on August 24, 2026
A multifactorial disease
Multiple sclerosis (MS) is an inflammatory and immune-mediated disease of the central nervous system in which genetic predisposition, environmental factors, and alterations in the immune response interact. The result is a pathological process characterized by demyelination, axonal damage, glial alterations, and, over time, neurodegenerative phenomena.
There is therefore no single "risk factor" capable of explaining on its own why a person develops the disease.
However, research in recent years has profoundly changed our understanding of MS. In addition to genetics, Epstein-Barr virus (EBV) infection, cigarette smoking, obesity—especially in adolescence, vitamin D availability, certain lifestyle factors, and the gut microbiota are now particularly studied. A 2026 review further highlighted the interaction between these factors and genetic predisposition, emphasizing the role of common immunological pathways that regulate antigen presentation, lymphocyte differentiation, and immune tolerance.
It is important, however, to distinguish between factors associated with the risk of developing the disease, factors that may influence its course, and conditions capable of temporarily worsening symptoms without representing a true new relapse.
The blood-brain barrier: a dynamic frontier
The blood-brain barrier (BBB) constitutes one of the main interfaces between the blood and the central nervous system.
It is composed mainly of the endothelial cells of the brain capillaries, their tight junctions, the basement membrane, and interactions with pericytes, astrocytes, and immune cells. Its function is to control the passage of molecules and cells from the bloodstream to the nervous tissue.
In multiple sclerosis, this barrier can become permeable.
One of the indicators used in diagnostic practice is precisely the appearance of lesions that take up gadolinium contrast on MRI: the phenomenon reflects an alteration of the barrier associated with the inflammatory activity of the disease.
This finding is fundamental, but it must be interpreted correctly: the alteration of the blood-brain barrier is above all a sign of the inflammatory activity of MS; it has not been proven that every event capable of "weakening the barrier" constitutes a primary cause of relapse.
The current model sees a complex interaction between peripheral immune cells, the endothelium, the blood-brain barrier, microglia, and glial cells. Inflammation can promote the entry of immune cells and mediators into the central nervous system, contributing to the formation of demyelinating lesions.
From inflammation to plaque
The characteristic lesion of MS is the demyelinating plaque.
In relapsing forms, immune system activation leads to an infiltration of immune cells into the central nervous system, involving T and B lymphocytes, macrophages, and microglia.
Myelin is damaged, and oligodendrocytes may be lost. At the same time, astrocytes become reactive and contribute to the formation of the glial scar.
The situation is more complex than a simple "inflammation that destroys myelin": axonal damage and neurodegenerative alterations can appear even in the early stages, while in progressive forms, inflammatory processes compartmentalized within the central nervous system gain greater importance.
This explains why MS is now considered simultaneously an immune-mediated, demyelinating, and neurodegenerative disease.
Epstein-Barr virus: the most compelling environmental factor
Among all the environmental factors studied, the one that has received the most important epidemiological evidence in recent years is the Epstein-Barr virus.
EBV is extremely common in the general population. Almost all adults are infected during their lifetime, but only a small percentage develop multiple sclerosis.
The relationship therefore cannot be interpreted as:
EBV = multiple sclerosis.
The situation is much more complex.
In the large longitudinal study published in Science in 2022, over 10 million young adults in the U.S. military were analyzed, among whom 955 cases of MS occurred. The risk of developing the disease increased by approximately 32 times after EBV seroconversion, while no similar increase was observed after infections with other studied viruses. Furthermore, levels of neurofilament light chain, a biomarker of neuroaxonal damage, increased after EBV seroconversion.
This finding is extremely important because it supports a much stronger causal relationship than simple epidemiological associations.
However, other elements are necessary: genetic predisposition, characteristics of the immune response, and other environmental factors may determine why EBV infection remains asymptomatic in the majority of people and is instead associated with MS in a minority.
Cigarette smoking
Smoking represents one of the modifiable factors most strongly associated with MS.
A systematic review and meta-analysis found a significant association between smoking and the risk of developing MS, with an aggregate OR/RR of approximately 1.54. The same analysis found an association with progression to the secondary progressive form, with an HR of approximately 1.80. Analysis according to the Bradford Hill criteria provided evidence supporting a causal role of smoking, especially in the development of the disease.
Possible mechanisms include:
- increased oxidative stress;
- alteration of the immune response;
- alteration of endothelial function;
- proinflammatory effects;
- interactions with the blood-brain barrier;
- alteration of the adaptive immune response.
For this reason, smoking cessation represents one of the most rational and best-supported preventive measures.
