Anti-aging and Anti-inflammatory Dietary Interventions in Multiple Sclerosis: A Narrative Review

Abstract

Multiple sclerosis (MS) is a chronic sex-biased (3♀:1♂) immune-mediated demyelinating disease of the central nervous system (CNS). Disease-modifying therapies targeting the peripheral immune cells efficiently limit relapses in early MS but cannot abrogate the chronic progressive component of the disease. The exact cause of MS remains elusive but interactions between predisposing genetic and environmental risk factors result in aberrant activation of pro-inflammatory immune cells targeting the CNS, leading to the formation of multifocal demyelinating lesions in the brain and spinal cord. MS-related genetic polymorphisms and viral triggers are currently not amenable to intervention. In contrast, obesity and gut dysbiosis represent potential modifiable risk factors contributing to MS pathogenesis and disease course. Diet influences obesity and metabolic diseases, shapes gut microbiota composition, modulates oxidative stress, and affects biological aging and inflammatory processes. Dietary patterns have emerged as factors modifying MS risk, disease activity, and progression. Therapeutic dietary interventions represent a promising avenue to promote healthy aging and regulate neuroinflammatory and neurodegenerative processes in MS. Here we describe the impact of diet on MS course and review the nutritional interventions investigated in MS and its animal models, with a focus on the mechanisms implicated including the impact on the gut microbiota.

Key Summary Points

Multiple sclerosis (MS) is the most common immune-mediated disease of the central nervous system (CNS) and affects women thrice as often as men. Available disease-modifying therapies in MS exhibit a diminishing benefit to risk ratio upon aging.

Unhealthy dietary patterns are associated with increased risk for developing MS, for experiencing clinical and radiological disease activity, and for exhibiting progression of disability.

Obesity and gut dysbiosis represent potential modifiable risk factors contributing to MS pathogenesis and disease course. Diet regulates metabolic health, gut microbiota composition, oxidative stress, inflammatory and senescence processes.

Dietary interventions show anti-aging and anti-inflammatory benefits in MS and preclinical animal models, contributing to more favorable clinical outcomes and to improved immunological, CNS, and gut microbiota profiles.

Understanding the impact of MS, of biological sex and of gender on adherence, tolerability, and outcomes related to specific dietary interventions, and establishing biomarkers to predict and monitor response to such interventions in people with MS, will be key to improve personalized care.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) affecting 2.8 million people worldwide. While MS onset is more frequent in females (3♀:1♂) and in young adults, male sex and older age are risk factors for accumulation and progression of irreversible disability [1–3]. High-efficacy immunosuppressive disease-modifying therapies dramatically decrease relapses in early MS when focal inflammatory activity prevail. No available treatment can, however, abrogate the progressive component of the disease when diffuse inflammation and neurodegenerative processes predominate [2–5]. The sequence of events triggering MS onset remains only partially understood but interactions between predisposing genetic and environmental risk factors lead to aberrant activation and subsequent CNS infiltration of pro-inflammatory immune cells across a dysfunctional blood–brain barrier (BBB), leading to reactive gliosis, demyelination and neuroaxonal injury [4, 6]. Genetic polymorphisms, mostly linked to immune function, and viral triggers, such as Epstein–Barr virus infection, are mostly associated with MS onset [7], and are not yet possible to target therapeutically. In contrast, lifestyle elements influence MS disease at all stages and can be targeted therapeutically. In recent years, obesity [8, 9] and gut dysbiosis [10, 11] have been identified as potential modifiable risk factors contributing to MS pathogenesis and to the development of cardiovascular comorbidities, which are associated with faster progression of clinical disability and of CNS atrophy in MS [12]. Diet can influence weight, body composition, and metabolic diseases, can contribute to select bacterial communities in the gut [13], and can promote or dampen oxidative stress, cell senescence, and inflammation [14–17]. Dietary factors modulate the risk of developing MS, and among people with MS (PwMS) the risk of relapses, CNS lesions, and progression [18–30]. Dietary and metabolism-based interventions represent potent therapeutic approaches to promote healthy aging and regulate neuroinflammatory and neurodegenerative processes in MS.

Multiple Sclerosis: Clinical Course, Diagnosis, and Pathobiology

MS is the most frequent immune-mediated disease of the CNS and shows both inflammatory and neurodegenerative components [4]. Most new MS cases, especially in younger individuals and female individuals, initially experience a relapsing–remitting (RRMS) course, characterized by bouts of neurological deterioration (e.g., subacute symptoms/signs compatible with optic neuritis, myelitis, brainstem syndrome, or hemispheric syndrome) followed by variable degree of recovery (Fig. 1). Around 10% of individuals exhibit insidious progression of neurological deficits without relapse activity from onset (primary progressive—PPMS), and more than half of initially RRMS develop secondary progression over years [1, 3, 5]. In recent years a prodrome phase preceding MS clinical onset has been recognized, associated with increased medical appointments, lower cognitive performance, and elevated levels of serum neurofilament light chain, a marker of neuroaxonal injury [31, 32]. MS diagnosis is based on clinical, radiological, and laboratory exams compatible with multifocal demyelinating inflammatory lesions of the CNS, in the absence of a better alternative explanation. New 2024 MS criteria use brain and spinal cord magnetic resonance imaging (MRI) and optic nerve evaluation in addition to laboratory tests to facilitate timely diagnosis [33]. Early diagnosis enables prompt initiation of disease-modifying therapy targeting the peripheral immune system to limit relapse-associated worsening of neurological function and to preserve CNS reserve [34], although the impact on progression of disability independent of relapse activity remains partial [35].

