The effect of nutrition and dietary supplements on the course of multiple sclerosis (MS) is a topic of great interest to both patients and clinicians. In particular, vitamin D status has been shown to influence both the incidence and the course of MS. High vitamin D levels are probably protective against the development of MS, although the efficacy of vitamin D supplementation in slowing progression of MS remains to be established. The influence of polyunsaturated fatty acids (PUFAs) on the development and course of MS has also long been under investigation. Small clinical trials suggest a modest reduction in the severity and duration of relapses in patients with MS receiving PUFA supplements. Other nutritional factors have been evaluated for their effect on MS disease progression, including milk proteins, gluten, probiotics, antioxidants (uric acid, vitamins A, C and E, lipoic acid), polyphenols, Ginkgo biloba extracts and curcumin. However, further studies are needed to evaluate the effects of these dietary components on the relapse rate and progression of MS. This Review gives an overview of the literature on the nutritional factors most commonly implicated as having an effect on MS and discusses the biological rationale that is thought to underlie their influence.
Dietary changes and nutritional supplements are widely used by patients with multiple sclerosis (MS), but reliable evidence of their risks, benefits, and underlying mechanisms is limited
In observational studies, low vitamin D levels are associated with a worse course of disease in patients with MS
Polyunsaturated fatty acid supplementation and a low-fat diet attenuate MS immune responses in vitro and in animal models, but limited trials have shown no clear benefit in patients with MS
Antioxidants, probiotics and vitamin B12 supplementation attenuate MS immune responses in vitro and reduce disease symptoms in animal models, but data from human studies are limited
Milk proteins and gluten are thought to worsen the outcomes of patients with MS, but no randomized controlled trials have assessed the effect of dietary restrictions in this setting
Multiple sclerosis (MS) is a chronic neurological disease that is a major cause of disability in young adults. In the majority of patients, the disease course is initially characterized by clinical exacerbations (known as attacks or relapses) associated with the development of demyelinating CNS lesions. Although degenerative changes might begin early in the disease course, neurodegeneration is principally thought to underlie the progressive neurological deterioration that occurs in later disease stages. MS is generally considered to be an autoimmune disease, although both genetic and environmental factors seem to have a role in its pathogenesis. Environmental factors that have been identified as increasing the risk of developing MS and/or affecting the prognosis of this disease include vitamin D status, cigarette smoking and evidence of prior infection with Epstein–Barr virus. In addition to vitamin D status, however, multiple other nutritional factors have been implicated as having an effect on the prognosis and risk of developing MS.
One of the first researchers to suggest a relationship between diet and MS was Roy Swank, who conducted epidemiological studies of MS in Norway in the 1940s. He found that people living inland in farming districts, who consumed high amounts of butterfat (the lipid component of milk), had higher rates of MS than were observed among people in coastal fishing villages, who consumed high amounts of fish. He concluded that a high butterfat intake leads to an increased risk of developing MS, whereas a fish-based diet is associated with a decreased risk of MS. He also developed dietary recommendations based on these findings.1 Subsequently, other dietary components and nutrients have been implicated in the development of MS, or as having an effect on its prognosis. Nutritional supplements and diets constitute an important part of complementary therapies for MS and are used by at least 30% of patients.2
In this Review, we provide an overview of the literature on nutritional factors that have been thought or shown to have an effect on either the course or prognosis of MS. This article also discusses the biological mechanisms that might underlie these associations.
Biosynthesis, dietary sources and insufficiency
The biologically active form of vitamin D, 1,25-dihydroxyvitamin D (calcitriol), is a fat-soluble compound synthesized in the kidneys from its precursor 25-hydroxyvitamin D.3 The majority of 25-hydroxyvitamin D is derived from 7-dehydrocholesterol, itself a derivative of cholesterol.4 This conversion occurs in the skin and requires exposure to sunlight, specifically ultraviolet B (UVB) light. The skin's ability to synthesize 25-hydroxyvitamin D decreases with advancing age, and absorption of UVB can also be significantly decreased by skin pigmentation, use of sunscreen, pollution and other environmental factors.5 Cholecalciferol (an inactive, unhydroxylated form of vitamin D3) and ergocalciferol (vitamin D2, an active, fungus-derived form of vitamin D), can also be ingested in foods, including some dairy products and fish. In many countries, including the US, Canada, and some European countries, vitamin D3 or vitamin D2 is added to foods such as milk, cereal, orange juice and cheese in a process called fortification. For this reason, a person's vitamin D status is best measured as their 25-hydroxyvitamin D level in serum or plasma, which indicates both vitamin D2 and vitamin D3 intake.
