Exploring the Effect of Genetic, Environmental and Lifestyle Factors on Multiple Sclerosis Susceptibility

Abstract

Multiple sclerosis (MS) is a central nervous system inflammatory illness that begins with immune system dysregulation and impairs information flow inside the brain as well as between the brain and the rest of the body. The cause of MS is yet unknown. The interplay of genetic predispositions with environmental/lifestyle factors, such as smoking, obesity, viral exposure, and insufficient sun exposure, has led to numerous theories. This is reinforced by a major discovery of gene–environment (GxE) interaction, which could provide information on the disease’s molecular pathways to aid in the identification of new therapy and preventative strategies, as well as steer disease exploration to new lifestyle suggestions. While some persons with the major susceptibility to MS have a human leukocyte antigen (HLA) Class II gene, according to genetic studies. We will cover recent studies relating to several genetic, environmental, and lifestyle factors, as well as their impact on MS, in this chapter.

1. Introduction

Multiple sclerosis (MS) is a central nervous system (CNS) immune-mediated disease characterized by demyelination and gliosis as a result of immune cell infiltration across the blood–brain barrier. The disease’s neurologic signs and symptoms are highly variable and dependent on the location of lesions in the CNS [1]. MS is the leading cause of non-traumatic disability in children. This disorder is a multifactorial, immune-mediated disease influenced by both genetic and environmental factors [2]. The prevalence of MS is expected to rise significantly in 2020, with an estimated 2.8 million people living with the disease worldwide in 2020, which is 30% more than in 2013, and it is more common in women than in men [3].

The exact cause of MS is unknown, but it is widely assumed that the disease is caused by complex gene–environment interactions [4, 5]. Genetic factors are important for characterizing pathogenetic mechanisms, and for elucidating the complex picture of disease initiation in the context of lifestyle and environmental factors Human leukocyte antigen (HLA) class I and II genes, which are the most strongly associated loci to MS. HLA class I and II genes encode for molecules that present antigens to CD4+ and CD8+ T lymphocytes [5]. In addition to genetic variants, lifestyle and environmental factors can be the important contributors to disease risk. Exposure to tobacco smoke and organic solvents, certain infections such as Epstein–Barr virus (EBV) infection, adolescent obesity, low levels of vitamin D and low exposure to sunlight, climate, and working night shifts are all risk factors (Figure 1), (Table 1). Use of oral tobacco, high coffee consumption, alcohol consumption, and serological evidence of cytomegalovirus (CMV) infection are all factors that may be associated with a lower risk (Table 1) [5, 6, 7, 8].

Figure 1.

The pathogenesis of multiple sclerosis is influenced by both genetic and environmental factors. Gender, disease-modifier genes, disease susceptibility genes, and single nucleotide polymorphisms are among the genetic factors that play a significant role in MS prevalence and pathogenesis. Environmental factors, on the other hand, such as smoking, vitamin D deficiency, exposure to pollutants, alcohol, diet style, Epstein Barr infection, dysbiosis of the gut microbiota, lack of exercise, and stress, are strongly linked to MS susceptibility and progression.

Factor	OR	HLA gene interaction	Combined OR	Immune system implied
Smoking	~1.5	Yes	14	yes
Oral tobacco	~0.5	ND	NA	yes
EBV infection (seropositivity)	~3.6	Yes	~16	yes
CMV infection (seropositivity)	~0.7	No	NA	yes
Work shift	~1.7	No	NA	yes
Adolescent obesity (BMI > 27)	~2	Yes	~15	Yes
Vitamin D level < 50 nM	~1.4	No	NA	Yes
Low sun exposure	~2	No	NA	Yes
Alcohol	~0.7–0.8	No	NA	Yes
Coffee	~0.7	No	NA	Yes

Table 1.

Summary of established and tentative lifestyle/environmental factors and their potential interactions with human leukocyte antigen (HLA) risk genes for multiple sclerosis (MS).

OR, Odd ratio; HLA, Human Leukocyte Antigen; EBV, Epstein–Barr virus; CMV, cytomegalovirus; BMI, body mass index; ND, not determined, NA, not applicable.

