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This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of multiple sclerosis? ​

Abstract ​

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the demyelination of nerve fibers in the central nervous system (CNS), affecting nearly 2 million individuals globally. The etiology of MS is multifactorial, with approximately 30% of the risk attributed to genetic factors and 70% influenced by environmental triggers. Understanding the mechanisms underlying MS is crucial for developing effective therapeutic strategies. This review explores the pathophysiology of MS, focusing on immune system involvement, inflammatory cytokines, genetic predispositions, environmental factors, neurodegeneration, gut microbiota, and lifestyle influences. The immune response in MS is complex, involving both adaptive and innate immune cells, regulatory T cells, and the impact of environmental factors such as infections and lifestyle choices. Oligodendrocyte dysfunction and axonal damage are central to the neurodegenerative aspects of MS. Recent findings suggest that gut microbiota play a significant role in modulating immune responses and influencing MS risk. Additionally, lifestyle factors, particularly diet and physical activity, significantly impact disease progression and patient quality of life. In conclusion, the mechanisms of MS are intricate, necessitating a comprehensive understanding to inform future research and therapeutic interventions aimed at improving outcomes for affected individuals.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Pathophysiology of Multiple Sclerosis
    • 2.1 Immune System Involvement
    • 2.2 Role of Inflammatory Cytokines
  • 3 Genetic and Environmental Factors
    • 3.1 Genetic Predisposition
    • 3.2 Environmental Triggers
  • 4 Neurodegeneration in MS
    • 4.1 Oligodendrocyte Dysfunction
    • 4.2 Axonal Damage and Neurodegeneration
  • 5 Role of the Gut Microbiota
    • 5.1 Microbiota Composition in MS Patients
    • 5.2 Mechanisms of Microbiota Influence on Immune Response
  • 6 Lifestyle Factors and Their Impact
    • 6.1 Diet and Nutrition
    • 6.2 Physical Activity and MS Progression
  • 7 Summary

1 Introduction ​

Multiple sclerosis (MS) is a complex autoimmune disorder characterized by the demyelination of nerve fibers in the central nervous system (CNS). Affecting nearly 2 million individuals worldwide, MS presents significant challenges not only to those diagnosed but also to healthcare systems due to its unpredictable course and varying degrees of disability [1]. The etiology of MS is multifactorial, with approximately 30% of the risk attributed to genetic factors, while the remaining 70% is influenced by environmental triggers [2]. These complexities underscore the necessity of understanding the mechanisms underlying MS to develop effective therapeutic strategies and improve patient outcomes.

The significance of studying MS mechanisms lies in the disease's profound impact on the quality of life of affected individuals. Current treatment options, while beneficial, often provide only partial relief and do not halt disease progression [3]. A deeper understanding of the pathophysiological processes involved in MS is crucial for identifying novel therapeutic targets and interventions that could alter the disease course [4]. Recent advances in immunology, genetics, and microbiome research have begun to shed light on the intricate interplay of factors contributing to MS, revealing potential pathways for targeted therapies [5].

Research into the pathophysiology of MS has evolved significantly over the past few decades. Initial hypotheses focused primarily on the role of immune-mediated mechanisms, particularly the involvement of T and B cells in the inflammatory response [6]. However, emerging studies have expanded the scope of investigation to include genetic predispositions, environmental factors, and lifestyle influences [7]. For instance, recent findings highlight the role of the gut microbiota in modulating immune responses and influencing MS risk, suggesting a complex interaction between host genetics, diet, and microbial composition [1]. Additionally, the contribution of oligodendrocyte dysfunction and axonal damage has been recognized as pivotal in the neurodegenerative aspect of MS [5].

The organization of this review will follow a structured outline, beginning with an in-depth exploration of the pathophysiology of MS, focusing on immune system involvement and the role of inflammatory cytokines. This will be followed by a discussion of genetic and environmental factors, including genetic predisposition and specific environmental triggers that may precipitate MS onset. The review will then delve into neurodegeneration in MS, emphasizing oligodendrocyte dysfunction and the mechanisms underlying axonal damage. Furthermore, we will examine the emerging role of gut microbiota in MS pathogenesis, detailing how microbiota composition in MS patients may influence immune responses. Finally, we will address lifestyle factors, such as diet and physical activity, and their impact on MS progression.

