relapsing forms [27]. This indicates that a new approach for the treatment of MS disease is being investigated.

Materials and Methods

Cochrane Register of Controlled Trials (CENTRAL), BioMed Central, and MED-LINE databases were thoroughly searched until December 2017. The selection criteria were clinical trials, in vivo trials and English language. The keywords that were used were “vitamin A”, “multiple sclerosis”, “supplementation”. Another se-lection criterion for the trials was the correlation of vitamin A supplementation with the effect of vitamin A or its derivatives on the progression or against disease development, progression and treatment of multiple sclerosis.


Utility of Vitamin A and its metabolites against MS pathogenesis: Potential beneficial actions

The role of Th17 cells and T regulatory (Treg) cells in MS pathogenesis, the effect of vitamin A and its active metabolite RA, as well as the management of inflammation have been analyzed by many, mainly in vitro, studies. Also, it is known that in MS, the balance between Th17 cells and Treg cells is impaired [28]. It was shown by magnetic resonance imaging that serum-retinol may predict new T1Gd (+) and T2 lesions six months ahead. Notably, an increase of retinol by 1μmol is likely to decrease the risk of developing Gadolinium (Gd) enhancing lesions (Gd-enhancement is a marker for blood brain barrier breakdown, and histologically is correlated with the inflammatory phase of lesion development), new T2 lesions and active lesions by 49%, 42% and 46%, respectively [29].

Vitamin A and its metabolites also appear to be effective in preventing progression of several autoimmune diseases, including MS. More to the point, vitamin A has been considered to be an essential nutrient that exerts important actions in immuno-logical responses and CNS [30]. Specifically, neuro-immunological functions of vita-min A are mediated through its active metabolite, RA. In the CNS, RA contributes to regeneration and plasticity, playing also a key role in enhancing tolerance and reducing inflammatory responses by regulating T- and B- cell and dendritic cell populations. Substantial clinical evidence has indicated that MS patients are characterised by significantly low plasma vitamin A levels and that vitamin A deficiency may lead to dysregulation of immune tolerance, inducing pathogenic immune cell production [30].

Vitamin A may ameliorate MS pathogenesis through several mechanisms, including reduction of inflammatory processes by re-establishing the balance between pathogenic (Th1, Th17, Th9) and immune-protective (Th2, Treg) cells, modulation of B-cells and dendritic cells functions, as well as increase of autoimmunity and regeneration tolerance in the CNS [30,31]. Thus, vitamin A could be considered as a potential co-treatment agent in MS disease management [30,31]. Vitamin A supplementation also inhibits Th1 cells’ and promotes Th2 cells’ differentiation, both in vitro and in vivo [20]. Moreover, RA promotes Th2 cells’ differentiation by inducing Gata3, Stat6, and IL-4 genes and inhibiting T-bet gene expression [20]. Vitamin A could also decrease peripheral blood mononuclear cells proliferation in the presence of myelin oligodendrocyte glycoprotein [25]. In addition, it has been reported that RA can modulate gene expression of specific nuclear receptors, including Fork box P3 (FoxP3) [3]. Several studies have also shown that RA may elicit pro-inflammatory Th1 and Th17 cells’ responses to infection [20]. Notably, RA receptor alpha (RARa) seems to be a critical mediator of the above beneficial effects. A functional role for RA-RARa axis in the development of both regulatory and inflammatory reactions governing adaptive immune system has also been suggested [13]. In Figure 1, the potential beneficial actions of vitamin A by its metabolites, against MS are depicted.

Citation: Tryfonos C, Mantzorou M, Fotiou D, Serdari A, Pavlidou E, Karampinaki M, et al. Clinical Evaluation of Vitamin A Supplementation on Disease Development, Progression and Treatment of Multiple Sclerosis: Current Evidence and Future Perspectives. Austin J Nutri Food Sci. 2022; 10(1): 1163.