Fig. 1.

Multiple sclerosis: clinical course, diagnosis, and pathobiology. APCs antigen-presenting cells, BBB blood–brain barrier, C+ MRI with contrast agent (gadolinium), CNS central nervous system, DMT disease-modifying therapy, FLAIR fluid attenuated inversion recovery, MRI magnetic resonance imaging, MS multiple sclerosis, PPMS primary progressive MS, RIS radiologically isolated syndrome, RRMS relapsing–remitting MS. Underlined text corresponds to factors impacted by diet. Created with BioRender.com

MS is the prototypical inflammatory disease of the CNS. Genetic polymorphisms associated with MS onset predominantly affect immune cell function, with major histocompatibility complex (MHC) class I and class II alleles, coding for proteins implicated in antigen presentation to T cells, representing the main genetic risk factors (Fig. 1) [4]. Environmental factors showing a strong association with MS also modulate immune function, namely chronic infection of B cells by the Epstein–Barr virus, vitamin D deficiency, smoking, obesity, unhealthy diet, and gut dysbiosis [4, 36]. New focal lesions in early MS form around a central vein showing BBB disruption and accumulation of myeloid cells, B cells, and T cells in the perivascular space, with reactive gliosis in the surrounding tissue [6]. Over time and upon aging, dominant pathobiology in MS shifts towards chronic diffuse CNS-compartmentalized inflammatory and degenerative processes, associated with tissue-resident lymphocytes and meningeal follicles, microglial activation, expansion of chronic lesions, CNS atrophy, and progression of disability independent of relapses [2, 5, 37] (Fig. 1).

Aging in MS

While the peak of incidence for MS remains in the fourth decade, the development of disease-modifying therapies, advances in care, and global population demographics have shifted the peak prevalence of MS to the 45- to 64-year age group in Europe and North America [2]. In older PwMS, the risks for infectious and neoplastic complications of immunosuppressive treatments increase while the clinical benefits on accumulation of disability decrease. Brain reserve—the capacity/plasticity to compensate for lesions and atrophy to preserve function—naturally decreases with aging, and can contribute to worsening of physical and cognitive disability in older PwMS independent of treatment [38, 39]. Prevalence of cardiovascular comorbidities increases upon aging and in MS these are associated with faster progression of clinical disability and of CNS atrophy [12]. Biological aging is associated with a less favorable clinical course in experimental encephalomyelitis (EAE), a well-established animal model of MS [40, 41], and in MS per se [42].

Cellular dysfunction associated with aging impairs homeostasis and function, inducing senescence, secretion of inflammatory mediators, oxidative stress, and gut dysbiosis [2, 43]. Biological aging of the immune system (immunosenescence) is associated with chronic diffuse inflammation and a lower capacity to mount a robust immune response against pathogens. Immunosenescence moreover fuels age-related CNS damage which, together with the decline of CNS repair mechanisms observed upon aging, contributes to neurodegenerative processes. Inflammation and autoimmunity in turn accelerate immunosenescence through replicative senescence [2]. Aging is also associated with gut dysbiosis and increased intestinal permeability (“leaky gut”) that contribute to systemic inflammation, cellular senescence, and oxidative stress in older individuals [44–46]. Communication between the gut microbiota and the brain modulates peripheral and CNS immune cell profile [47]. In addition to neuronal connections, multiple mechanisms are implicated in the gut–brain axis, including bacterial translocation across the intestinal barrier, production of microbial metabolites such as anti-inflammatory short-chain fatty acids (SCFA), and CNS transmigration of immune cells educated in the gut [47, 48]. Studies consistently show that older adults exhibit reduced microbial diversity [49], which can lead to the expansion of bacteria implicated in inflammatory disorders such as rheumatoid arthritis and colitis. In contrast, healthy aging is associated with higher abundances of beneficial taxa with anti-inflammatory properties such as SCFA-producing organisms [50]. PwMS show features of premature biological aging, including shorter telomere length [2, 42], increased senescence markers [51], altered DNA methylation [52], evidence of accelerated metabolic aging (mAge) [53] and elevated oxidative stress [3, 54]. In addition, individuals with MS display marked gut dysbiosis [55], while transplantation of their microbiota into mice promotes the development of EAE [10, 11].