Vitamin D insufficiency and deficiency are common worldwide, although the specific concentrations that define these states are still controversial. In 2010, the US Institute of Medicine increased its recommended dietary intake of vitamin D for adults under the age of 70 years from 400 IU to 600 IU daily.6 By contrast, the recommendation in several European countries, including Germany, is 800 IU daily. However, in Canada, despite milk being fortified with vitamin D at about 400 IU/l, the actual dietary intake in the general population is only about 200 IU daily.7 In Germany, dietary intake is even lower, with a median daily intake of 2.9 µg (116 IU) in men and 2.2 µg (88 IU) in women.8
Association with multiple sclerosis
Evidence is growing that in addition to increasing the risk of developing MS,9 vitamin D deficiency worsens both the clinical course and disease burden seen by MRI in patients with MS. In a large cross-sectional study conducted in Australia, low vitamin D levels were associated with high scores on the Expanded Disability Status Scale (EDSS) in MS patients.10 A retrospective study, conducted in the Netherlands, demonstrated that low levels of vitamin D were associated with increased relapse rate and disability in MS patients in the 2 years preceding enrolment.11 However, these cross-sectional and retrospective studies could not determine whether vitamin D deficiency was the result, rather than the cause, of increased disability. This problem was addressed in a retrospective study of patients with paediatric-onset MS and clinically isolated syndrome, which demonstrated that participants' baseline vitamin D levels were inversely associated with their subsequent risk of relapse.12 Each 10 ng/ml increment in vitamin D concentration was associated with a 34% decrease in the risk of subsequent relapse, after adjusting for potential confounding factors, including age, sex, race, ethnicity, disease duration and disease-modifying therapy. A similar 3 year prospective cohort study in adults demonstrated that levels of vitamin D have an inverse linear correlation with the risk of MS relapse.13
Vitamin D levels also seem to be inversely associated with the development of new brain lesions on MRI, which is often considered a correlate of attacks. In a cohort of patients with MS who were followed up for 5 years, each 10 ng/ml increment in vitamin D level was associated with a 15% lower risk of subsequently developing new lesions detectable by T2-weighted MRI, and a 32% lower risk of subsequently developing new lesions detectable by gadolinium-enhanced MRI.14 This inverse association between vitamin D levels and MRI evidence of disease activity was confirmed in a study that involved serial assessments of both vitamin D levels and MRI findings.15 However, the association was only seen before initiation of treatment with interferon β (IFN-β). The authors of the study suggested that IFN-β treatment reduced disease activity detectable by MRI so much that an additional effect of vitamin D was difficult to appreciate, though more-complex interactions between disease-modifying therapies and vitamin D levels are possible.
That vitamin D could have a role in the pathogenesis of MS is biologically plausible, given the growing body of in vitro evidence demonstrating an effect of vitamin D on immune function. Antigen-presenting cells (dendritic cells, macrophages and B cells) as well as monocytes and activated T cells express vitamin D receptors.16 1,25-dihydroxyvitamin D3 inhibits the proliferation of B cells and plasma cells and enhances apoptosis of activated B lymphocytes.17 High levels of vitamin D are associated with reduced immunoglobulin synthesis.18 Vitamin D also suppresses terminal differentiation of dendritic cells.19,20 However, no association was found between intrathecal levels of IgG and 25-hydroxyvitamin D concentrations in patients with MS,21 and vitamin D supplementation in patients with MS did not affect B-cell phenotype or isotype switching; as such, the effect of vitamin D on humoral immunity requires further investigation.22 Dendritic cells and monocytes exposed to 1,25-dihydroxyvitamin D3 downregulate MHC class II HLAs and produce more IL-10 and less IL-12 than do unexposed cells, which results in decreased T-cell activation and the induction of regulatory T cells.23 Moreover, proliferation of CD4+CD25+ regulatory T cells increases on addition of vitamin D receptor agonists, consistent with an overall anti-inflammatory effect of vitamin D.24,25 Finally, abnormal T-cell responses to myelin basic protein in the blood of patients with MS can be suppressed in vivo by treatment with vitamin D.26 A summary of the potential effects of different nutritional supplements, including vitamin D on MS disease course is given in Figure 1.