MS risk and severity are influenced by a combination of genetic, environmental, and lifestyle/behavioral variables. This chapter explores the evidence regarding the impact of environmental and lifestyle factors such as sunshine and/or vitamin D, EBV infection, smoking and alcohol consumption, and other factors at various life stages, and addresses the issues in-depth and the impact of genetic variability on some.

2. Evidence for genetic factors

2.1 HLA-associated genetic variants

Human leukocyte antigen (HLA) class I and II genes are particularly important disease risk modifiers: class II gene variants encode products that present antigens to CD4+ T lymphocytes, while class I products present antigens to CD8+ lymphocytes. The class II variant HLADRB1*15: 01 is a risk allele of MS (odds ratio (OR) ~3) and is carried by 25–30% of the population in northern Europe and the United States. The second most powerful MS gene, class I variant HLAA*02, is associated with a lower risk of MS (OR ~0.6). While the absence of HLAA*02 combined with the presence of DRB1*15: 01 has a combined OR of ~5 [5, 9, 10, 11, 12].

Several cohort studies suggest that the HLA genotype can influence environmental influences on MS risk. The harmful effects of childhood obesity [13], smoking [14, 15, 16], infectious mononucleosis, and solvent exposure [16] on MS risk are amplified in those who carry the HLA DRB1*15 allele and lack the protective HLA A*02 genotype. A recent study found a strong link between higher childhood body mass index (BMI) at age 10, smoking before the age of 20, and earlier menarche and MS. In a combined model that included the HLA DRB1*15:01 and HLA A*02:01 genotypes, the effects of these three risk factors remained similar [6]. Environmental risk factors have been shown to play an important role in the development of MS disease in genetically susceptible populations (class II HLA-DRB1*15:01 carriers) [17].

3. Environmental factors

3.1 Past viral infections

3.1.1 Epstein-Barr virus (EBV)

The mechanisms by which previous viral infections and viral reactivation may contribute to MS onset are still unknown. Epstein-Barr virus (EBV) is one of these viruses that has been linked to an increased risk of MS, as it has been discovered that people who have had clinically overt infectious mononucleosis (IM) have a more than twofold risk of developing MS [18, 19]. This organization has recently received funding. According to a longitudinal study, the risk of MS increased 32-fold after infection with EBV but not after infection with other viruses [20]. Supporting the link between EBV and MS, EBV-induced infectious mononucleosis, positivity for EBV nuclear antigen (EBNA)-1 IgG, or higher EBNA-1 titers have all been linked to an increased risk of MS (OR ~3.6) [21, 22]. Furthermore, there appears to be a critical time window for EBV infection, with infection occurring during adolescence or later implying an increased risk of developing MS, whereas this is not the case in childhood [23].

The genetic risk for elevated antiEBNA1 titers has been found to be positively correlated with the development of MS [24], which could be interpreted as additional evidence for EBV’s causality in MS. It has been reported that EBNA positivity interacts with both HLA-A*02 and HLA-DRB1*15 [25, 26]. Another study of MS cases and healthy non-MS controls who were seropositive for EBV found that HLA-A*A02-positive individuals had the lowest EBV viral load and HLA-DRB1*15-positive individuals had the highest. These findings support EBV’s causal role in MS, which is modulated by the HLA Class 1 genotype via changes in antigen presentation to T cells [27]. It has also been reported that an additive interaction of EBV status with HLA DRB1*15:01 modifies MS risk [28, 29]. People who tested positive for HLA-DRB1 *15, negative for HLA-A* 02, and had high EBNA-1 titers, had a 16-fold increased risk of MS compared to those who did not carry any of these factors, with a combined OR of ~16 [26].

The genetic risk for elevated antiEBNA1 titers is positively correlated with the development of MS, which could be further evidence for EBV causality in MS [24]. Infectious mononucleosis and increased EBNA1 antibody titers interact with HLA MS risk genetic variants [26]; and infectious mononucleosis interacts with HLA DRB1*15:01 [30] to increase the risk of MS in a pattern similar to smoking. Because HLA risk alleles encode molecules that regulate T cell adaptive immunity, the interaction with EBV infection measures may point to common pathogenetic pathways in MS [5].