Overweight and obesity
Body weight also appears to play a role, especially when excess weight manifests early in life.
A meta-analysis published in 2024 found that, compared with people of normal weight, overweight was associated with an increased risk of MS, with an RR of 1.38, and obesity was associated with an RR of 1.88. The authors discussed low-grade chronic inflammation, immune alterations, adipocytes, and changes in the gut microbiota as possible mechanisms.
This does not mean that overweight directly "causes" MS.
It means that excess adiposity may create a metabolic and immunological environment that is potentially conducive to the development of the disease in genetically predisposed individuals.
Visceral adiposity, in particular, is metabolically active and produces adipokines and mediators that can influence the immune system.
Vitamin D and sun exposure
The relationship between vitamin D and MS has been studied extensively because the disease has a geographical distribution that has historically suggested a possible role for latitude and sun exposure.
Vitamin D also has effects on the immune system and can modulate the differentiation and function of various lymphocyte populations.
The challenge is to distinguish:
the association between low vitamin D levels and MS
from
evidence that vitamin D supplementation prevents or modifies the disease.
The first relationship is supported by numerous observational studies; the second remains less definitive.
For this reason, in a person with MS, assessing vitamin status may be reasonable, but supplementation must be tailored to blood levels and clinical indications, without considering vitamin D as a substitute for disease-modifying drugs.
Diet: inflammation, metabolism, and overall dietary quality
Diet is one of the most discussed topics among people with MS, but also one of the most exposed to overly simplistic interpretations.
There is insufficient evidence to state that a single food category is responsible for multiple sclerosis or that eliminating a single food can "cure" the disease.
It is, however, plausible that the overall dietary pattern influences certain factors associated with prognosis: body weight, cardiovascular health, glucose metabolism, inflammatory status, micronutrient availability, and microbiota composition.
Among dietary patterns, the Mediterranean diet currently has one of the most compelling rational bases.
A 2024 systematic review identified 11 studies on the Mediterranean diet or similar patterns in MS and reported possible benefits for inflammation, fatigue, quality of life, relapse frequency, and cognitive function, while highlighting the limited number of high-quality randomized trials.
A small randomized trial in 2019 also studied a modified Mediterranean diet in 36 women with MS. After six months, improvements were observed in the trajectory of neurological fatigue and, in the analysis conducted, also in disease impact and EDSS scores. The same authors highlighted the need for larger studies.
A subsequent meta-analysis of five randomized trials, including 540 participants, found an average reduction in BMI associated with the Mediterranean diet; the improvement in fatigue, however, was only marginal and not statistically significant.
The most cautious conclusion is therefore that a balanced Mediterranean diet represents a reasonable choice for overall health and can contribute to managing certain aspects of MS, but cannot be considered a disease-modifying therapy.
Products of animal origin: what can we really say?
One of the most widespread claims in MS communication needs to be corrected: it is not scientifically accurate to state that all foods of animal origin are inherently pro-inflammatory or that milk consumption necessarily leads to an increase in intestinal permeability responsible for MS.
Nutritional research is much more complex.
High consumption of certain foods rich in saturated fats and ultra-processed products can contribute to a less favorable metabolic profile, while fish, yogurt, and other foods of animal origin can be part of dietary patterns associated with good health outcomes.
Regarding milk and casein, there is insufficient clinical evidence to state that cow's milk consumption causes a "systemic destruction of intestinal villi" in the general population or that it is a cause of MS.
Similarly, the idea that animal proteins systematically make the blood "acidic," causing the pathological mobilization of calcium from the bones, does not correctly describe human acid-base balance physiology.
The nutritional issue must therefore be addressed through the overall quality of the diet, not by identifying a single food as a universal cause of inflammation.
The gut microbiota: a fascinating connection, still under study
The gut microbiota is probably one of the most interesting areas of contemporary MS research.
The gut and immune system communicate continuously through metabolites, short-chain fatty acids, microbial components, and signals from the intestinal epithelium.
Some metabolites produced by gut bacteria can influence regulatory T cell differentiation, dendritic cell function, and the balance between pro- and anti-inflammatory responses.
This has led to the hypothesis of a gut-brain-immunity axis involved in MS.
But even in this case, excessive conclusions must be avoided.
A 2024 systematic review analyzed 23 studies involving a total of 1,760 people with MS. The majority of studies assessing microbiota diversity found no clear relationship between microbial diversity and disease activity. Some specific bacterial groups, however, were associated with different clinical outcomes. In particular, some producers of short-chain fatty acids were associated with better outcomes, while other taxa were associated with greater activity or disability. The authors emphasize, however, that the majority of studies are cross-sectional and do not allow for causality to be established.