By synthesizing current knowledge and recent findings in these areas, this review aims to enhance our understanding of the mechanisms of MS and identify potential avenues for future research and therapeutic interventions. Through a comprehensive analysis of the multifaceted nature of MS, we hope to contribute to the ongoing efforts to develop more effective treatments and improve the quality of life for those affected by this challenging condition.

2 Pathophysiology of Multiple Sclerosis ​

2.1 Immune System Involvement ​

Multiple sclerosis (MS) is characterized by a complex interplay of immune mechanisms that contribute to its pathophysiology, primarily involving autoimmune responses leading to demyelination and neurodegeneration within the central nervous system (CNS). The disease is marked by the destruction of the myelin sheath surrounding neuronal axons, which is driven by both adaptive and innate immune cells.

Historically, MS was thought to be predominantly mediated by adaptive immune responses, particularly autoreactive T cells, which play a significant role in the pathophysiology. Recent findings, however, indicate that innate immune cells also significantly contribute to the initiation and progression of the disease. This includes macrophages, microglia, astrocytes, dendritic cells, and natural killer (NK) cells, which exhibit varied roles in the context of MS. The involvement of these innate immune cells suggests a more intricate mechanism than previously understood, emphasizing the need for a multipronged approach to fully elucidate the underlying pathophysiological processes (Sarkar et al., 2024) [8].

The immune response in MS is further complicated by the presence of regulatory T cells (Tregs), which can have both protective and pathogenic roles depending on their context and location within the CNS. While T and B lymphocytes are primarily associated with exacerbating MS pathology, Tregs may help mitigate the autoimmune response under certain conditions (Buc, 2013) [9].

Environmental factors, such as infections (notably Epstein-Barr virus), genetic predispositions, and lifestyle factors, also play crucial roles in modulating the immune response in MS. These factors can influence the recruitment and activation of immune cells within the CNS, contributing to the inflammatory milieu characteristic of the disease (Kirschner et al., 2025) [10]. The interactions between these immune cells and their microenvironment are pivotal, as they can shift the balance between protective and pathogenic responses, thus influencing disease progression and severity.

Moreover, recent studies have highlighted the importance of understanding the mechanisms of immune dysregulation in MS. This dysregulation is believed to stem from a combination of genetic susceptibility and environmental triggers, leading to an inappropriate immune response against self-antigens. The role of B cells and their production of pathogenic antibodies has gained attention, indicating that MS is not solely a T cell-mediated disease but involves a broader spectrum of immune dysregulation (Yadav et al., 2015) [11].

The pathological features of MS include inflammatory reactions, demyelination, axonal disintegration, and reactive gliosis. The initial studies emphasized T cell-mediated cellular immunity as a key driver of these pathological changes. However, the recognition of the contributions of B cells and innate immune cells has shifted the understanding of MS pathogenesis towards a more integrated model that considers multiple immune cell types and their interactions (Ma et al., 2023) [12].

In summary, the pathophysiology of multiple sclerosis is characterized by a complex interplay of adaptive and innate immune mechanisms, influenced by genetic and environmental factors. The involvement of various immune cell types, including autoreactive T cells, regulatory T cells, B cells, and innate immune cells, underscores the multifaceted nature of MS and highlights the necessity for comprehensive therapeutic strategies targeting these diverse pathways.

2.2 Role of Inflammatory Cytokines ​

Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by demyelination of axons in both white and gray matter of the central nervous system (CNS). The pathophysiology of MS is complex and involves various mechanisms, particularly the role of inflammatory cytokines and immune cell interactions.