In mice, vitamin D deficiency in utero leads to impaired development of invariant natural killer cells that cannot be reversed by postnatal treatment with calcitriol.27 Invariant natural killer cells are important suppressors of autoimmune disease, including experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS. High levels of 1,25-dihydroxyvitamin D3 prevent the onset and reduce symptoms of EAE in mice,28 although this effect might depend on the presence of sufficient calcium levels.29 Vitamin D regulates calcium and phosphate levels in the blood by promoting the absorption of calcium in the gut, and research suggests that calcium intake can in turn influence metabolic consumption of vitamin D. UV radiation also protects against development of EAE; this effect was independent of vitamin D levels and may be caused by direct effects of UV radiation on the immune system such as inhibition of antigen presentation, alteration of inflammatory cytokine levels or induction of suppressor T-cell populations.30,31
In Lewis rats with chronic relapsing EAE, treatment with 1,25-dihydroxyvitamin D3, vitamin D analogues or vitamin D receptor agonists leads to rapid clinical improvement.32 Animals with EAE that are treated with vitamin D have significantly reduced inflammation in white matter and meninges compared with controls.33,34 A study published in 2011 showed that supplementation with 1,25-dihydroxyvitamin D3 ameliorates EAE symptoms only in animals with T cells that have a functional vitamin D receptor, suggesting a beneficial effect of vitamin D directly on the population of CD4+ T cells that drive EAE.35 Treatment of animals with experimental autoimmune prostatitis with vitamin D agonists inhibits the proliferation of proinflammatory T helper 1 (TH1) cells and reduces production of IL-17,36 which modulates disease activity in EAE.37 Other studies, however, report contradictory data, such as delayed onset and reduced severity of EAE in vitamin-D-deficient mice38 and their offspring.39 The implications of these findings are unclear, though it has been suggested that early vitamin D deficiency may affect the development of the immune system.
Vitamin D might also reduce demyelination independently of its effects on immune-mediated processes. This effect was studied in a mouse model of MS that used cuprizone to achieve toxic, rather than lymphocyte-mediated, demyelination.40 Both high (6,200 IU/kg) and very high (12,500 IU/kg) doses of vitamin D significantly reduced the extent of demyelination and attenuated microglial activation. Additionally, some evidence suggests that vitamin D might protect against neurodegeneration. Vitamin D is converted into its biologically active form in microglia,41 in which it upregulates the expression of neurotrophins and glutathione.42,43 In vitro, vitamin D can protect neurons from the glutamate-induced cytotoxicity that has been associated with active MS lesions and EAE;44 however, the role of glutamate excitotoxicity in the pathogenesis of MS is still a matter of contention.
Whether vitamin D supplementation can improve the course of MS in humans remains unclear. Most trials published to date are limited by their small sample sizes. An open-label, 1-year randomized controlled trial involving 49 patients, 24 of whom were given no additional vitamin D (although these control patients were permitted to take up to 4,000 IU per day of their own volition) and 25 of whom received increasing doses of vitamin D for 28 weeks (up to 40,000 IU per day) followed by a gradual taper until week 48, when the treatment was stopped, showed that in the treated patients, significantly fewer had an increase in EDSS score at the end of the trial.45 The study also showed trends towards a lower annual relapse rate and a higher proportion of relapse-free patients in the treatment group than in the control group (Table 1).
In a Norwegian study, 71 patients with relapsing–remitting MS (RRMS) were randomly allocated to receive 96 weeks of either 20,000 IU vitamin D weekly or placebo.46 No statistically significant difference was found between the two groups in annual relapse rates, EDSS scores, grip strength or fatigue. A small randomized trial in 23 patients with MS found no significant difference in MRI evidence of disease activity between patients receiving low-dose (1,000 IU) or high-dose (6,000 IU, adjusted to achieve a target serum level of 130–175 nmol/l) vitamin D, given over 6 months.47 By contrast, a small, 1-year study in 66 patients with MS, which compared the effects of 20,000 IU per week of vitamin D to those of placebo, found a significantly lower number of lesions on gadolinium-enhanced MRI, as well as a tendency to develop fewer new MRI lesions, reduced disability accrual and improved timed tandem walk results in the treatment group, but no change in the annual relapse rate.48 A phase II, randomized, placebo-controlled trial in 50 patients with MS showed no difference in relapse rate and EDSS scores between the groups after 1 year of treatment with 0.5 µg calcitriol.49 Larger trials to assess the effect of vitamin D supplementation in patients with MS are currently under way.50
Polyunsaturated fatty acids