3.1.2 Cytomegalovirus (CMV)

Cytomegalovirus (CMV) is a herpes virus that is related to EBV. CMV infection is mostly asymptomatic. Multiple studies have found a negative correlation between CMV seropositivity and MS diagnosis (protective association) in both pediatric and adult populations, with an OR of ~0.7 [31, 32, 33, 34, 35]. While a few studies have failed to find a link between CMV seropositivity and MS risk [36, 37, 38],

CMV infection may have a potentially protective effect due to its ability to induce not only pro-inflammatory antiviral responses, but also several anti-inflammatory responses, such as decreased mononuclear cell proliferation, increased anti-inflammatory cytokine secretion, and decreased cell surface HLA class I and II expression [31]. CMV infection alters the phenotype and function of B cells in MS, modulating the influence of IFN and reducing the proinflammatory B cell profile, according to new research. These findings may help to explain the potential impact of this viral infection on MS [39].

3.1.3 Herpes simplex virus (HSV)

Controversial findings regarding the relationship between HSV infection and MS risk [40, 41, 42]. According to a new study, HSV infection is modestly associated with MS risk, particularly in Whites, raising the possibility that the disparity between previous reports is due to the racial make-up of study populations [29]. This study also confirmed the link between HLADRB1 status, HSV infection, and the risk of MS. HSV infection was linked to an increased risk of MS only in HLA-DRB1*15:01 negative subjects [29, 32].

3.2 Sun exposure/Vitamin

There are large number of studies on sun exposure/vitamin D, provoked by epidemiologic observations of a latitude-dependent difference in MS incidence and prevalence, despite being confounded by the distribution of the HLA DRB1*15:01 risk predisposing genotype in gradients [43, 44].

Because we rely on ultraviolet radiation (UVR) to convert vitamin D to an active metabolite, distinguishing the effect of UVR from that of vitamin D is difficult. Both of these exposures have been linked to a lower risk of MS, according to a recent and extensive review [45]. A higher level of UVR exposure is associated with a lower risk of MS [43, 46, 47]. Even after accounting for vitamin D levels, there was still a link between UVR exposure habits and the risk of MS [47], though this finding should be interpreted with caution because vitamin D levels were not measured prior to the preclinical phase. The physiological reason for UVR’s putative protective impact is still being researched. UVR exposure protects against MS even if vitamin D isn’t present. When tested in the animal model EAE [48], UVR exposure lowers peripheral inflammation in mice [49], with a T regulatory (Treg) cell activation and dampening effects on antigen-presenting dendritic cells [50, 51]. In these instances, cis-uronic acid production could be involved [52].

Increased vitamin D levels have been linked to a lower incidence of MS, particularly before the age of 20 [53], which is consistent with later results on supplementation and sun exposure [54, 55]. Furthermore, in the situation of minimal sunlight exposure, a diet rich in vitamin D containing fatty fish reduces MS risk [56]. In one study of vitamin D levels during pregnancy in humans using birth samples, no difference between MS cases and controls was found; despite large confidence intervals [57], which is consistent with studies on experimental autoimmune encephalomyelitis (EAE) in which only adolescent rats (not pregnancy or adult rats) showed an effect of vitamin D [58]. This discovery is not without controversy, as mothers with low vitamin D levels during the first trimester had a two-fold greater risk of MS in their offspring [59]. Variations in sampling timing, storing issues, or possible “inherited” behavior differences regarding sun exposure are all possible explanations for the disparate results. In Australia, epidemiologic studies of sun exposure found a link between low sun exposure in mothers during the first trimester and the risk of MS in their children [60]. Regardless, vitamin D and/or sun exposure appear to be significant during a temporal window of adolescence when vitamin supplementation may reduce MS risk to some extent. Vitamin D’s importance is also confirmed by genetic data, which shows that mutations around the CYP27B1 gene, which is involved in vitamin D metabolism, are linked to MS [61, 62]. In two case-control investigations, recent genomic data on a series of genes that regulate Vitamin D levels revealed significant effects. Because the distribution of these gene variants is random, it resembles a blinded clinical trial or Mendelian randomization in certain ways [63, 64]. In vitro investigations using the biggest MS risk gene, HLA DRB1*15:01, identified vitamin D as the first example of a gene–environment interaction [65], although this finding has not been replicated in humans [47].