Cytokines are soluble glycoproteins that play a crucial role in the regulation of immune cell functions. In the context of MS, they are implicated in both the initiation and maintenance of inflammatory responses. The disease is associated with the infiltration of leukocytes into the CNS, leading to inflammation, demyelination, and neurodegeneration. Specifically, tumor necrosis factors (TNFs) have been identified as key players in the pathogenesis of MS. They are involved in the effector arm of cellular immune responses and have shown to contribute to the inflammatory processes observed in the disease [13].

Research has highlighted that various cytokines, including pro-inflammatory and anti-inflammatory types, are dysregulated in MS. For instance, a study analyzed cytokine production in patients with different clinical forms of MS and found a similar percentage of cytokine-producing cells between healthy controls and MS patients, indicating a complex interplay of immune responses in the disease [14]. Moreover, elevated levels of pro-inflammatory cytokines such as IL-2RA, CCL5, and IFNγ have been documented in the cerebrospinal fluid (CSF) of MS patients, suggesting their role in mediating the inflammatory environment within the CNS [15].

The inflammasome complexes, which are components of the innate immune response, have also been implicated in MS pathogenesis. They are involved in the activation of pro-inflammatory cytokines like IL-1β and IL-18, contributing to cellular death mechanisms such as pyroptosis. This activation can exacerbate inflammatory processes and promote the progression of MS [16].

Astrocytes, the predominant glial cells in the CNS, have emerged as significant modulators of inflammation in MS. They respond to cytokines and play a dual role by secreting various cytokines and chemokines that can either promote or mitigate inflammation. For example, astrocytic signaling influenced by IFNγ is crucial in regulating stress responses that may affect the pathology of MS [17]. This highlights the importance of astrocytes in the cytokine network during autoimmune neuroinflammation [18].

Furthermore, mast cells have been shown to participate in the angiogenic processes related to chronic inflammation in MS, releasing angiogenic cytokines that can influence the inflammatory milieu and contribute to disease progression [19].

In summary, the pathophysiology of MS is characterized by a complex interplay of cytokines, immune cell activation, and the involvement of glial cells, all of which contribute to the inflammatory and neurodegenerative processes that define the disease. Understanding these mechanisms is crucial for developing targeted therapies aimed at modulating the immune response in MS.

3 Genetic and Environmental Factors ​

3.1 Genetic Predisposition ​

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disorder of the central nervous system (CNS) characterized by complex interactions between genetic and environmental factors. Genetic predisposition plays a crucial role in the development of MS, as evidenced by numerous studies identifying various genetic risk factors associated with the disease.

Research has confirmed a significant association between MS and specific genetic variants, particularly within the human leukocyte antigen (HLA) region. The HLA-DRB1 allele has been established as a major genetic risk factor for MS, with strong links to the disease's susceptibility. In addition to HLA, advances in genomic studies have identified over 50 non-HLA genetic risk factors, which predominantly involve immune system pathways and other relevant biological processes (Gourraud et al., 2012; Nischwitz et al., 2011). However, these genetic factors alone do not fully account for the heritability of MS, indicating that environmental factors also play a significant role in the disease's etiology (Amato et al., 2018).

Environmental factors, such as geographical location, diet, and the gut microbiome, have been shown to influence the onset and progression of MS. For instance, vitamin D deficiency has been associated with increased susceptibility to MS, as individuals living in regions with lower sunlight exposure exhibit higher prevalence rates of the disease (Giovannoni & Ebers, 2007). Furthermore, the role of infections, particularly Epstein-Barr virus, has garnered attention as a potential environmental trigger for MS. Epidemiological studies indicate that prior exposure to this virus is overrepresented in MS patients, suggesting a complex interplay between genetic predisposition and environmental exposure (Kantarci & Wingerchuk, 2006; Lauer, 2010).

The mechanisms through which genetic and environmental factors contribute to MS pathogenesis may involve immune-mediated responses triggered by both genetic predisposition and environmental exposures. Genetic variations can influence immune system functionality, potentially leading to aberrant immune responses when individuals are exposed to specific environmental triggers, such as infections or toxins (Lincoln & Cook, 2009). Additionally, epigenetic mechanisms, including DNA methylation and histone modifications, may further modulate the expression of genes associated with MS susceptibility, adding another layer of complexity to the disease's etiology (Mechelli et al., 2010).

