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Diet and Interventions on Multiple Sclerosis: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Panagiotis Stoiloudis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation and neurodegeneration. The most prominent clinical features include visual loss and sensorimotor symptoms and mainly affects those of young age. Some of the factors affecting its pathogenesis are genetic and/or environmental including viruses, smoking, obesity, and nutrition. 

  • multiple sclerosis
  • diet
  • nutrition

1. Neurodegeneration

It is already known that neurodegeneration is presented even at the earliest stages of the disease [5][1]. In experimental models, oxidative stress leads to mitochondrial dysfunction, causing cell membrane disruption and eventually neuronal cell death [9][2]. Dietary antioxidant factors can dampen oxidative stress and may help against chronic demyelination and neuronal or axonal damage [5][1]. Both oxidative and mitochondrial injury primarily disrupt the function of neurons and glia, causing disturbances in cellular communication [10][3].

1.1. Oxidative Stress

Oxidative injury is involved in both relapsing-remitting and progressive forms of MS [11][4]. Inflammatory cytokines, reactive oxygen species, and phagocytes lead to damage of myelin and axons. It is found that oxidative stress enhances inflammation and causes damage of the myelin, consequently leading to cell death. Clinically, the course of MS has been associated with inflammatory and oxidative stress mediators including cytokines such as IL-1β, IL-6, IL-17, TNF-α, and INF-γ [12][5].
Dietary antioxidant factors may regulate the activation of immune inflammatory cells, leading to the reduction in inflammatory and may also dampen oxidative stress, thus preventing chronic demyelination and axonal damage. Antioxidant factors such as curcumin, vitamin D, and fatty acids have been studied and seem to play a role in the regulation of oxidative stress [13][6]. Curcumin, derived from the plant Curcuma longa [12][5], has been advocated to inhibit proinflammatory cytokines [14][7]. In animal models of MS, curcumin was shown to reduce clinical severity and decrease CNS infiltration by inflammatory cells in mice. Curcumin possesses antioxidant and anti-inflammatory properties. Its anti-oxidant effects have been assessed in several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and MS [15][8]. Another nutritional factor is melatonin, which is produced naturally by the pineal gland during the night. It is formed exogenously from tryptophan. Melatonin is mainly consumed from meat, oily fish such as salmon, eggs, milk, seeds, nuts, almonds, and soy products. Melatonin is suggested to regulate anti-oxidative defensive systems by stimulating the synthesis of superoxide dismutase and glutathione peroxidase, especially in patients with SPMS [16][9].
Vitamin D plays a significant role not only in calcium homeostasis and bone health, but also in immunomodulation and the reduction in oxidative stress. MS patients frequently exhibit vitamin D deficiency [1][10]. Studies report that low levels of vitamin D are associated with a higher risk for the development and relapse of MS [8,17][11][12]. Supplementation with vitamin D has been shown to have anti-inflammatory and immunomodulatory effects on MS pathogenetic mechanisms by inhibiting the production of CD4+ T cells, thus lowering the risk of MS and diminishing disease progression [18][13]. However, Bagur et al. reported in their systematic review that existing studies on the effect of vitamin D supplementation in MS are inconsistent with respect to EDSS, MRI lesions, overall functional status, and relapse rate [13][6]. It has been suggested that empirical replacement with high doses of vitamin D supplementation (at least 4000 IU/day orally) and for a prolonged period appears to be safe and is associated with low risk for adverse events, although available data are limited [12,19,20,21][5][14][15][16].
Vitamin A is a fat-soluble nutrient with a variety of functions in visual ability, skin, and immunity. Vitamin A includes retinoids and carotenoids, available in liver, milk, cheese, green leaves, oil, vegetables, and fruit. Association between the pathogenesis of MS and vitamin A remains undefined. Studies in animal models demonstrate a possible role of vitamin A in the modulation of immunity [22,23][17][18]. A negative correlation has been found between the development of MS and low levels of vitamin A in plasma [12][5]. A randomized controlled trial showed benefits in fatigue, depression, and cognitive status of MS patients supplemented with high doses of vitamin A (400 IU/day), which were considered safe and were not associated with adverse effects [24][19].
Fatty acids, especially omega-3 polyunsaturated fatty acids (PUFAs), are other antioxidant compounds that are associated with ameliorating neurodegeneration in MS. Intake of PUFAs consumed via fish, nuts, and seeds seems to be associated with protective effects against demyelination [5][1]. In animal models, PUFAs decrease inflammation, maintain immunomodulation and promote neuroprotection and remyelination [5][1]. Some studies have shown inconsistent results indicating the effect of PUFAs mainly against progression. In one study, association between PUFA intake and MS incidence seems to be non-significant. Conversely, one Swedish and one Australian study reported low incidence of MS in people following diets enriched in PUFAs [5,12,13,25,26][1][5][6][20][21]. Results from meta-analyses suggest that PUFAs may reduce the frequency of relapses, but are not effective against the progression of the disease [1,19][10][14]. In human studies, a low fat diet supplemented with PUFAs was associated with lower levels of disability assessed by EDSS, slight improvement in relapse rat, as well as improved quality of life [13,25][6][20]. Another study provided evidence of PUFA-related improvement with respect to specific markers linked with inflammation and/or neurodegeneration in patients with MS (for instance, matrix metallopeptidase-9 (MMP-9) rather than in quality of life, EDSS score, or fatigue [26][21].
Among PUFAs, α-linolenic acid (ALA) is associated with low incidence of MS. It can contribute to the immune pathway by decreasing markers of inflammation. Eicosapentaenoic acids (EPAs) and docosahexaenoic acids (DHAs) can also play a role in in decreasing MMP-9 levels in patients with MS [25][20]. Riccio et al. reported that fish oil supplementation enriched with omega-3 fatty acids have a beneficial effect in the inhibition of the expression and reduction in the levels of MMP-9 in MS patients [27][22]. Ramirez et al. reported the beneficial effects of fish oil containing high amounts of omega-3 PUFAs into protecting against inflammation and oxidative stress [25][20]. Omega-3 fatty acid supplementation results in the decrease in proinflammatory cytokines, free radicals, and as a result, improving the quality of life of patients with MS by decreasing relapse rates [25][20].
Polyphenols, which are included in vegetables, fruit, wine, and tea, have been proven to be beneficial, leading to modulation of the immune response and affecting the expression of genes encoding pro-survival proteins including antioxidant enzymes. Polyphenols can also enhance neuronal survival [28][23]. Studies have focused particularly on polyphenols such as resveratrol and ginkgo biloba. In animal studies, these compounds seemed to promote protection against oxidative stress, also protecting against demyelination and axonal injury [26][21]. Khalili et al. suggested that lipoic acid consumption by patients with MS results in the improvement of total antioxidant capacity [13][6].
Randomized clinical trials seem to confirm the efficacy of some of the compounds discussed above such as melatonin, vitamin D3, omega-3 PUFAs, and polyphenol compounds. However, further research is needed in order to understand the potential protective effects exerted by antioxidants on the cellular immunology of MS neurodegeneration [12][5].