It is still unclear whether vitamin D or sun exposure has a strong therapeutic effect once MS has been diagnosed. Despite the fact that vitamin D has been introduced to conventional therapy in multiple research, its value has yet to be determined. Importantly, high vitamin D levels are linked to reduced axonal injury as evaluated by cerebrospinal fluid (CSF), neurofilament light [66], and greater vitamin D levels were linked to lower MRI activity and delayed disease development during an interferon study [67, 68].

Vitamin D supplementation is thought to be non-toxic even at very high doses, so it seems reasonable to conduct large clinical trials in people at risk for MS, such as close relatives, or even to recommend supplementation at relatively high doses for all adolescents; vitamin D appears to play a role in a variety of diseases, not just MS. Because of the risk of skin cancer, it is more difficult to make sun exposure recommendations. Moderate exposure, on the other hand, is a good idea. Variations in the timing of sample, storage challenges, or possible “inherited” behavior variances towards sun exposure are all plausible causes for the lack of consensus on whether vitamin D supplementation is beneficial in individuals. Notably, epidemiologic studies of sun exposure in Australia found evidence of a link between low sun exposure in mothers and the development of MS. Many MS patients, on the other hand, are aware of the link between vitamin D and MS risk and take it, especially during the winter.

3.3 Air pollution

The link between air pollutant exposure and MS risk is unclear. Particulate matter (PM) exposure causes an inflammatory response in the lung, resulting in the release of inflammatory cytokines and elevated systemic levels. Long-term exposure to air pollution has been linked to neuroinflammation and blood–brain barrier damage. Studies examining exposure to particles with an aerodynamic diameter of less than10 μm (PM10) produced conflicting results [69, 70, 71]. Seasonal exposure to nitrogen dioxide during the cold season or ozone during the hot season has been linked to an increased risk of MS relapse, whereas exposure to benzene and carbon monoxide was not [72].

4. Lifestyle factors

4.1 Smoking and oral tobacco

Cigarette smoking is a well-established risk factor for MS (OR of 1.5) [73, 74]; this finding result was later confirmed in a larger case-control study [75, 76], with a clear dose-response relationship [76, 77]; cumulative smoking is associated with an increase in risk [15, 75, 78, 79]. Elevated levels of cotinine in the serum or plasma (≥ 10 ng/ml) from patients before they developed MS were associated with a significantly increased risk of MS (OR of 1.5). The effect on the risk for MS by cotinine levels was significant in individuals younger than 26 years old with OR of 2.2 [80]. However, the age at which a person first began smoking had no effect on the association between smoking and MS risk [76]. Passive smoking exposure, including water pipe smoking, but not oral tobacco use in the form of moist snuff, has also been linked to an increased risk of MS [14, 81]. Also, children raised in environments associated with smoker parents had more than double the risk of a first MS episode when compared with unexposed children, this increase in risk was significantly associated with the longer duration of exposure [82]. In addition, children exposed to second-hand smoke and with HLA-DBR1*15 alleles have a higher risk of MS [83], implying that even minor lung irritation is significant [84]. If the association is due to nonspecific irritation, one might consider a factor such as air pollution as a trigger of CNS neuroinflammation, as long-term exposure to air pollutants has been confirmed as an environmental risk factor in MS [69]. On the other hand, smoking increases risk of developing neutralizing antibodies against some MS treatments, such as natalizumab and interferon β [85, 86].