In summary, the mechanisms of multiple sclerosis involve a multifactorial interplay between genetic predisposition and environmental factors. Genetic variants, particularly those related to immune function, contribute significantly to disease susceptibility, while environmental influences such as infections, vitamin D levels, and dietary factors can modulate disease onset and progression. Understanding these interactions is essential for developing targeted prevention and treatment strategies for MS.

3.2 Environmental Triggers ​

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disorder of the central nervous system (CNS), characterized by a complex interplay of genetic and environmental factors that contribute to its pathogenesis. Environmental triggers play a significant role in the onset and progression of the disease, influencing immune responses and potentially exacerbating the condition.

The etiology of MS is not fully understood, but it is conceptualized as a multifactorial disease resulting from interactions between genetic predisposition and various environmental factors. These environmental factors include infections, dietary habits, exposure to toxins, and lifestyle choices, which can modulate immune responses and contribute to disease development (Amato et al. 2018). For instance, the role of viral infections, particularly Epstein-Barr virus (EBV), has been highlighted in numerous studies. Evidence suggests that EBV exposure is overrepresented in MS patients, indicating a potential infectious trigger for the disease (Kantarci & Wingerchuk 2006).

Additionally, the influence of vitamin D deficiency has been extensively studied. Low levels of vitamin D, which is crucial for immune regulation, have been associated with increased susceptibility to MS. This association may be linked to geographical variations in MS prevalence, as populations with higher sunlight exposure (and thus higher vitamin D synthesis) tend to have lower MS rates (Giovannoni & Ebers 2007). Furthermore, dietary factors, including adherence to specific dietary patterns such as the Mediterranean diet, have been suggested to have protective effects against MS (Lauer 2010).

The timing of environmental exposures is also critical, as certain factors may have a more pronounced effect during specific developmental windows. Research indicates that environmental exposures occurring long before the clinical onset of MS can contribute to disease susceptibility (Handel et al. 2010). This temporal aspect underscores the complexity of the disease and the need for a nuanced understanding of how and when these environmental factors interact with genetic predispositions.

In summary, the mechanisms underlying multiple sclerosis involve a dynamic interplay between genetic and environmental factors, with specific environmental triggers such as infections, dietary habits, and vitamin D levels significantly influencing disease susceptibility and progression. Ongoing research aims to elucidate these interactions further, potentially leading to new preventive and therapeutic strategies for MS (Rothhammer & Quintana 2016).

4 Neurodegeneration in MS ​

4.1 Oligodendrocyte Dysfunction ​

Multiple sclerosis (MS) is a complex autoimmune disease characterized by demyelination and neurodegeneration within the central nervous system (CNS). The mechanisms underlying MS are multifaceted, with a central role played by oligodendrocytes, the myelinating cells responsible for maintaining the integrity of myelin sheaths around axons. The dysfunction of oligodendrocytes contributes significantly to the pathogenesis of MS, leading to impaired myelin repair and exacerbated neurodegeneration.

Oligodendrocytes are essential for the metabolic support of axons and the modulation of neural circuits. In MS, oligodendrocytes experience dysfunction due to various factors, including mitochondrial dysfunction, altered glucose and lipid metabolism, and increased vulnerability to inflammatory cytokines and oxidative stress. These metabolic changes result in energy deficits that critically affect oligodendrocyte function and myelin synthesis, ultimately leading to myelin damage and axonal degeneration [20].

Mitochondrial dysfunction is particularly notable in both oligodendrocytes and immune cells within the CNS of MS patients. Impaired mitochondrial function can lead to energy deficits, which compromise essential processes such as impulse transmission and axonal transport. Furthermore, this dysfunction is associated with the generation of reactive oxygen species (ROS), which exacerbate myelin damage and inflammation [20].