This means that the microbiota is probably a modulator, not a single "switch" for the disease.
Antibiotics and the microbiota: beware of simplifications
Antibiotics can profoundly alter the gut microbiota, especially when used repeatedly or in broad-spectrum combinations.
This does not, however, mean that every course of antibiotics causes a permanent loss of intestinal biodiversity or that antibiotics are a proven cause of multiple sclerosis.
Antibiotics remain essential tools for treating bacterial infections and, when indicated, their benefits can far outweigh the risks.
The scientifically sound recommendation is therefore to avoid the inappropriate use of antibiotics, not to avoid them altogether.
The same principle applies to proton pump inhibitors: they can alter the microbiota and have been associated in some studies with specific infectious and metabolic changes, but it is incorrect to say that they cause "general chronic inflammation" or that they cause MS.
Pharmacotherapy must always be assessed on an individual basis, weighing the benefits against the risks.
Physical activity: not just rehabilitation
For many years, people with MS were advised to avoid excessive exertion. Today we know that physical activity, appropriately adapted to individual circumstances, is an important part of managing the disease.
Exercise should not be considered a treatment for MS, but it can improve many functional aspects.
A 2024 meta-analysis of 40 studies involving more than 2,000 participants found significant improvements in balance, walking ability, endurance, fatigue, and quality of life.
A 2025 meta-analysis also found that structured physical activity programs can clinically significantly reduce the severity and impact of fatigue.
Exercise should therefore be tailored to:
- degree of disability;
- balance and fall risk;
- muscle strength;
- cardiovascular capacity;
- ambient temperature;
- fatigue;
- any sensory impairments;
- the presence of comorbidities.
Heat and the Uhthoff phenomenon: worsening does not necessarily mean a relapse
Heat deserves an important clarification.
An increase in body temperature can temporarily worsen some neurological symptoms in MS. This phenomenon is known as the Uhthoff phenomenon.
Hyperthermia can impair the conduction of impulses along already demyelinated nerve fibers and make weakness, visual disturbances, fatigue, or other symptoms more apparent.
But this does not necessarily mean that a new plaque is forming.
A relapse and a temporary worsening due to heat are different phenomena.
For this reason, it is reasonable to avoid conditions of excessive overheating during exercise, especially in people who are highly sensitive to temperature.
Infections and relapses
Infections can temporarily worsen neurological symptoms and, in some circumstances, may be associated with increased disease activity.
Urinary tract infections are particularly important in people with bladder dysfunction, because urinary retention increases the risk of infection.
However, it is not correct to recommend indiscriminate screening or preventive antibiotics.
Management must be individualized: when symptoms consistent with an infection are present, it must be diagnosed and treated appropriately.
Distinguishing between a true relapse and a pseudo-relapse associated with infection, fever, or heat is clinically important.
Stress and sleep
Psychological stress, sleep disturbances, depression, and reduced physical activity can significantly affect the perception of fatigue and quality of life.
Their role as direct causes of MS, however, is much less clearly defined.
It is therefore preferable to speak of factors that can affect well-being and disease management, rather than proven causes of relapses.
Regular sleep, stress management, physical activity, and maintaining social relationships are part of a comprehensive health strategy, but they do not replace neurological therapies.
An important example: dimethyl fumarate and the role of Nrf2
Pharmacological research on MS shows how complex the relationship between inflammation, cellular metabolism, and oxidative stress is.
Dimethyl fumarate, a drug used in relapsing forms of MS, provides a particularly interesting example.
Its mechanism includes immunomodulatory effects and the activation of the Nrf2 pathway, a cellular response system involved in protection against oxidative stress.
The interesting point is that a biological mechanism identified in the laboratory was subsequently associated with a measurable clinical effect.
In the DEFINE phase III trial, dimethyl fumarate reduced the percentage of patients with a relapse at two years compared with placebo and reduced the annualized relapse rate, disability progression, and radiological activity on MRI.
The pooled analysis of the two large DEFINE and CONFIRM phase III studies confirmed a reduction of approximately 49% in the annualized relapse rate with 240 mg twice daily, along with a significant reduction in new lesions on MRI.
This example is important because it shows the difference between a biological hypothesis and a clinically proven treatment.
Medicinal plants and multiple sclerosis: what do we really know?
Research on plant products is interesting, but the evidence is still far weaker than that available for disease-modifying therapies.