Oral tobacco reduces the risk of developing MS in a dose-dependent manner [75, 87]. Nicotine may have such a protective effect due to its agonistic effect on the alpha 7 subunit of acetylcholine, expressed on the surface of CD4(+) T cells [88]. This finding lends credence to the idea that, despite nicotine’s apparent protective effects, it is lung inflammation that drives the increase in risk.

Smoking has a remarkable interaction with HLA risk genes associated with MS. In the Scandinavian population, carriers of the HLA DRB1*15:01 confer an OR of 3, and lack of HLA-A*02 confers an OR of ∼1.8, resulting in a combined OR of 5 among nonsmokers; however, among smokers, the combined OR is ∼14, much higher than the sum of the main effects associated with each factor [15]. In studies of passive smoke exposure, such a gene–environment interaction has been replicated [14]. These findings indicate a strong link between HLA genotypes and disease development [89].

Smoking also interacts with a non-HLA gene variant, the N-Acetyltransferase 1 (NAT1) gene (gene encoding the N-acetyltransferase 1 enzyme, which is important in the metabolism of aromatic amines present in cigarette smoke), as smokers with NAT1 single nucleotide polymorphisms are at a higher risk of developing MS [90]. As a result, the impact of smoking is highly dependent on genetic context [5, 7].

4.2 Obesity and body mass index

Female adolescent obesity has been linked to MS in large cohorts [91]. It has been found that adolescent obesity was associated with an OR of ∼2 in both males and females, despite the fact that adult body mass index (BMI) at diagnosis had no effect [13]. The link is highest with a BMI of > 27, but increased ORs can be seen at lower BMI levels as well. Obesity has been linked to a higher incidence of MS in children [91, 92]. It has been discovered that the critical period for adult MS appears to be during adolescence rather than at the age of ten [93]. A Norwegian/Italian study published results that were very comparable [94]. Furthermore, Mendelian randomization studies reveal that genetic determinants for high BMI are related to an increased risk of MS, despite several possible confounders and biases attributed to reverse causation, indicating that this lifestyle factor plays a causative role [64, 95].

In this scenario, there is also an interaction with MS HLA risk genes; specifically, DRB1*15:01 positive and HLA A*02 negative persons with a high BMI have an OR of ∼14 [13], indicating that biological pathways are shared and that obesity is a causal factor. Even however, the underlying mechanistic routes are still unknown. At the very least, we evaluate three non-exclusive and somewhat overlapping pathways: (1) Obesity is associated with “low-grade” inflammation, in which fat tissue produces higher quantities of proinflammatory mediators [96, 97]. Promotion of T helper (Th) 1-biased immune responses and decreased function of Treg cells have been described [98]; (2) In the presence of obesity, increased levels of leptin, a mediator connected to proinflammation, are observed [99]; (3) Obesity also leads to decreased bioavailability of vitamin D, in turn with options for a pro-inflammatory bias [100]. Any of the potential mechanisms may enhance the activation and functional proinflammatory bias of adaptive autoreactive immune cells, which may cause the neuroinflammatory bouts, a sequence of events that is supported by the HLA gene interaction; HLA genes encode the antigen-presenting molecules necessary for activation of T cells.

The observed interaction between EBV/IM and BMI, acting independently of the HLA DRB1*15:01 class II risk allele, where each of the two lifestyle/environmental factors results in ORs of 2, but approaches 14 when combined, strongly supports the relevance of obesity with regard to a putative immune attack on the CNS [101]. The causes for the interaction are still unknown. Obesity is linked to a less effective immune response to infections in general, so it’s possible that obesity will result in a less effective immune response to EBV [102, 103]. It’s also possible that a combined proinflammatory environment during obesity, as well as the as-yet-undefined effects of EBV linked to MS, are exacerbating the risk of neuroinflammation. Our argument is based on the fact that there is an interaction between EBV and obesity, two MS risk factors, in the development of MS, supporting the idea that both of them play a causal role in triggering onset.

Obesity data and MS may have a direct link with prevention in this scenario, especially for those who are at high risk for MS, such as children or other relatives of people with MS. It’s also relevant to the global obesity pandemic, and it could be one of the factors contributing to the rise in MS cases among women around the world.