The metabolic landscape of oligodendrocytes is altered in MS, with dysregulated lipid metabolism resulting in changes to the composition of myelin, affecting its stability and integrity. Low levels of polyunsaturated fatty acids in MS patients are correlated with enhanced glucose catabolism and upregulated lipid metabolism, indicating a complex interplay between metabolic pathways that contributes to oligodendrocyte dysfunction [20].

In addition to metabolic changes, oligodendrocyte dysfunction can also be influenced by autoimmune mechanisms. The autoimmune attack targeting oligodendrocytes and myelin leads to their demise, significantly contributing to the pathogenesis of MS [21]. The interplay between oligodendrocyte death and inflammation is critical; it remains uncertain whether oligodendrocyte apoptosis precedes inflammation or if the inflammatory response primarily drives oligodendrocyte death [22].

Recent research highlights the importance of oligodendrocyte progenitor cells (OPCs) in the context of remyelination. In MS, there is an imbalance between demyelination and remyelination processes, where OPCs are unable to sufficiently proliferate and differentiate into mature oligodendrocytes to repair damaged myelin [23]. Factors such as microglial activation and altered signaling pathways can impede the maturation of OPCs, further complicating the recovery of myelin integrity [24].

In summary, the mechanisms of neurodegeneration in MS are closely tied to oligodendrocyte dysfunction, which is influenced by metabolic disturbances, inflammatory responses, and impaired regenerative capacity. Understanding these mechanisms is crucial for developing targeted therapies aimed at preserving oligodendrocyte function and promoting remyelination, thereby improving clinical outcomes for individuals with MS [25][26].

4.2 Axonal Damage and Neurodegeneration ​

Multiple sclerosis (MS) is characterized by a complex interplay of neurodegenerative and inflammatory processes that lead to significant axonal damage and subsequent neuronal loss. The mechanisms underlying neurodegeneration in MS are multifaceted and involve various cellular and molecular pathways.

One primary mechanism of neurodegeneration in MS is the dysfunction of mitochondria within axons. Mitochondrial impairment has been identified as a crucial factor in axonal degeneration, particularly in the context of chronic demyelination. Mitochondria serve as the main energy source for axons, and their dysfunction can lead to energy failure, which is particularly detrimental to the maintenance of axonal integrity. In chronic MS lesions, axonal damage is observed in both demyelinated and myelinated regions, suggesting that mitochondrial abnormalities may increase the vulnerability of axons to degeneration (Campbell et al., 2014)[27].

Furthermore, axonal injury in MS is closely associated with inflammatory processes. The presence of activated immune cells, such as T cells and macrophages, in MS lesions contributes to axonal damage through the release of pro-inflammatory cytokines and other neurotoxic substances. This inflammation can lead to oxidative stress, which further exacerbates mitochondrial dysfunction and promotes a cascade of neurodegenerative events (Brück, 2005)[28].

Calcium dysregulation also plays a critical role in axonal injury. The plasma-membrane Ca(2+)-ATPase 2 (PMCA2) and the Na(+)/Ca(2+) exchanger (NCX) are vital for maintaining calcium homeostasis in neurons. Alterations in the expression or activity of these calcium regulatory proteins can lead to increased intracellular calcium levels, triggering various catabolic pathways that contribute to axonal degeneration (Kurnellas et al., 2007)[29].

Additionally, the phenomenon of virtual hypoxia in chronically demyelinated axons has been described, where the increased energy demand for impulse conduction exceeds the available ATP production, leading to a state of chronic necrosis. This condition is exacerbated by mitochondrial dysfunction and the subsequent release of toxic calcium and reactive oxygen species, which collectively drive axonal degeneration (Trapp & Stys, 2009)[30].

The interplay between neuroinflammation and neurodegeneration suggests that the mechanisms of axonal damage in MS are not isolated but rather interconnected. Inflammatory processes may initiate axonal injury, while the resulting neurodegeneration can further perpetuate inflammatory responses, creating a vicious cycle that contributes to the progressive nature of the disease (Mahad et al., 2015)[31].