1.2. Mitochondria—Energy Production

Mitochondrial injury or the accumulation of iron in the brain is also enhanced in the progressive phase of the disease [12][5]. In patients with MS, mitochondrial structural changes and enzyme activity increase ROS production and cause oxidative damage [12][5]. Among the other antioxidants, curcumin is especially reported to play a major role against free radicals. Curcumin may benefit patients with MS by binding transition metals and forming stable inactive complexes, especially with ferrous ions, protecting against neurodegeneration [29][24].

2. Immune System (Innate and Adaptive) Responses—Factors of Immune System Activation

Nutrients and special diets such as saturated and ‘trans’ fatty acids, α-lipoic acid, polyphenols, high-fat diet, and high-carbohydrate diet result in the modulation of the components of inflammatory cascade. Several studies have shown that saturated and ‘trans’ fatty acids and lipopolysaccharide (LPS) may upregulate the activity of proinflammatory compounds, promoting inflammation; on the other hand, calorie restriction, polyphenols, and Ω-3 PUFAs would exert the opposite effect [26][21]. The influence of diet on inflammatory and autoimmune processes in MS is highlighted, supporting the hypothesis of a close relationship between nutritional factors and the immune system responses that play a role in the pathogenesis of MS [26][21].

3. Proinflammatory Diet

Recent studies have highlighted the role of proinflammatory diets in the pathogenesis of MS. Fatty acids and polyphenols as well as diets high in carbohydrates and fats may induce inflammatory cascade [26][21]. Diet can induce the production of inflammatory factors such as tumor necrosis factor, interleukins, MMP9, prostaglandins, and leukotrienes, leading to inflammation and oxidative stress [26][21].
Swank et al. reported adverse effects of saturated fatty acids (SFAs) on the course of MS, emphasizing their proinflammatory character [9][2]. High intake of SFAs leads to a dysbiosis of gut microbiota. Additionally, the consumption of vegetable oils, which are enriched with trans fatty acids, is associated with gut inflammation and the upregulation of proinflammatory cells [30][25]. Red meat leads to the formation of nitrous compounds increasing chronic inflammation. Red meat also contains arachidonic acid, which participates in inflammatory pathways by activating Th17 cells [27][22]. Furthermore, a high consumption of sugar-sweetened beverages and refined cereals leads to the production of insulin, which, in this way, is responsible for the upregulation of synthesis and the production of arachidonic acid. High salt intake can induce the production of Th17 cells and proinflammatory cytokines [27][22]. Proteins contained in cow-milk may play a role in the mechanisms of pathogenesis of MS. Particularly, butyrophilin can induce EAE by mechanisms of molecular mimicry with myelin oligodendrocyte glycoprotein [27][22].