Dietary composition and nutrient availability profoundly affect aging-related processes, influencing both immunosenescence and gut microbiota composition, and consequently systemic and CNS health [47, 56]. For instance, elderly individuals in long-term care have less diverse microbiota and greater frailty compared to community dwellers, a pattern associated with a low-fiber, high-fat diet [57]. Conversely, an international cohort study showed that adherence to a Mediterranean diet in older people alters the gut microbiota, reducing frailty and improving cognitive function [58]. Along with exercise [39], which can be challenging in the context of MS, dietary interventions are recognized as one of the most effective strategies to modulate biological aging and inflammatory processes, to limit oxidative stress, and to restore disease-protective gut microbiota [13, 14, 16, 59]. Accordingly, accumulating evidence supports a crucial impact of dietary patterns and nutrition in MS.

Here we describe the impact of diet on MS course and review the nutritional interventions investigated in MS and its animal models, with a focus on the mechanisms implicated including the impact on the gut microbiota.

Literature Search Methods

We searched PubMed for peer-reviewed articles published between January 2010 and October 2025 and written in English using the search terms “multiple sclerosis” or “EAE” AND “diet”, “ketogenic diet”, “Mediterranean diet”, “Paleolithic diet”, “fasting”, “caloric restriction”, “gut”, “microbiota”, or “aging”. All authors agreed on the final list of references, which was selected on the basis of topic relevance, impact, originality, and year of publication. References of relevant articles were also hand-searched.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Impact of Diet on MS

Diet and Nutrition: Impact on Onset, Disease Activity, and Progression in MS

Emerging evidence suggests that, in addition to its impact on obesity and related comorbidities which modulate MS course, diet directly influences both the risk of developing MS and the subsequent clinical trajectory of the disease [18, 60, 61]. Dietary components affect metabolism and modulate systemic inflammation, oxidative stress, senescence, and gut microbiota composition [62], factors increasingly recognized as key contributors to pathobiological processes in MS [4] (Fig. 2).

Fig. 2.

Impact of diet on biological processes relevant to multiple sclerosis. CNS central nervous system, DMT disease-modifying therapy, MS multiple sclerosis. Created with BioRender.com

Impact of Diet on the Risk of Developing MS

In addition to modulating body mass index, dietary factors directly influence the incidence of MS [19–21, 30, 63]. Adherence to a Mediterranean diet (Fig. 3, characterized by low intake of red meat and high consumption of olive oil, vegetables, and whole grains) has been associated with a reduced risk of developing MS [18, 19]. Similarly, higher scores on the alternative Mediterranean diet index (aMED), as well as greater intake of dietary fiber and iron, have each been linked to a lower risk of pediatric-onset MS [30]. Regular consumption of oily fish has also been correlated with decreased MS risk compared to no consumption [19], while higher intakes of fruits (across all ages), yogurt (across all ages), and legumes (11–15 years old) were associated with a reduced incidence of adult-onset MS [21]. Conversely, low consumption of fiber, vitamin D, and alpha-linolenic acid, combined with a high intake of simple sugars and animal protein, constitute dietary risk factors for developing a first demyelinating event [63]. Moreover, adherence to a pro-inflammatory dietary pattern, characterized by high intake of saturated fats, processed meat, refined carbohydrates, and low consumption of fruits and vegetables, has been associated with an increased risk of a first clinical diagnosis of CNS demyelination in women [64]. Finally, higher consumption of ultra-processed foods has been shown to increase the risk of CNS demyelinating event [20].

Fig. 3.

Overview of the composition of different diets. Created with BioRender.com

Impact of Diet on Disease Activity and Accumulation of Disability

Beyond its influence on MS risk, dietary habits influence MS progression, clinical activity, and long-term disability. Indeed, higher intake of saturated fats has been associated with an increased risk of relapse, whereas greater consumption of vegetables appears to exert a protective effect in pediatric MS [22]. In line with this, higher overall dietary quality correlates with smaller volume of MS periventricular CNS lesions, an indicator of lesion burden and inflammatory activity, and a lower risk of relapse [23, 24], as well as lower scores for disability, depression, fatigue, and cognitive impairment [65, 66]. Conversely, a pro-inflammatory dietary pattern has been linked to higher relapse risk and greater CNS periventricular lesion volume [67]. In contrast, adherence to the Mediterranean diet is associated with lower disease severity [26, 27], reduced fatigue [28, 29], better performance on the Multiple Sclerosis Functional Composite (MSFC; a quantitative disability metric) [29], lower depression scores, and improved quality of life [25]. Finally, higher consumption of ultra-processed foods has been associated with greater MS severity [68].

Together, these findings support the concept that diet represents a modifiable environmental factor influencing both MS susceptibility and disease trajectory.

Dietary Interventions in MS

Clinical Trials in MS

Dietary interventions are difficult to implement in clinic because of adherence issues and have been studied in the context of MS on small groups of participants, in whom they appear to modulate immune responses, CNS processes, and disease outcomes (Table 1). In people with RRMS, short-term fasting or caloric restriction (CR) (Fig. 3) improved emotional well-being, fatigue, pain, and quality of life, and led to weight loss, better preservation of brain volume, and lower serum neurofilament light chain levels [69–72]. A recent study further described benefits on cognitive function as measured by the symbol digit modality test (SDMT) in only 12 weeks in participants on intermittent CR [73]. Participants with RRMS following a ketogenic diet (KD, high fat, low carbohydrates) (Fig. 3) for 6 months showed decreased fatigue, depression, and leptin levels, along with improved mobility, physical and mental quality of life [61, 74, 75]. Similarly, implementation of a Mediterranean diet showed reduced fatigue, body mass index, and disability scores, and improved quality of life in RRMS [76–78]. PwMS on a paleolithic diet (Fig. 3, meat, vegetables, fish, no transformed products) experienced lower fatigue, improved motor performance, and better quality of life, alongside elevated vitamin K levels [79].