Lippia citriodora
One of the most interesting clinical studies concerns the extract of Lippia citriodora, or lemon verbena, standardized to 10% verbascoside.
It was a small randomized, double-blind, placebo-controlled study involving 30 people with different forms of MS. After 28 days, C-reactive protein and several cytokines were assessed.
The authors observed changes in some pro- and anti-inflammatory markers, including a reduction in IFN-γ in several groups and changes in IL-12, IL-4, and IL-10 in specific subgroups. In the secondary progressive form, a significant reduction in C-reactive protein compared to placebo was also observed.
It is an interesting result from a biological point of view, but it does not show that verbena reduces relapses, slows progression, or modifies disability in MS.
The study is small, short, and focused mainly on inflammatory biomarkers.
Green tea EGCG
Epigallocatechin-3-gallate (EGCG), a green tea catechin, has also been studied in MS.
A randomized crossover study from 2015, conducted on 18 people with relapsing-remitting MS, observed the effects of 600 mg/day of EGCG on energy metabolism during rest and exercise. The results suggested changes in the metabolism of energy substrates during physical exercise.
But this result should not be interpreted as evidence of therapeutic efficacy for MS.
A subsequent multicenter, randomized, placebo-controlled trial studied up to 800 mg/day of EGCG for 18 months in 122 patients with relapsing-remitting MS already treated with glatiramer acetate. No significant differences compared to placebo were demonstrated in the primary radiological endpoint or in the clinical endpoints, including EDSS and annualized relapse rate.
The conclusion is therefore particularly instructive: an interesting biological mechanism and a small metabolic study are not enough to demonstrate clinical efficacy for the disease.
Which behaviors today have the best balance between plausibility and evidence?
In light of the available literature, a reasonable strategy for a person with MS should focus mainly on the factors with the strongest evidence:
not smoking or quitting smoking, because its relationship with risk and progression is well documented;
maintaining a healthy body weight, especially considering the association between obesity and MS risk;
following a balanced diet, mainly Mediterranean, avoiding extreme restrictions not supported by adequate evidence;
engaging in regular, personalized physical activity, with particular attention to aerobic exercise, strength, balance, and functional capacity;
correcting any documented nutritional deficiencies, including vitamin D when present;
protecting sleep and psychological health;
preventing and correctly treating infections, avoiding both underestimation and improper use of antibiotics;
avoiding excessive overheating, especially in people sensitive to the Uhthoff phenomenon.
These interventions should not be presented as substitutes for disease-modifying therapies.
MS as the result of a network of signals
Modern research is gradually moving beyond the model in which MS is determined by a single factor.
We can imagine a network in which interact:
genetic predisposition → infections and environment → immune system → blood-brain barrier → neuroinflammation → demyelination → axonal damage
Added to this network are metabolism, adiposity, microbiota, diet, physical activity, sleep, and other environmental factors.
The microbiota could modulate immunity. Adipose tissue can produce inflammatory signals. Smoking alters the immune environment. EBV can represent an important immune stimulus. Vitamin D participates in immune regulation. Exercise alters metabolism and neuromuscular function.
But none of these elements, taken in isolation, explains the disease.
True prevention is multifactorial
Knowledge of risk factors should not turn into a list of prohibitions or the search for a single cause.
The most important lesson of MS research is precisely this: the disease arises from the interaction of numerous biological systems.
The realistic goal of lifestyle is not to "cure" MS through diet or the microbiota, but to create metabolic, cardiovascular, immunological, and functional conditions as favorable as possible.
In the same way, the study of natural substances can provide new pharmacological hypotheses — as shown by lemon verbena, EGCG, and numerous other phytochemicals — but every hypothesis must be verified through adequate clinical studies.
Research on dimethyl fumarate shows how powerful this path can be: from the understanding of cellular mechanisms, to the identification of a molecular target, to the demonstration through large randomized studies of a reduction in relapses and radiological activity.
This is the most solid direction of modern medicine: understand biological signals, identify modifiable factors, and distinguish what is plausible from what is actually demonstrated in humans.
Note: the evidence regarding diet, microbiota, vitamin D, and plant substances is heterogeneous and, in many cases, still insufficient to demonstrate an effect on the progression of multiple sclerosis. None of the nutritional or phytotherapeutic strategies described should be considered a substitute for the therapies prescribed by the neurologist. Furthermore, in MS, it is particularly important to distinguish a true relapse from a transient worsening of symptoms associated with fever, infections, or increased body temperature.
Bibliographic references
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