Saturated fatty acids lack carbon–carbon double bonds and are mainly derived from animal fats in the diet (not including fish oils). Polyunsaturated fatty acids (PUFAs) are long-chain fatty acids that possess more than one carbon–carbon double bond and are named on the basis of the distance of the last carbon–carbon double bond from the terminal methyl group. Omega-3 (n-3) PUFAs are primarily derived from fish oils, whereas omega-6 (n-6) PUFAs are obtained from plant sources, including sunflower, corn and soybean oils.51 Fish contains high amounts of PUFAs, and some fish (particularly wild salmon or tuna) are also rich in vitamin D. Several epidemiological investigations1,52,53,54,55 and case–control studies56,57,58 have suggested that the incidence of MS is increased in populations with a diet low in PUFAs and high in animal or saturated fats. In the only prospective study to assess the influence of dietary fat on the incidence of MS, neither animal nor saturated fats were associated with an increased risk of developing MS; however, there was a trend towards an inverse association between the risk of MS and intake of the n-3 PUFA linolenic acid.59
The immunomodulatory and anti-inflammatory effects of PUFAs have been suggested as a rationale for their potential therapeutic use in patients with MS. The anti-inflammatory prostaglandins E1 and E2 are derivatives of n-6 PUFAs that inhibit the production of proinflammatory cytokines,60,61 and linoleic acid is a precursor of arachidonic acid, which is converted to prostaglandin E2 and alters immune function in the CNS.62 Studies in patients with MS showed a reduction in T-cell proliferation in patients receiving PUFA supplementation,63 as well as a decrease in the levels of proinflammatory cytokines, such as IL-2, tumour necrosis factor (TNF) and IFN-γ.64,65 Moreover, n-3 PUFAs seem to inhibit leukocyte migration.66 In addition to having anti-inflammatory properties, n-3 PUFAs (which are key components of glial and neuronal membrane phospholipids) also promote the expression of myelin proteins.67 Whether diets with different compositions of PUFAs influence demyelination and remyelination in MS was assessed in the cuprizone mouse model.68 Mice that were fed salmon over 6 weeks had decreased evidence of demyelination on MRI and in pathology studies compared with mice fed with cod liver oil (which, like wild salmon, is rich in n-3 PUFAs and vitamin D) and animals fed soybean oil (which is rich in n-6 PUFAs).
Data on the effects of dietary fats on the course of MS in humans are also limited in scope and/or quality. Small randomized trials of n-3 or n-6 PUFA supplements in patients with RRMS suggested a possible reduction in the severity and duration of relapses,69,70,71,72 but failed to show a significant effect on disease progression as measured with the EDSS. High dropout rates further limit the conclusions that can be drawn from these studies. A study in 69 patients with progressive MS found no effect of supplementation with linoleic acid or n-6 PUFAs on accrual of disability.73 The low frequency of reported adverse events suggests that no major toxic effects are associated with PUFA administration; however, the available data are insufficient to assess whether PUFA supplementation results in any specific benefit or harm.74
An epidemiological study conducted using data from 36 countries found that mortality from MS was higher in populations with a diet high in saturated fatty acids from animal sources other than fish.75 A large retrospective survey of Belgian patients with MS found an inverse correlation between disability progression (defined as the time to reach an EDSS score of 6) and levels of regular consumption of alcohol, coffee and fish in patients with relapsing-onset disease.76 However, the same study found no association between diet and disease progression in patients with progressive-onset MS, except that faster progression to disability occurred in those preferring fatty fish over lean fish. The retrospective nature of this study makes the interpretation of these data difficult; for example, prior progressive disability could have influenced subsequent dietary choices.
In a multicentre, randomized, placebo-controlled trial, in which 92 patients with RRMS received either n-3 fatty acids or placebo, no significant difference was found in either the number of lesions on gadolinium-enhanced MRI at 6 months or the relapse rate at 6 or 24 months.77 Furthermore, no differences were detected in disability progression, fatigue or quality-of-life scores. However, no dietary restrictions or recommendations were given to participants, which might have attenuated any benefit of the fatty acid supplementation. One of the most popular diets among patients with MS is the so-called Swank diet, which is low in saturated fats. Swank and Goodwin reported increased survival among 70 patients with MS who strictly followed this diet for 34 years.78
Cholesterol and phytosterols
Cholesterol levels are also affected by fat intake in the diet. Total cholesterol, as well as LDL and HDL cholesterol, have been extensively investigated for their effect on the risk of cardiovascular disease. The American Heart Association recommends a maximum daily cholesterol intake of 300 mg per day for healthy adults. A large cross-sectional study published in 2011 showed an association between high serum levels of LDL and total cholesterol and increased EDSS and MS severity scores, whereas high HDL cholesterol levels were inversely associated with MRI lesion volume.79 Interestingly, another cross-sectional study showed an association between cholesterol levels and deseasonalized vitamin D levels.80 Specifically, a high total cholesterol:HDL ratio did not correlate strongly with low vitamin D levels or with greater disability. The authors suggest that deseasonalized vitamin D and cholesterol levels are interdependent, but the study design and lack of assessment of interactions between these variables in their effect on disease outcomes limits the conclusions that can be drawn from this study.