4.3 Alcohol consumption

A number of research have been carried out to look into the role of alcohol in MS. There was evidence indicating a dose-dependent inverse connection between MS and alcohol in two large case-control studies, with ORs in the range of 0.7–0.8 [104]. Low and moderate alcohol use has been demonstrated to lower innate inflammatory responses in humans [105, 106, 107], which is consistent with recent data that show alcohol consumption is negatively related to MS risk. In terms of MS risk, it has been discovered that the existence of DRB1*15:01 and non-drinking, as well as smoking and non-drinking, have interactions [108].

Although still significant, the relationship between non-drinking and smoking was less prominent among previous smokers than among current smokers. This finding may not come as a surprise, given the long-term negative impact of smoking on MS risk after quitting [76]. Interleukin-21 is a major immune modulator that may enhance autoimmune responses through various mechanisms such as the development and activation of helper T-17 and follicular helper T cells, as well as the suppression of regulatory T cells [109], which has been shown to be reduced by alcohol and its metabolite acetate. Interleukin-21 has been linked to the onset of a number of autoimmune illnesses and has also been linked to the severity and progression of MS [110, 111].

Due to preexisting detrimental effects on CNS by the MS process, individuals may experience decreased alcohol tolerance and so restrict their alcohol consumption before the beginning of MS. Alcohol intake, on the other hand, has been linked to an increased risk of various autoimmune illnesses that do not directly damage the CNS [112, 113, 114]. Furthermore, alcohol use throughout adolescence was linked to a decreased incidence of MS [115] in a recent Danish case–control study.

To summarize, non-drinkers have a higher risk of developing MS than drinkers, and non-drinking combines with DRB1*15:01 and smoking to raise disease risk. Alcohol use has been shown to have negative effects on other disease conditions, and a greater understanding of the mechanisms behind our findings may aid in the development of new approaches to guard against MS without using alcohol.

4.4 Coffee consumption

Only a few studies have looked at the effects of coffee consumption on the risk and severity of MS, in contrast to the intense interest in the effects of smoking. Two independent population-based case-control studies recently looked into the link between coffee consumption and MS risk. The risk of MS was significantly lowered in individuals who reported drinking more than 900 mL of coffee per day (OR 0.70) [116]. In a case–control research with 93 cases and 186 controls, of which 92 were hospital controls and 94 were population controls, persons who took coffee before the age of 15 years had a higher risk of MS; however, there was no link between MS risk and coffee consumption beyond that age [117]. Increased coffee consumption was linked to an increased incidence of MS in a hospital-based case–control research with 210 incident cases and 210 individually matched controls. The inverse relationship between coffee drinking and the beginning of chronic diseases such as cardiovascular disease, diabetes, Parkinson’s disease, and various malignancies has led the US Dietary Guidelines Advisory Committee to suggest moderate coffee consumption as part of a healthy diet [118]. Coffee drinking could play a role in MS through a number of different processes. Caffeine therapy protects against experimental autoimmune encephalomyelitis by increasing the number of adenosine 1A receptors [119, 120]. In addition, caffeine administration of human monocytoid cells in vitro boosted the expression of adenosine 1A receptors while lowering pro-inflammatory cytokine output [121]. Although this study was cross-sectional, a causal relationship could not be verified, coffee drinking has also been linked to a slower progression of disability in relapsing onset MS [122]. More research is needed to determine whether the findings are due to caffeine or another molecule in coffee, to longitudinally assess the association between coffee consumption and MS disease activity, and to evaluate the mechanisms by which coffee may act, which could lead to new therapeutic targets.

4.5 Diet

The experimental findings regarding immune system modulation by salt concentration have been validated. In vitro studies suggest that lower intracellular sodium concentrations and sodium intake may have immune-protective effects [123, 124, 125]. While a large epidemiological study aimed at determining the relationship between dietary sodium intake and MS found that neither baseline energy-adjusted sodium levels nor cumulative longitudinal sodium intake was associated with an increased risk of developing MS [126, 127]. Other studies sought to determine the effect of salt consumption on the ongoing disease process, as it has been reported that individuals with MS who consumed a lot of salt had a lot more relapses and magnetic resonance imaging (MRI) evidenced disease activity than those who ate less salt [128]. On the contrary, studies that looked at patients’ sodium urine excretion levels found no correlation with conversion to clinically definite MS, nor with clinical or MRI outcomes over a five-year period [127]. The same results have been shown in the pediatric MS population [129, 130].