In summary, the mechanisms of neurodegeneration in multiple sclerosis, particularly concerning axonal damage, involve mitochondrial dysfunction, inflammatory processes, calcium dysregulation, and the interplay between these factors. Understanding these mechanisms is essential for developing effective therapeutic strategies aimed at preventing neurodegeneration and promoting neuronal protection in MS.

5 Role of the Gut Microbiota ​

5.1 Microbiota Composition in MS Patients ​

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by demyelination and neurodegeneration. The etiology of MS is multifactorial, involving both genetic and environmental factors, with the gut microbiota emerging as a significant environmental modifier in the disease's pathogenesis. The gut microbiota comprises trillions of microorganisms that play a crucial role in maintaining host health, including the regulation of immune responses and metabolic processes.

Research has demonstrated that individuals with MS exhibit gut microbial dysbiosis, which is characterized by alterations in the composition and diversity of the gut microbiome compared to healthy controls. For instance, studies have shown that the gut microbiota of MS patients is often less diverse, indicating a state of dysbiosis, which can influence immune homeostasis and potentially contribute to the disease's progression [1][32][33].

In healthy adults, the gut microbiota typically consists of five major bacterial phyla: Firmicutes (approximately 79.4%), Bacteroidetes (16.9%), Actinobacteria (2.5%), Proteobacteria (1%), and Verrucomicrobia (0.1%). However, in MS patients, certain bacterial families may be enriched or depleted. For example, a study comparing the gut microbiome of MS patients to that of their healthy relatives found an increase in families such as Ruminococcaceae and Clostridiales in MS patients, while Bacteroidaceae and Tannerellaceae were more abundant in healthy controls [34].

The dysbiosis observed in MS patients is believed to impact the immune system by promoting pro-inflammatory responses. Specific microbial taxa, such as Prevotella and Faecalibacterium, have been suggested to have protective roles, while others, such as Akkermansia muciniphila, have been associated with disease aggravation [35]. This imbalance in microbial composition can lead to elevated levels of pro-inflammatory cytokines and disruption of the gut-brain axis, which is critical in the development and progression of MS [36].

Moreover, dietary factors have been identified as significant influencers of gut microbiota composition, which can further modulate MS risk. For example, MS patients often lack gut bacteria capable of metabolizing dietary phytoestrogens, indicating that dietary patterns can significantly impact the microbiome and, consequently, the immune response [33].

The interplay between gut microbiota and host immune responses suggests that therapeutic strategies aimed at modulating the gut microbiome—such as the use of probiotics, prebiotics, and dietary interventions—may offer new avenues for MS treatment [37][38]. Understanding the specific microbial compositions and their functional implications in MS could lead to personalized therapeutic approaches that consider individual genetic backgrounds and dietary habits [1].

In conclusion, the gut microbiota plays a central role in the pathogenesis of multiple sclerosis through mechanisms involving immune modulation, dysbiosis, and interactions with dietary components. The complexity of these interactions highlights the potential for microbiota-targeted therapies in the management of MS, emphasizing the need for further research to elucidate the precise mechanisms involved.

5.2 Mechanisms of Microbiota Influence on Immune Response ​

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammation and demyelination in the central nervous system (CNS). Recent research has highlighted the role of gut microbiota in the pathogenesis of MS, revealing complex mechanisms through which gut microbiota influence immune responses.

The gut microbiota is a diverse community of microorganisms residing in the gastrointestinal tract, and its composition can significantly affect systemic immune responses. One of the primary mechanisms by which gut microbiota influence immune function is through the modulation of immune cell activity. Studies have shown that gut microbiota can impact the balance of T-cell populations, particularly influencing the differentiation of T-helper cells. For instance, certain microbial taxa are associated with protective roles in MS, while others, such as Akkermansia muciniphila, have been linked to disease aggravation (Nemati et al. 2025) [35].

Dysbiosis, or an imbalance in gut microbiota composition, has been observed in MS patients. This dysbiosis can lead to increased intestinal permeability, which may facilitate the translocation of microbial products into systemic circulation, triggering autoimmune responses. Specifically, the gut microbiota can influence the permeability of the intestinal barrier and disrupt the integrity of the blood-brain barrier, allowing for the infiltration of immune cells into the CNS and exacerbating neuroinflammation (Wang et al. 2022) [39].