Table 1.

Dietary interventions in MS from human trials

References	Diet	Type of study	M/F (n/n)	Population (age range in years)	MS course	Duration of adherence to the diet	Outcome
Fitzgerald et al., 2018, Multiple Sclerosis and Related Disorder [124 ]	1) Intermittent fasting (75% restriction in energy intake, 2 days a week) 2) Caloric restriction (20% restriction in daily energy intake) 3) Control group	Randomized controlled trial (3-arm)	7:29	Adults (18–50)	RRMS	8 weeks	↓ Weight in both CR and IF groups ↓ Cholesterol levels in both CR and IF groups ↑ Emotional well-being based on the FAMS score in both CR and IF groups
Fitzgerald et al., 2022, EbioMedicine [69]	1) Intermittent fasting (75% restriction in energy intake, 2 days a week) 2) Caloric restriction (20% restriction in energy intake) 3) Control group	Randomized controlled trial (3-arm)	7:29	Adults (18–50)	RRMS	8 weeks	↓ Memory T cells in the IF group
Ghezzi et al., 2025, JNNP [73]	1) Intermittent caloric restriction 2) Control group	Randomized, controlled trial	6:28	Adults (≥ 18)	RRMS	12 weeks	↓ Serum leptin ↑ Blood CD45RO+ regulatory T cell numbers ↑ Cognitive functions (SDMT)
Cignarella et al., 2018, Cell Metabolism [84]	1) Intermittent fasting diet (< 500 kcal/day every other day) 2) Control group	Randomized controlled pilot trial	4:12	Adults (18–60)	RRMS	15 days	↓ Serum leptin ↑ (trend) abundance of Faecalibacterim, Lachnospiraceae incertae sedis, and Blautia in the gut microbiota
Wingo et al., 2022, Frontiers in Neurology [70]	Time-restricted eating	Single arm pilot trial	2:10	Adults (18–65)	RRMS	8 weeks	↑ SDMT and 9HPT scores ↓ Pain ↔ No significant difference in adiponectin levels
Choi et al., 2016, Cell Reports [80]	1) Fasting mimicking diet (FMD) (single cycle of modified FMD for 7 days) followed by a Mediterranean diet for 6 months 2) Ketogenic diet 3) Control group	Randomized pilot trial	FMD 3:15 KD 4:14 Control 3:9	Adults (18–67)	RRMS	6 months	FMD and KD ↑ Health-related quality of life (HRQoL), FMD ↑ overall QoL
Rahmani et al., 2023, Journal of Alzheimer’s Disease [71]	Intermittent caloric restriction	Randomized controlled trial	2:8	Adults (46 ± 10)	RRMS	12 weeks	↑ Brain cortex and volume ↓ Neuroinflammation
Bock et al., 2021, Neurology: Neuroimmunology & Neuroinflammation [72]	1) CR (200–350 kcal/day for the first 7 days, then isocaloric common diet) 2) Modified KD (< 50 g carbohydrates, > 160 g fat, and protein intake ≤ 100 g per day) 3) Control group	Randomized controlled trial	9:31	Adults (18–86)	RRMS	6 months	↓Serum neurofilament light chain (NfL) level after 6 months in the modified KD group vs control group ↔ There was no change in the group that received a CR diet for 7 days vs control group
Brenton et al., 2019, Neurology: Neuroimmunology & Neuroinflammation [74]	Modified KD, Atkins diet (KDMAD) (< 20 g of carbohydrates per day, greater fat intake)	Single-arm, open-label pilot trial	3:17	Teenagers and adults (15–50)	RRMS	6 months	↓ Body mass index and total fat mass ↓ Serum leptin levels ↓ Fatigue and depression
Brenton et al., 2023, Multiple Sclerosis and Related Disorders [61]	KDMAD	Phase II prospective trial	9:55	Teenagers and adults (12–55)	RRMS	6 months	↑ MS QoL, physical and mental health scores, Expanded Disability Status Scale, 6-min walk and 9HPT scores ↓ Serum leptin ↑ Adiponectin levels
Katz Sand et al., 2019, Multiple Sclerosis and Related Disorders [77]	1) Modified Mediterranean diet (exclusion of meat and dairy products, limitation of sodium intake to < 2 g/day) 2) Control group (no dietary intervention)	Randomized controlled trial	0:36	Adults (18–65)	28 RRMS 3 SPMS 1 PPMS	6 months	↓ NFI-MS, MSIS-29, and EDSS scores
Razeghi-Jahromi et al., 2020, Current Journal of Neurology [78]	1) Modified Mediterranean diet (red wine and some foods omitted according to Iranian culture) 2) Control diet (according to healthy eating recommendations)	Single-blind randomized controlled trial	8:64	Adults (18–55)	RRMS	1 year	↓ Fatigue (MFIS), body mass index ↔ Cognitive status
Moravejolahkami et al., 2020, International Journal of Food Properties [76]	1) Modified Mediterranean diet (changes were made according to Iranian culture) 2) Traditional Iranian diet	Single-center, two parallel arms, single-blind, randomized clinical trial	25:122	Adults (20–60)	RRMS	1 year	↑ MS QoL score ↓ Fatigue
Yadav et al., 2016, Multiple Sclerosis Related Disorders [126]	Low-fat, plant-based diet	Randomized, controlled, assessor-blinded trial	4:57	Adults (18–70)	RRMS	1 year	↓ Fatigue (MFIS), body mass index ↔ Brain MRI, relapse rate or disability (EDSS)
Saresella et al., 2017, Front Immunol [101]	1) High-vegetable/low-protein diet (HV/LP) 2) Western diet	Non-randomized prospective trial	5:15	Adults (40–52)	RRMS	1 year	In high-vegetable/low-protein diet (HV/LP): ↓ Relapse rate, EDSS ↑ Lachnospiraceae family in the gut microbiota ↓ IL-17-producing and PD-1 expressing CD4+ T cells. ↑ PD-L1-expressing monocytes
Irish et al., 2017, Degener Neurol Neuromuscul [79]	Paleolithic diet	Randomized controlled trial	2:15	Adults (18–45)	RRMS	3.5 months	↑ 9HPT and MS QoL scores ↑ Serum vitamin K in levels ↓ Fatigue (FSS)