Phytosterols are plant sterols that are enriched in diets high in nuts, seeds and legumes, and might exert immunomodulatory effects. Consumption of phytosterols also lowers cholesterol levels by interfering with absorption of dietary cholesterol. Administration of phytosterols delays the onset of EAE and decreases disease severity by reducing infiltration of immune cells into the CNS, and by reducing the inflammatory activity of such cells.81 In humans, a small study of 11 patients with MS and seven controls showed that treatment with the phytosterol β-sitosterol decreased the release of proinflammatory cytokines such as TNF and IL-12 from peripheral blood mononuclear cells.82 No trials studying the effects of phytosterols on clinical or radiological correlates of disease have been published to date.
Free radicals are compounds that contain one or more unpaired electrons and are thus highly reactive. For example, oxygen free radicals, also called reactive oxygen species, readily oxidize other molecules. Antioxidants are molecules that inhibit the oxidation of other molecules by reacting with oxygen free radicals. Free radicals are suspected to contribute to demyelination and axonal damage in EAE and MS.83
Activated microglia and macrophages produce high levels of reactive oxygen species, such as NO and H2O2. MS plaques exhibit increased free radical activity and decreased levels of important antioxidants, such as glutathione, α-tocopherol (vitamin E) and uric acid.84 Low levels of antioxidant activity in white matter and high levels of free radicals are thought to lead to increased peroxidation of myelin lipids in EAE.85 Evidence of lipid peroxidation has been shown in the blood and cerebrospinal fluid (CSF) of patients with MS.86,87 In EAE, treatment with catalase (an H2O2 scavenger) resulted in markedly suppressed disease severity,88 and oral administration of N-acetylcysteine, a potent scavenger of oxidant molecules inhibits the induction of acute EAE.89 A few studies have shown that inhibition of NO synthesis and scavenging of NO suppress EAE induction and pathology,90,91 whereas others have shown worsening of EAE symptoms after NO inhibition.92,93 The exact role of NO in EAE pathology is, therefore, unclear.94
The issue of whether antioxidants have a role in ameliorating the course of MS in humans is still under investigation. Many different foods and dietary supplements are thought to have antioxidant properties; however, only those studied in patients with MS are described below.
Uric acid is a purine metabolite and a scavenger of peroxynitrite, the breakdown product of the free radicals NO and superoxide. Peroxynitrite is toxic to neurons, axons and glial cells, and contributes to demyelination, oligodendrocyte destruction and axonal damage when injected into rat brains.95 Administration of uric acid prevents the development of EAE by interfering with the invasion of inflammatory cells into the CNS and promotes recovery from EAE by blocking apoptosis caused by free radicals.96 An evaluation of more than 20 million medical records from patients included in Medicare and Medicaid databases revealed that MS and gout (hyperuricaemic syndrome) might be mutually exclusive diseases, suggesting that hyperuricaemia protects against the development of MS.97 However, in a prospective case–control study, serum levels of uric acid were not predictive of the risk of developing MS.98 A retrospective analysis of patients with RRMS showed that serum levels of uric acid are lower during relapses than in the remitting phase of the disease, and that serum levels of uric acid increased (though not to values above the normal range) after initiation of treatment with the disease-modifying MS medications IFN-β or glatiramer acetate.99 This observation indicates that low uric acid levels might reflect disease activity in patients with MS. A meta-analysis of 12 case–control studies with 1,037 patients with MS and 556 controls showed that uric acid levels in serum were decreased during clinical disease activity. However, no correlation was found between uric acid levels and disease activity on MRI or disability as measured on the EDSS.100
The question of whether increasing patients' serum levels of uric acid leads to reduced frequency or severity of attacks, or reduced disability accrual in MS has been investigated in two studies. Since oral uric acid supplementation does not sufficiently raise serum levels owing to its poor absorption and breakdown by gut bacteria, the precursor inosine has been used for dietary supplementation.101 A randomized, placebo-controlled, pilot trial in 16 patients with RRMS revealed inverse correlations between serum uric acid levels and both the number of lesions on gadolinium-enhanced MRI and the EDSS score.102 However, a 2-year trial of 159 patients with RRMS treated with IFN-β, who were randomly allocated to receive either inosine or placebo in addition to this treatment, showed no reduction in EDSS scores or annual relapse rate.103 It is possible that the lack of a treatment effect shown in this trial was attributable to the fact that IFN-β was also administered.