Moreover, the production of microbial metabolites, such as short-chain fatty acids (SCFAs), plays a crucial role in immune modulation. SCFAs are produced through the fermentation of dietary fibers by gut bacteria and have been shown to promote the generation of regulatory T cells (Tregs), which are essential for maintaining immune homeostasis and preventing excessive inflammation (Haase et al. 2018) [40]. Conversely, alterations in SCFA production due to dysbiosis can lead to a decrease in Treg populations, contributing to an inflammatory environment conducive to MS progression.

In addition to T-cell modulation, gut microbiota also influence the production of pro-inflammatory cytokines. Specific components of the microbiome have been implicated in the upregulation of inflammatory cytokines, which can exacerbate the autoimmune response in MS. For instance, certain bacteria may promote the differentiation of Th17 cells, which are known to play a role in the pathogenesis of MS by promoting inflammation and tissue damage (Ladakis & Bhargava 2023) [41].

Furthermore, the gut microbiota can also impact the metabolism of dietary components, which in turn affects immune responses. Dietary phytoestrogens and their metabolizing gut bacteria have been shown to influence MS pathobiology, suggesting that dietary interventions could be a potential therapeutic strategy (Lehman et al. 2023) [33].

Overall, the interplay between gut microbiota and the immune system is complex and multifaceted, with implications for the development and progression of MS. Understanding these mechanisms may pave the way for novel therapeutic approaches aimed at modulating gut microbiota to alleviate disease-related immune dysfunction and improve clinical outcomes in MS patients.

6 Lifestyle Factors and Their Impact ​

6.1 Diet and Nutrition ​

Multiple sclerosis (MS) is an autoimmune disease characterized by complex interactions among genetic, immunological, infective, and biochemical mechanisms, which collectively contribute to the disease's pathogenesis. While the exact etiology of MS remains largely unknown, both genetic predisposition and environmental factors, including lifestyle choices such as diet and nutrition, play significant roles in influencing disease risk and progression.

Diet has emerged as a critical environmental factor that may modulate the risk and severity of MS. Epidemiological studies suggest that certain dietary patterns, particularly high-fat diets, may exacerbate neuroinflammation and contribute to the pathology associated with MS. Research conducted by Timmermans et al. (2014) indicated that a high-fat diet (HFD) increases immune cell infiltration and inflammatory mediator production in the central nervous system (CNS), thereby aggravating experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The activation of the renin-angiotensin system (RAS) was associated with the HFD-mediated effects on EAE severity, highlighting the potential of dietary fat intake to influence neuroinflammatory responses in MS[42].

Moreover, the composition of the gut microbiome, which is influenced by diet, has been implicated in the pathogenesis of MS. Montgomery et al. (2024) reviewed the role of gut microbiota in modulating MS risk, emphasizing that dietary inputs and gut microbial metabolism, particularly the production of short-chain fatty acids and tryptophan metabolism, can act as environmental modifiers of disease risk. In genetically susceptible individuals, the interplay between gut microbiota and diet may significantly impact MS progression and severity[1].

In addition to dietary fat and gut microbiota, other lifestyle factors such as vitamin D levels have also been implicated in MS. Tiwari et al. (2018) discussed how environmental exposures, including vitamin D deficiency, are strongly associated with MS pathogenesis. Vitamin D is believed to play a role in immune regulation, and its deficiency has been linked to increased risk of MS, suggesting that nutritional factors influencing vitamin D levels could also impact disease outcomes[43].

Furthermore, the interaction between dietary factors and genetic predisposition is crucial. Genetic variants associated with MS may influence how individuals respond to dietary components, thereby affecting disease susceptibility. For instance, specific dietary patterns may exert divergent effects on individuals carrying distinct genetic risk alleles, as highlighted by Montgomery et al. (2024), which suggests a complex gene-by-environment interaction that is pivotal in understanding MS pathogenesis[1].