9HPT 9-hole peg test, 9MS QoL MS Quality of Life, CR caloric restriction, EDSS Expanded Disability Status Scale, FAMS Functional assessment of Multiple Sclerosis, FSS Fatigue Severity Scale, FMD fasting mimicking diet, KD ketogenic diet, KD^MAD keto modified Atkins diet, HR QoL Health Related Quality of Life, MRI magnetic resonance imaging, MFIS Modified Fatigue Impact Scale, MSIS-29 Multiple Sclerosis Impact Scale-29 scores, MS QoL MS quality of life, NFI-MS Neurological Fatigue Index-MS, PPMS primary progressive MS, RRMS relapsing–remitting MS, SPMS secondary progressive MS, SDMT symbol digit modalities test

Mechanisms Implicated

Different dietary interventions can improve clinical parameters in PwMS. The pathways implicated are complex, impacting neuroinflammatory processes, gut microbiota composition, and aging processes. In addition to data from clinical studies, dietary interventions have been studied in animal models of MS such as EAE and in the model of toxic demyelination induced by cuprizone to elucidate the biological mechanisms mediating clinical benefits (Tables 1 and 2).

Table 2.

Dietary interventions in MS animal models

Diet	Sex	Prophylactic/therapeutic	Clinical impact	Impact on CNS	Impact on immune system	Impact on metabolism	Impact on gut microbiota
FMD [80, 82, 85]	F	Prophylactic [80] and therapeutic if started at early stage of the disease [82, 85]	FMD ↓ clinical severity in active EAE model and delays its onset [80, 85]	↑ Oligodendrocyte precursor cell regeneration [80] ↑ Remyelination [80,85] ↓ Demyelination and axonal injury	↑ Treg cell and IL-10 [80, 82] ↓ Pro-inflammatory cytokines, TH1 and TH17 cells, and APCs [80, 82, 85] ↓ Cytotoxicity, IFNγ-producing CD4+ T cells and immune cells infiltration in CNS [82, 85]	↑ Corticosterone levels [80]	N/A
Caloric restriction [81, 83]	F [83] M [81]	Prophylactic regime in active EAE [83] Therapeutic in CPZ model [81]	Caloric restriction ↓ clinical severity in active EAE model and delays its onset [83] ↑ Motor coordination and balance performance in CPZ mice [81]	↓ Demyelination and axonal injury [83] ↑ Remyelination of the corpus callosum in the CPZ model ↓ Astrogliosis and microgliosis ↑ Oligodendrogenesis [81]	↓ Inflammation, IL-6 ↑ IL-16 levels in the plasma	↑ Corticosterone, and adiponectin in the plasma [83] ↓ Leptin in the plasma	N/A
IF [84]	F	Prophylactic regime in active EAE	IF delayed onset, ↓ incidence, and ↓ clinical EAE score in active EAE model	N/A	↑ Treg cell ↓ Th17-producing T cells	↓ Leptin in the plasma before EAE induction	↑ Microbiome richness ↑ Ketone formation and glutathione metabolism, enhancing antioxidative pathways
KD [87–90]	F + M [87] F [88] M [89] NA [90]	Prophylactic and therapeutic regime	Prophylactic regimen: delays onset of active EAE and ↓ motor disability, cognitive impairment, and CNS lesions [87–90] Therapeutic regimen, KD restores motor and visual function within 4 days post EAE induction [87]	= Oligodendrocytes preservation [87, 89] ↓ Inflammatory infiltration of the optic nerve [87] ↓ Microglial activation and shifted microglial polarization toward the protective M2 phenotype [88, 89] ↓ Reactive astrocytes ↓ Expression levels of CCL2, CCR2, CCL3, CCR1, CCR5, CXCL10, and CXCR3 in the spinal cord and spleen [88] ↓ Oxidative stress in the CNS [90] ↓ Hippocampal atrophy and periventricular lesions [90] ↑ CA1 hippocampal synaptic plasticity (long-term potentiation) [90]	↓ Cytokines in the circulation associated with EAE-mediated pathological inflammation [87] ↑ Treg cells in the CNS [90] ↓ CD4+ cells in the CNS [90] ↓ IL-1β, IL-6, TNFα, IL-12, IL-17), and chemokines (IFNγ, MCP-1, MIP-1α, MIP-1β) in the periphery and CNS [90] ↑ Anti-inflammatory cytokines such as TGFβ [88] ↓ Monocyte/macrophage infiltration in the CNS [88]	N/A	N/A
MR [86]	F	Prophylactic regime	In active EAE model, MR significantly delays onset and reduces the overall number of symptomatic mice	N/A	↓ Immune cells infiltration in the CNS ↓ IL-17-producing cells in the CNS		N/A