Vitamin C (ascorbic acid), vitamin E (α-tocopherol) and vitamin A derivatives (β-carotene and retinol) have antioxidant properties. Their levels are decreased in the blood of patients with MS during a relapse compared with those in the remitting phase, which might point to increased antioxidant demand during active demyelination.104 Vitamin E levels were also decreased in MS plaques in human tissue,84 although levels of vitamin E in CSF were no different between patients with MS and controls.105
The effects of antioxidant vitamins on the course of MS have not been formally assessed in humans, but animal studies provide some rationale for a role in MS. Vitamin C prevents the development of EAE and ameliorates its symptoms, although less effectively than uric acid does.101 The effects of vitamin E have not been tested in EAE, but this vitamin attenuates demyelination and potentiates remyelination in animal models of toxin-mediated demyelination.106,107 The vitamin A derivative retinoic acid delays the onset of EAE108,109,110 and treated animals were shown to have a milder disease course, even when the supplement was given after disease onset.111 Retinoic acid treatment led to an increase in IL-4 expression in animals with EAE, which suggested that its positive effect might be attributable to a shift from a predominantly TH2-mediated immune response to a TH1-mediated response.111 Retinoic acid also inhibits TH17 cell development and promotes the development of regulatory T cells in vitro, although this latter effect has not been replicated in animals with EAE.112 Given these data, human trials studying the effects of vitamin A on the course of MS might be warranted.
Lipoic acid is a naturally occurring antioxidant that is available as a synthesized oral supplement, which, unlike supplements from botanical extracts, has little variability in concentration and does not contain other biologically active ingredients. Lipoic acid prevents the onset and reduces the symptoms of EAE113,114,115 and experimental autoimmune optic neuritis.116 A small pilot study of lipoic acid in 37 patients with MS showed good tolerability,117 and a detailed pharmacokinetic study showed that an oral dose of 1,200 mg daily delivers serum levels equivalent to the therapeutic doses used in EAE.118 Large randomized controlled trials are now needed to assess the efficacy of this supplement in patients with MS.
Polyphenols, which are found predominantly in plants, also have immunomodulatory effects in EAE: they alter antigen presentation,119 block IL-12 signalling,120 decrease IL-6 expression121 and inhibit NF-κB signalling.122
Blueberries are a source of polyphenols and have neuroprotective effects in animal models of stroke,123 Alzheimer disease124 and Parkinson disease.125 One study found that dietary supplementation with whole, freeze-dried blueberries at a dose equivalent to one cup of blueberries a day reduced the incidence of EAE by 50% in a chronic EAE model.126 Mice with chronic EAE, as well as mice with relapsing–remitting EAE, also showed significantly improved scores in motor tests versus controls when given blueberries as a dietary supplement.126
Green tea also contains polyphenols, and its antioxidant properties have been presumed to be neuroprotective in neurodegenerative disorders such as Alzheimer disease and Parkinson disease.127 Green tea also has immunomodulatory effects: in EAE, green-tea extracts inhibit both TNF production and neutrophil-mediated responses.123 In vitro experiments showed that green-tea extracts inhibited T-cell expansion128 and metalloproteinase activity.129
Resveratrol is a polyphenol found in grape skins, red wine, berries and nuts. In an animal model of optic neuritis, local application of resveratrol attenuated the loss of retinal ganglion cells.130 Animals treated orally with resveratrol had decreased axonal loss in the optic nerve tracts and spinal cord compared with controls.131 In vitro, resveratrol reduces the expression of several cytokines, including IL-6, IL-12, IL-23 and TNF.132,133 Since IL-17 and the TH17 cells that produce it are implicated in the pathogenesis of MS, researchers were surprised to find that resveratrol increases IL-17 levels in mice with EAE134 and does not seem to inhibit either the maturation of TH17 lymphocytes or their infiltration into the brain in this model.121 The authors suggest that the beneficial effects of resveratrol in EAE are mediated through reduction of IL-6 and IL-23, rather than through IL-17 pathways. Further studies to investigate resveratrol and its possible therapeutic effects in patients with MS are needed.
Extracts from the leaves of the Ginkgo biloba tree improve cognitive functioning in patients with Alzheimer disease.135 G. biloba was reported as the most common herbal supplement used by patients with MS in an Australian analysis of 416 questionnaire responses and in a survey of 2,026 US patients with MS.136,137 G. biloba extract contains flavonoids, which act as antioxidants, as well as terpene lactones, which are antagonists of platelet-activating factor (PAF).138 This extract might, therefore, have an antithrombotic effect and could increase the risk of bleeding.139 However, PAF is not only involved in coagulation, but also has proinflammatory effects and increases disease activity in EAE.140 Two studies, each including fewer than 30 patients with MS, suggested that G. biloba extract might help to reduce the number of demyelinating episodes.141,142 A placebo-controlled trial in 104 patients with MS did not replicate this finding,143 however, and no studies addressing whether this extract has any disease-modifying effects in MS or affects patients' long-term disability have been conducted. A preliminary report from a randomized controlled trial in the USA suggests that G. biloba extract might improve MS-related cognitive dysfunction,144 but this finding still needs to be confirmed.