In conclusion, the mechanisms of MS are multifaceted, involving an intricate interplay of genetic susceptibility and environmental factors, particularly diet and nutrition. The modulation of the gut microbiome through dietary choices, the impact of high-fat diets on neuroinflammation, and the role of vitamin D are critical areas of research that may inform future therapeutic strategies aimed at preventing or treating MS. Understanding these interactions is essential for developing personalized approaches to manage the disease effectively.

6.2 Physical Activity and MS Progression ​

Multiple sclerosis (MS) is characterized as a chronic autoimmune inflammatory demyelinating disorder of the central nervous system (CNS), which results in significant disability and necessitates extensive medical intervention. The disease manifests through recurrent episodes of inflammatory demyelination, leading to axonal deterioration and resulting in functional decline and lasting disability, particularly among young adults [44].

The pathophysiology of MS is multifaceted, involving both genetic and environmental factors that modulate the disease's progression. Genetic predispositions contribute to the likelihood of developing MS, yet they are not amenable to therapeutic intervention. Conversely, environmental factors, including geographical location, diet, and the gut microbiome, play a crucial role in influencing disease activity and progression [45].

Physical activity has emerged as a significant lifestyle factor that can positively influence the progression and symptomatology of MS. Exercise has been shown to counteract fatigue and depression, thereby improving the overall quality of life for MS patients [44]. Additionally, recent studies have indicated that exercise can ameliorate chronic neuroinflammation, shifting cytokine profiles towards an anti-inflammatory state, which is particularly relevant in the context of MS [44].

Recent investigations have also focused on the direct effects of exercise on the innate immune system, particularly through the modulation of toll-like receptors (TLRs). These receptors are pivotal in governing the innate immune response and are implicated in the neuroinflammatory processes associated with MS [44]. This suggests that exercise may serve as an immunomodulatory therapy that can alter innate signaling mechanisms, thereby potentially influencing MS symptom development and progression.

Moreover, exercise is associated with various physiological benefits that are crucial for MS management. It enhances aerobic capacity, balance, muscle strength, and overall immune and hormonal functions [46]. Different exercise modalities, such as aerobic, resistance, and flexibility training, have been recommended, with tailored protocols suggested for MS patients to maximize benefits while minimizing risks associated with fatigue and physical limitations [46].

The interplay between physical activity and neuroplasticity is another area of interest, as exercise has been shown to positively affect brain structure and function, potentially contributing to improved cognitive and physical outcomes in MS patients [46]. Thus, the incorporation of exercise into the management strategies for MS is increasingly recognized as essential for enhancing the quality of life and possibly modulating disease progression [46].

In summary, the mechanisms of MS involve a complex interaction of genetic and environmental factors, with physical activity playing a critical role in modulating disease progression and symptomatology. Exercise not only offers physiological benefits but also serves as a potential immunomodulatory therapy that can positively influence the innate immune response and overall disease management.

7 Conclusion ​

The mechanisms underlying multiple sclerosis (MS) are complex and multifaceted, involving intricate interactions between genetic predispositions, environmental triggers, immune responses, and lifestyle factors. Key findings indicate that both adaptive and innate immune mechanisms play significant roles in the pathophysiology of MS, with autoreactive T and B cells contributing to demyelination and neurodegeneration. Furthermore, the dysregulation of inflammatory cytokines and the involvement of oligodendrocytes are critical in understanding the neurodegenerative processes associated with the disease. Genetic risk factors, particularly those related to immune system pathways, have been identified, alongside environmental influences such as vitamin D levels, infections, and dietary habits that modulate disease onset and progression. The gut microbiota emerges as a significant player in MS pathogenesis, affecting immune responses and highlighting the potential for microbiota-targeted therapies. Lifestyle factors, including diet and physical activity, are also crucial, as they can influence disease severity and patient quality of life. Future research should focus on elucidating the precise mechanisms through which these factors interact and contribute to MS, paving the way for innovative therapeutic strategies aimed at modifying disease progression and improving patient outcomes.

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