APC antigen-presenting cell, CCL CC chemokine, CCR CC chemokine receptor, CPZ cuprizone, CXCL CXC chemokine, CXCR CXC chemokine receptor, CNS central nervous system, EAE experimental autoimmune encephalomyelitis, FMD fasting mimicking diet, IF intermittent fasting, IFN interferon, IL interleukin, KD ketogenic diet, MR methionine restriction, N/A data not available, Treg cells regulatory T cells

Impact on Neuroinflammatory Processes

In animal models of MS (EAE, cuprizone), interventions limiting calorie intake—intermittent fasting (IF), caloric restriction (CR), and fasting mimicking diet (FMD)—increased oligodendrocyte regeneration and promoted remyelination in the CNS compartment [80, 81]. In the immune cell compartments, these interventions shifted the balance toward an anti-inflammatory profile during EAE in rodents, characterized by increased regulatory T (Treg) cells, interleukin (IL)-10, and adiponectin (anti-inflammatory adipokine), but decreased adipokine leptin (considered pro-inflammatory) and pro-inflammatory cytokines [80–84], and reduced infiltration of the CNS by inflammatory immune cells [80, 85]. Restriction of the essential amino acid methionine (methionine restriction, MR) without caloric restriction limited the development of pro-inflammatory Th17 cells in the peripheral lymphoid organs and reduced their infiltration in the CNS during EAE, indicating potent anti-inflammatory effects [86]. In line with this, in PwMS, intermittent CR has been associated with improved cognitive function and a reduction in memory T cell frequency [69], while intermittent CR led to an expansion of Treg cells, and a global decrease of inflammation [71, 73].

KD diet in EAE models is neuroprotective: it delays onset of neurological symptoms, preserves myelin integrity and oligodendrocyte survival, and reduces microglial activation and oxidative stress [87–90]. Its neuroprotective effects seem to arise from reduced blood glucose levels and a metabolic shift toward ketone-body utilization [91]. Ketone bodies, produced via β-oxidation of fatty acids, serve as efficient energy substrates for the brain, allowing one to sustain neuronal bioenergetic homeostasis. Moreover, ketone bodies, e.g., β-hydroxybutyrate, exert anti-inflammatory effects by inhibiting the NLRP3 inflammasome independently of AMPK, autophagy, or glycolytic suppression, thereby preventing caspase-1 activation and the release of pro-inflammatory cytokines IL-1β and IL-18 [92]. KD also decreases oxidative stress markers, including inducible nitric oxide synthase (NOS2) and superoxide, while upregulating antioxidant enzymes such as superoxide dismutase 2 (SOD2) [93, 94]. In addition, KD modifies the immune response during EAE, decreasing pro-inflammatory cytokine production [88, 90]. In humans, in infants with refractory epilepsy, KD resulted in a decreased Th17 to Treg cells ratio and reduced seizure activity [95], while in PwMS it reduced leptin and increased adiponectin [61]. Collectively, these metabolic and immunomodulatory alterations could confer broad neuroprotective and anti-inflammatory effects.

Mechanistic studies on the Mediterranean diet are limited, as this dietary pattern is difficult to reproduce in animal models. In Alzheimer’s disease, the Mediterranean diet showed protective effects against memory decline and medial temporal atrophy [96]. Beyond MS, adherence to the Mediterranean diet is consistently linked to anti-inflammatory and antioxidant effects. A systematic review of 14 studies showed that higher adherence was associated with lower circulating levels of pro-inflammatory biomarkers such as C-reactive protein (CRP), IL-6, and fibrinogen, as well as improved oxidative stress markers, including F2-isoprostanes and total antioxidant capacity [97]. Supporting these findings, a primate study comparing Mediterranean and Western diet, characterized by a high intake of ultra-processed food, saturated fat, and refined sugar, found that the Mediterranean diet reduced expression of the pro-inflammatory gene CDK14 and increased genes involved in anti-inflammatory and neuroprotective pathways [98]. In contrast, animals on the Western diet showed greater anxiety and social isolation, highlighting a diet-related influence on brain health and socioemotional behavior [98].