4. Gut Brain-Axis and MS

4.1. Gut Microbiota

The gut–brain axis represents a bidirectional communication system between the CNS and the gastrointestinal system that includes the CNS, the enteric nervous system, the autonomic nervous system, the immune system, and the gut microbiota [31,32][26][27]. The role of gut microbiota is crucial because of its impact on regulating and maintaining the normal function of the innate immune system [31,32][26][27]. From birth to adolescence, commensal microbiota infests the gastrointestinal system, remaining in a stable condition, a state called eubiosis [31,32][26][27]. However, in early stages of life, factors such as antibiotics, infections, or unhealthy dietary habits may lead to alterations of the relative distribution and frequency of commensal microbiota, thus also, at least in part, predisposing to gut colonization by pathogens, a state called dysbiosis. In dysbiosis, there is an increase in the number of pathogenic bacteria and decrease in their biodiversity, resulting in gastrointestinal and systemic inflammation, possibly leading to increased risk for local or systemic inflammatory disease [31,32][26][27].
Metabolism of nutrients, especially carbohydrates, the production of neurotransmitters and vitamins, and competition with other colonizing pathogens are some of the main physiological functions of gut microbiota [32][27]. Furthermore, gut microbiota is possibly associated with CNS homeostasis and development and also with neuroimmunological and neurodegenerative disease [32][27]. Diet comprises a main factor determining the synthesis and metabolism of gut microbiota, thus enabling the host to defend against pathogens. The role of gut microbiota is also significant for the regulation of the immune system by affecting the overall activation status of T cells and other cells of the innate and adaptive immunity. In particular, T regulatory cells and T helper cells type 2 may suppress the activation of the immune system [1,32,33,39][10][27][28][29]. Moreover, short-chain fatty acids (SCFAs) such as butyrate, derived from gut microbiota, promote anti-inflammatory processes by producing anti-inflammatory cytokines and by inhibiting the connection of leukocytes to epithelium [1,32,33,39][10][27][28][29]. It is believed that the consumption of a diet with high fiber intake may increase the production of butyrate, thus leading to improved outcomes in patients with CNS disorders [1,32,33,39][10][27][28][29]. Studies in animal models demonstrated a strong and important connection between the microbiota, butyrate production, and the CNS. Patients with MS have lower levels of SCFAs in feces as well as reduced frequency of SCFA-producing bacteria in the gut [1,32,33,39][10][27][28][29].
Nutrition and dietary interventions regulate the gut microbiota affecting its composition and its functionality [32][27]. Diets characterized by a high intake of fat, sugar, and animal protein may lead to the development of specific pathogenic bacteria species such as Bacteroidetes in the gut, which, in turn, may induce enteric inflammation, damage of the intestinal barrier and increase in cross-reactive cells of the adaptive immunity [31][26]. Moreover, diet-induced low biodiversity of gut microbiota is associated with metabolic changes as well as an increase in inflammation markers [31][26].

4.2. Effects of Pre- and Probiotics in Patients with Multiple Sclerosis

The impact of diet on gut microbiota has been experimentally studied through the observations of effects of pre- and probiotics in patients with autoimmune diseases [37][30]. Prebiotics are nonviable compounds of living microorganisms with an ability to beneficially manipulate the host’s microbiota. Many fermentable carbohydrates have prebiotic effects. Non digestible oligosaccharides such as fructans and glycans, which are utilized by Bifidobacteria, are reported to have the most beneficial effects. In addition, oligasaccharides identified in dairy products are reported to act as prebiotics. Probiotics are mostly consumable live microorganisms such as Lactobacillus. Sources of probiotics are contained in food such as yogurt [38][31]. Kouchaki et al. reported improvement in EDSS scale and decrease in inflammatory markers in patients with MS who were treated with probiotic supplementation [39][29]. A number of studies have encouraged the use of pre- and probiotics in patients with MS due to their benefits in maintaining the homeostasis of the CNS, improving the intestinal microbial balance and regulating the composition of gut microbiota. 

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