The relationship between polyunsaturated fatty acids (PUFAs) and MS has been investigated. Several studies [56, 131, 132] found that a higher intake of total PUFA at baseline was associated with a lower risk of MS. Clinical trials, on the other hand, have found no effect of a low-fat diet on relapse rate or MRI activity [133]. Furthermore, omega-3 supplementation had no effect on disease activity [134]. A higher saturated fat intake was associated with higher relapse risk in children with MS, whereas vegetable intake may be an independent protective factor [135].

In experimental MS models, the effects of various dietary changes have been studied (i.e., experimental autoimmune encephalomyelitis [EAE]). When compared to mice fed a normal diet, mice fed a high-fat diet showed increased gene expression of renin–angiotensin aldosterone system (RAAS) brain components, which coincided with increased vascular endothelial permeability, recruitment of inflammatory cells, upregulation of adhesion molecules, more severe exacerbations, and higher mean disease scores. The use of captopril which acts as an angiotensin-converting enzyme (ACE) inhibitor improves the outcomes of EAE disease [136]. A high-fat diet has also been linked to increased brain inflammation, decreased protective neurotrophic factors, and decreased neural plasticity, all of which impair learning and memory functions [137]. The EAE RAAS studies have proposed cardiovascular health as a potential link between dietary changes and MS outcomes by indicating a high-fat diet as a factor in MS [138].

4.6 Work shift

The relationship between shift work (night work) and MS has been studied. Shift work during adolescence (before the age of 20 years) has been shown to increase the risk of MS (OR ∼1.7). Other studies [139, 140, 141] have confirmed these findings. These findings highlight the importance of melatonin in the disease. Shift work consequences, such as circadian disruption and sleep restriction, have been linked to disturbed melatonin secretion and increased proinflammatory responses, and may thus be part of the mechanism underlying the association [139, 142]. Avoiding night shift work, especially in people at high risk of MS, is another modifiable lifestyle factor that may help prevent the disease [5].

4.7 Gut microbiota

The composition and abundance of microbes in the intestinal microbiota are risk factors for the development of MS. MS in humans can be caused by changes in certain microbial populations in the gastrointestinal tract. Furthermore, the gut microbiota promotes an anti-inflammatory and protective environment capable of inhibiting the growth of pathogenic microorganisms that cause a variety of diseases [143, 144]. Furthermore, many factors, such as diet, obesity, antibiotic use, cigarette smoking, and stress, influence the gut microbiota and may influence the risk and/or course of MS [144]. The gut microbiota appears to be crucial in the pathogenesis of MS. It appears to be involved in immune system modulation, changes the integrity and function of biological barriers (blood−brain barrier), has a direct effect on several types of central nervous system-resident cells, and causes autoimmune demyelination [144, 145].

5. Conclusion

The influence of lifestyle/environmental factors on MS is becoming clearer. Combining genetics and environmental factors has aided the understanding of MS; factors interacting with MS risk genes, primarily HLA risk genes, can be argued to share etiologic pathways underlying the disease, as well as their effect on the immune system. This is true for adolescent obesity, tobacco use, and EBV infection. The understanding method is still in its early stages, but the vast majority of recognized factors may be related to immune system impacts, comparable to hereditary predisposing factors, implying that the peripheral immune system plays a critical role in MS. Factors that cause disease are increasingly being incorporated into practical health treatment and even prevention, particularly for people at high risk of MS, especially if the disease runs in the family.

Acknowledgments

Acknowledgment to our student Massa Zahdeh ([e-mail]) in the faculty of pharmacy/Al-Quds University for drawing the figure.

Conflict of interest

The authors declare no conflict of interest.