In PwMS, adherence to a modified Paleolithic diet, which is gluten-free, has been associated with reduced fatigue and improved quality of life, potentially mediated by decreased oxidative stress and modulation of immune signaling [79]. Studies on mechanisms implicated are, however, scarce.

In summary, across clinical studies in MS, largely conducted in women with RRMS, dietary interventions such as FMD, IF/CR, KD, and the Mediterranean diet consistently improved clinical and metabolic outcomes. Animal data complement these findings to understand mechanisms at play—anti-inflammatory, neuroprotective, and gut microbiota-mediated—though evidence in progressive MS and male participants remains limited.

Impact on Gut Microbiota

Gut dysbiosis may exacerbate MS through several mechanisms (Fig. 4), including the overproduction of reactive oxygen species (ROS) by pathogenic bacteria, which disrupt intracellular signaling pathways and amplify neuroinflammatory responses [99], whereas segmented filamentous bacteria (SFB) stimulate Th17 differentiation, increasing susceptibility to EAE [100]. Dysbiosis can also disrupt gut humoral immunity by impairing regulatory B cell and IgA⁺ plasma cell development; these IgA⁺ B cells can migrate to the CNS and attenuate the neuroinflammatory processes [48]. Moreover, anti-inflammatory SCFA-producing bacteria are significantly reduced in PwMS [101], while their intestinal barrier shows signs of “leaky gut”, associated with microbial antigens and pro-inflammatory molecules entering systemic circulation, triggering inflammation and autoimmune processes [102].

Fig. 4.

Mechanisms linking the gut microbiota to neuroinflammation in multiple sclerosis. In healthy individuals (left panel), a balanced gut microbiome maintains immune homeostasis. Commensal bacteria ferment dietary fibers to produce short-chain fatty acids (SCFAs), which exert anti-inflammatory and immunomodulatory effects. SCFAs promote the differentiation of T cells into anti-inflammatory regulatory T (Treg) cells while reducing pro-inflammatory Th1 and Th17 cells, thereby contributing to an overall anti-inflammatory state. Bacterial metabolites and antigens in the gut also influence naïve B cells, promoting their differentiation into regulatory B (Breg) cells. These Breg cells secrete anti-inflammatory cytokines such as IL-10, fostering an anti-inflammatory environment within the gut. In addition, commensal bacteria stimulate plasma cells to produce IgA antibodies. IgA⁺ B cells can migrate to the central nervous system (CNS) and help attenuate neuroinflammatory processes. In neuroinflammatory conditions such as seen in multiple sclerosis (MS) (right panel), gut dysbiosis disrupts these regulatory mechanisms. A decrease in SCFA-producing bacteria leads to reduced Treg differentiation, while an increase in segmented filamentous bacteria (SFB) promotes Th17 differentiation—resulting in an imbalance between Treg and Th17 cells. Dysbiosis is also associated with impaired intestinal barrier integrity (“leaky gut”), allowing microbial products to translocate into circulation and trigger systemic inflammation. Created with BioRender.com

Diet is a key modulator of gut microbiota composition and immune responses in PwMS and healthy controls [103]. In EAE, a high-salt diet—commonly consumed in the Western diet—exacerbates disease by promoting Th17 cell infiltration into the CNS through microbiota-dependent mechanisms, notably via the loss of Lactobacillus murinus, a change reversible by bacterial supplementation [104]. Similarly, long-term intake of high-sugar beverages, another hallmark of Western dietary patterns, aggravates EAE by altering microbial composition and enhancing Th17 responses, whereas microbiota depletion reduces disease susceptibility [105]. In contrast, dietary fibers exert protective effects: fermentable fibers enhance SCFA production and immune regulation, while non-fermentable cellulose also mitigates EAE independently of SCFAs [106]. On the other hand, IF also ameliorates EAE severity by reshaping the gut microbiota, characterized by increased bacterial richness, enrichment of Lactobacillaceae, Bacteroidaceae, and Prevotellaceae, and enhanced antioxidative metabolic pathways [84]. KD has been shown to modulate the gut–brain axis by reshaping the intestinal microbiota, and alterations in bacteria composition induced by KD have been associated with seizure reduction, highlighting the capacity of the diet to restore microbial balance and influence neuroimmune signaling [107]. In humans, one study suggested that the Mediterranean diet can reduce MS odds by modulating the gut microbiota [30]. Moreover, long-term adherence to Paleolithic dietary patterns reshapes intestinal microbial diversity, reducing taxa associated with the production of trimethylamine-N-oxide (TMAO) [108]. These microbiota changes may attenuate peripheral immune activation and microglial reactivity, thereby providing a plausible link to reduced neuroinflammation. Despite these encouraging preliminary results, evidence remains limited because of small sample sizes and heterogeneous dietary implementations. Furthermore, the complexity and variability of Paleolithic dietary patterns make them difficult to reproduce and standardize in animal models.