Curcumin is a yellow, naturally occurring polyphenol isolated from the rhizome of the turmeric plant, Curcuma longa.145,146 Curcumin has both antioxidant and anti-inflammatory effects. It inhibits production of the free radicals H2O2 and NO by macrophages147,148 and astrocytes149 in vitro. In EAE, curcumin inhibits lymphocyte proliferation, decreases IL-17 production by TH17 cells, and downregulates the expression of Toll-like receptors 4 and 9.145,146,147,148,149,150,151 Furthermore, curcumin seems to increase the integrity of the blood–brain barrier in animal models of haemorrhagic stroke.152 The severity of EAE is reduced in animals treated with curcumin, and they exhibit a reduction in inflammatory cell infiltration into the spinal cord.145 Curcumin might also have neuroprotective effects in patients with MS.153 However, no trials to assess the efficacy of curcumin as a disease-modifying agent in patients with MS have been undertaken to date.
Vitamin B12 is an essential factor in the synthesis of myelin and is also suspected to have immunomodulatory properties. Lymphocyte counts (especially of CD8+ T cells) and the activity of natural killer cells are both reduced in patients with vitamin B12 deficiency and increase with vitamin B12 treatment.154 Additionally, vitamin B12 deficiency can induce clinical symptoms and MRI findings similar to those of MS.
Most patients with MS have normal serum vitamin B12 concentrations.155 However, one study found low levels of this vitamin in the CSF of patients with MS, despite normal serum levels.156 An open-label study of high-dose vitamin B12 supplementation (administered for 6 months to six severely disabled patients with progressive MS) showed no clinical benefit, but the latency of brainstem auditory and visual evoked potentials decreased in treated individuals.157 A larger, placebo-controlled trial of 138 patients with progressive MS or RRMS showed a trend towards a beneficial effect from high-dose parenteral vitamin B12.158 However, the data from this trial are difficult to evaluate, as vitamin B12 treatment was combined with lofepramine and L-phenylalanine (the so-called Cari Loder regime), which makes it difficult to determine whether the observed effect was solely due to vitamin B12 supplementation.158 Overall, data on the effects of vitamin B12 are currently insufficient to determine whether it can alleviate the symptoms of MS.
Some researchers recommend that patients with MS should avoid cow's milk.159 This recommendation is based on a few early cross-sectional epidemiological studies that suggested an increased incidence of MS in populations with high consumption of cow's-milk products.160,161 Molecular mimicry between myelin autoantigens and milk fat globule membrane proteins has been proposed to underlie a potential adverse effect of milk on the course of MS. One such protein, butyrophilin, is of particular interest, owing to its high level of sequence similarity to myelin oligodendrocyte glycoprotein (MOG). Butyrophilin stimulates MOG-specific T-cell responses in vitro and induces EAE in rodents;162 moreover, cross-reactivity between antibodies against MOG and butyrophilin has been observed in patients with MS.163,164 However, butyrophilin also inhibits MOG-induced EAE.162 Unfortunately, no studies have addressed the possible influence of milk proteins on the disease course or prognosis of MS in humans.
The elimination of gluten, a protein found in wheat, has been espoused by many patients with MS. Hypersensitivity to gluten can lead to coeliac disease, an intestinal disorder that often occurs in association with other autoimmune disorders. Data on the prevalence of coeliac disease in patients with MS are conflicting. One study in 12 patients with MS showed a high incidence of pathological changes in small-bowel biopsy samples;165 however, this finding was not confirmed in another study of intestinal morphology and biochemical changes in 14 patients with MS.166 Antibodies against gluten were detected significantly more often in the blood of 36 patients with MS than in blood from 26 controls in a Norwegian study,167 and similar observations were made in a Spanish cohort of 72 patients with MS,168 but not in larger cross-sectional studies conducted in Iran and Italy, each involving more than 100 patients.169,170 Data on the potential mechanisms by which gluten might influence the immune system are very limited, although it has been shown to inhibit the generation of regulatory T cells in patients with gluten sensitivity, in an animal model of autoimmune diabetes, and in experiments investigating type 1 diabetes mellitus in vitro.171
A study addressing the effect of a gluten-free diet on the course of EAE showed no change in the number of relapses and a slight increase in disability scores in the animals receiving the gluten-free diet.172 An observational study in 42 patients with MS that did not include controls indicated ongoing relapses and progression of disability despite a gluten-free diet.173 No randomized controlled trials have addressed the efficacy of a gluten-free diet in patients with MS. As such, many MS specialists do not have specific recommendations about the consumption of gluten.