In PwMS, high meat intake was correlated with decreased gut microbe Bacteroides thetaiotaomicron (a fiber-digesting bacterium), increased Th17 cell and greater abundance of meat-associated blood metabolites, namely methyl donor S-adenosyl-l-methionine (SAM) that is a metabolic product from methionine, an essential amino acid enriched in meat [109]. Moreover, the protective effect of IF appears to be partially mediated by modulating the gut microbiota in PwMS, with an increase in Faecalibacterium, Lachnospiraceae incertae sedis, and Blautia [84], which could partly account for the observed changes in immune responses.

Impact on Aging

Well-known anti-aging interventions include CR [110], FMD [111], and MR [16, 17]. Fasting-based interventions—including IF, CR, and FMD—consistently reduced disease severity and delayed onset in animal models of MS [80, 83, 85]. Restriction of methionine also delayed disease onset in the EAE model [86]. On the contrary, methionine supplementation is associated with loss of synapses, accumulation of misfolded proteins in the CNS, and impaired neurological function in mice [112, 113]. A recent study has directly assessed the effects of dietary interventions on biological aging in MS. Siavoshi et al. indeed found that FMD, including modified Atkins KD characterized by a greater fat intake and less than 20 g of carbohydrates per day, and intermittent CR, can both reverse mAge independently from weight loss [114].

Biological Sex Considerations

While dietary interventions clearly impact neuroinflammatory, microbial, and aging-related pathways, these processes are modulated by biological sex. There is growing evidence that anti-aging dietary interventions do not have the same impact in males and females [115]. In mice on MR diet, the weight loss is more pronounced in males [116]. In humans, the Mediterranean diet appears to be more effective in men: after 4 weeks, men show increased insulin sensitivity [117]; after 12 weeks, a reduction in lipid levels and body fat percentage [118]; and after 12 months, a decrease in both systolic and diastolic blood pressure compared to women [119]. In a very-low-calorie diet over 8 weeks, men experienced greater weight loss [120] and more pronounced improvements in cardiometabolic parameters [121, 122], but also exhibited a stronger rebound effect during the follow-up period compared to women [122]. In MS, one study reported that in male PwMS, frequent fruit consumption during childhood was associated with lower odds of relapsing onset MS, whereas no such association was found in female PwMS [123]. However, few studies have so far considered the influence of biological sex or gender on dietary interventions in MS or its experimental models. This represents a critical knowledge gap that future research on dietary strategies for MS should address.

Conclusions

Evidence from both human and experimental studies suggests dietary interventions represent a promising, low risk therapeutic strategy for PwMS, capable of modulating neuroinflammatory processes, immune profile, gut–brain communication, and biological aging. It is yet important to emphasize that no single dietary regimen can be considered universally optimal. This review summarizes the available literature, but the heterogeneity of study designs, populations, and intervention types precludes recommending a specific diet for PwMS outside of recommendations for healthy dietary choices. Moreover, the influence of biological sex on metabolic and immune responses introduces an additional layer of complexity that remains largely unexplored in MS research. Sex-specific differences in the efficacy and sustainability of dietary interventions highlight the need for more personalized strategies. Likewise, factors such as disease stage, comorbidities, nutritional status, and gut microbiota composition are likely to shape individual responses to diet-based interventions; however, metabolic, immune, and gut microbiota biomarkers to predict and monitor the impact of dietary interventions in MS are lacking.

Weight loss and metabolic improvements are frequently reported as positive outcomes, but these may not be beneficial for all, and particularly in older adults, where excessive weight loss could exacerbate frailty. Moving forward, combining elements from complementary dietary strategies, such as time-restricted eating with Mediterranean patterns, in parallel with exercise and use of disease-modifying therapies when applicable, may optimize neuroprotective and anti-inflammatory benefits while maintaining long-term feasibility and adherence. Ultimately, rigorous, large-scale, and sex-stratified clinical trials are essential to define evidence-based dietary guidelines tailored to the diverse needs of PwMS.

Author Contributions

Tayma Shaaban Kabakibo, Fanny Martinez, Pierre Gledel, Crystèle Hogue, Chantal Bémeur and Catherine Larochelle contributed to the review conception and design. Tayma Shaaban Kabakibo, Fanny Martinez, and Pierre Gledel performed literature analysis and synthesis. Tayma Shaaban Kabakibo, Fanny Martinez, and Catherine Larochelle wrote the initial draft. All authors reviewed and approved the final version.

Funding

No funding or sponsorship was received for this study or publication of this article. Tayma Shaaban Kabakibo holds a scholarship from MS Canada. Catherine Larochelle holds a Junior 2 clinician-researcher award from the FRQS.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Tayma Shaaban Kabakibo, Fanny Martinez, Pierre Gledel, Crystèle Hogue, Chantal Bémeur and Catherine Larochelle have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.