Probiotics are defined by the WHO as live microorganisms that confer a health benefit to the host.174 Studies evaluating the effect of probiotics on EAE show conflicting results. Some reports suggest that probiotics stimulate TH1-mediated immune responses in EAE and exacerbate disease symptoms,175,176 whereas others indicate that they have no effect on neurological symptoms in EAE.177 Another trial showed a protective effect of probiotics on EAE.178
Oral administration of live Bacteroides fragilis (the cell walls of which contain polysaccharide A) or purified B. fragilis polysaccharide A prevented and attenuated EAE, probably by promoting the expansion of IL-10-producing regulatory T cells.179,180 Administration of a mixture of three Lactobacillus strains to mice with EAE led to reduced IL-17 and increased IL-10 production by T cells and prevented or attenuated the clinical and histological signs of EAE.181 Lactobacillus casei also seems to modulate the function of regulatory T cells and acts as a potent immunomodulator of T-cell-mediated autoimmunity.181 The potential for probiotics to affect the onset or course of MS is supported by the fact that treatment with broad-spectrum antibiotics also increased the number of CD5+ B cells; moreover, adoptive transfer of these cells led to a reduced TH1-mediated or TH17-mediated immune response.182 A small pilot study demonstrated no overall shift in the gut microbiota in 15 patients with MS versus controls, but the researchers commented that treatment with glatiramer acetate or vitamin D might alter gut bacterial populations.183
A phase I study has assessed the effect of fortnightly administration of ova from the nonpathogenic helminth Trichuris suis in five treatment-naive patients with newly diagnosed RRMS. The researchers found increased serum levels of IL-4 and IL-10 and a decrease in the number of lesions on gadolinium enhanced MRI in patients who were receiving this treatment (which was administered for 3 months) compared with baseline and post-treatment MRI scans.184 Further investigations are warranted to elucidate the effects of the gut flora on the development and disease course of MS.
The potential capability of nutritional factors and dietary supplements to influence the course of MS is of great interest; however, only limited data support any of these interventions at this time. From the existing evidence, vitamin D sufficiency probably protects against the development of MS as well as its progression, although the target range of vitamin D levels, and whether vitamin D replacement therapy is truly effective in altering the disease course in patients with MS, remains to be established. Although a multicentre, placebo-controlled trial of PUFA supplementation did not show any benefit in patients with MS, the potential of these compounds to slow the disease course of MS should be evaluated further given trends in small studies and the seemingly low toxicity of PUFAs. By contrast, strong evidence to support specific dietary modifications or the use of other nutritional supplements is lacking at this point. Many pilot studies are ongoing to assess the effects of some of these interventions on MS disease course; however, the small sample sizes might preclude firm conclusions from these studies. Larger studies are warranted, but the associated costs make them difficult to conduct.
Nonetheless, many patients with MS adhere to exclusion diets or use nutritional supplements, underscoring the importance of continuing to study these interventions, especially since they are relatively inexpensive. Many studies addressing the effects of nutritional factors in patients with MS have included small numbers of participants, possibly owing to a lack of funding. A positive effect of an investigated dietary intervention cannot be excluded even when a study result is negative, because often the number of study participants is too low to draw firm conclusions, limiting the clinical utility of such studies. Furthermore, nutritional factors might have different effects in patients with RRMS, in whom active lesions are caused by immune-mediated processes, than in patients with progressive MS, in whom pathology is thought to be predominantly neurodegenerative. Most trials of conventional treatments for MS analyse the results in these two groups of patients separately; however, many published trials of the effect of nutritional factors on MS have included heterogeneous populations of patients. Future trials should be carefully designed to include adequate sample sizes of patients with well-defined characteristics, and should be randomized so that potential confounding variables (in particular, other dietary factors and supplements used) are equally distributed between groups. Such trials should also use validated outcome measures, such as MRI, EDSS and annual relapse rate, to assess efficacy.
We searched PubMed for full-text papers published in English from January 1990 to March 2012. Search terms used were “nutrition”, “diet”, “supplements”, “multiple sclerosis” and “experimental allergic encephalomyelitis”, alone and in combination. In addition, we reviewed the reference lists from key articles identified by this method to check for additional relevant material.
G. von Geldern is supported by grants from Project Restore at the Johns Hopkins University Comprehensive MS Center. E. Mowry is supported by a grant from the NIH (K23NS067055).
About this article
Neurological Sciences (2018)