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 Nutritional Neuroscience
An International Journal on Nutrition, Diet and Nervous System

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The role of diet in multiple sclerosis: A review

Sabrina Esposito, Simona Bonavita, Maddalena Sparaco, Antonio Gallo &

Gioacchino Tedeschi

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The role of diet in multiple sclerosis: A review
Sabrina Esposito 1,2, Simona Bonavita1,3,4, Maddalena Sparaco 1, Antonio
Gallo 1,3,4, Gioacchino Tedeschi 1,3,4
1
I Clinic of Neurology, Second University of Naples, 80138, Italy, 2Department of Neuroscience, Psychology,
Drug Research and Child Health, University of Florence, Italy, 3MRI Research Center SUN-FISM, Second
University of Naples, Italy, 4Institute for Diagnosis and Care “Hermitage Capodimonte”, Naples, Italy

Multiple sclerosis (MS) is a multifactorial, inflammatory, and neurodegenerative disease of the central nervous
system, where environmental factors interact with genetic susceptibility. The role of diet on MS has not been
comprehensively elucidated; therefore, through an extensive search of relevant literature, this review reports
the most significant evidence regarding nutrition as a possible co-factor influencing the inflammatory
cascade by acting on both its molecular pathways and gut microbiota. Since nutritional status and dietary
habits in MS patients have not been extensively reported, the lack of a scientific-based consensus on
dietary recommendation in MS could encourage many patients to experiment alternative dietetic
regimens, increasing the risk of malnutrition. This work investigates the health implications of an
unbalanced diet in MS, and collects recent findings on nutrients of great interest among MS patients and
physicians. The aim of this review is to elucidate the role of an accurate nutritional counseling in MS to
move toward a multidisciplinary management of the disease and to encourage future studies
demonstrating the role of a healthy diet on the onset and course of MS.
Keywords: Multiple sclerosis, Diet, Inflammation, Gut microbiota, Malnutrition, Nutrients in multiple sclerosis, Nutritional assessment, Dietary
recommendation

Introduction Moreover, MS is characterized by a large spectrum

Multiple sclerosis (MS) is an inflammatory, neurode-
generative, and demyelinating disease of the central
nervous system, and it is the most common neurologi-
cal disorder in young adults, especially women, usually
occurring between ages 20 and 40, albeit in 3–5% of all
cases it occurs before age 16 (early onset)1 and in 3.4–
12.7% after age 50 (late onset).2 Its multifactorial
nature has not been fully elucidated, but an immune
dysregulation, caused by the interaction of genetic sus-
ceptibility and environmental factors (geographical,
infectious, and/or nutritional), appears central to
explain its etiopathogenesis.3 The disease is marked
by an autoimmune process leading to blood–brain
barrier disruption, perivascular inflammation, injury
of myelin sheath, axonal damage, and progressive
neuronal loss. The predominance of inflammation or
neurodegeneration warrants, in part, a different clini-
cal phenotype. Recently, the classic MS clinical
courses (relapsing-remitting, progressive relapsing,
primary and secondary progressive) have been rede-
fined according to the evidence of two indicators: (i)
disease activity and (ii) clinical progression, reflecting
inflammatory and neurodegenerative processes,
respectively.4
Correspondence to: Sabrina Esposito, I Clinic of Neurology, Second
University of Naples, Piazza L. Miraglia, 2, Naples 80138, Italy. Email: sa-
esposito@libero.it
of symptoms that may be conditioned by nutritional
status and contribute to increasing the risk of malnu-
trition. On the other hand, diet-related health issues,
frequently observed in MS population, such as cardio-
vascular disease and metabolic syndrome, may concur
to aggravate the disease.
Nowadays, as shown below, despite a number of
scientific studies exploring the relationship between
nutrition and MS, there is no consensus on the
dietary habits to follow to ameliorate the course
and/or the symptoms of the disease. Therefore,
many MS patients experiment with alternative dietetic
regimens, including special diets or nutritional sup-
plements, with no scientific support.5 Such a behavior
may only partially reflect a general mistrust in medical
science, while a major contribution may arise from
patients’ need to have an active role in the disease
care. The role of different nutritional strategies on
MS pathogenesis and symptoms has not been compre-
hensively investigated; therefore, our aim was review-
ing scientific evidence regarding nutrition in MS, in
order to elucidate the role of diet in the multidisciplin-
ary management of MS patients.
The impact of diet on MS pathogenesis
The hypothesis that diet might influence the incidence
and course of MS stems from results of

© 2017 Informa UK Limited, trading as Taylor & Francis Group

DOI 10.1080/1028415X.2017.1303016 Nutritional Neuroscience 2017 1
Esposito et al. The role of diet in multiple sclerosis: a review
epidemiological studies, showing an increased incidence
of MS in populations with high intake of saturated fats
and low levels of vitamin D.3 As discussed below, even
though epidemiological and animal studies globally
showed moderate benefits of some dietary interventions
in MS, especially on inflammation, controlled clinical
trials failed to produce conclusive results. A large part
of these studies suffered from some limitations related
to the study design as well as sample size and patients’
characteristics. Moreover, although accumulating evi-
dence indicates a dissociation between inflammation
and neurodegeneration in the pathogenesis of MS,6
studies investigating the impact of diet on neurodegen-
erative processes are even more insufficient than work
focused on the inflammatory component of MS. One
of the reasons could be that the experimental animal
model of MS experimental auto-immune encephalo-
myelitis (EAE) is an autoimmune/inflammatory
model with limited power to accurately represent neuro-
degeneration in humans.7 Overall, the research in this
field suffers from the limited interest within the scientific
community; indeed, either the lack of robust pathophy-
siological knowledge about the link between nutrition,
immunity, neurodegeneration and MS, or the enormous
amount of resources needed to conduct a properly
designed, independent, controlled clinical trial, may
play a detrimental role in the performance of powerful
conclusive studies.
Possible role of diet as a risk factor in MS
The higher prevalence of the disease in Western
countries and in territories distant from the Equator
(above 40 degrees of latitude) might be linked to
regional dietary habits, suggesting a contribution of
hyper-caloric diets typical to these areas.8–10 Looking
at food-consumption data of the member countries
of the Organisation for Economic Cooperation and
Development, Arganoff et al.11 not only showed that
consumption of dairy fats and red meat was associated
with an increased risk of MS, but also found that veg-
etable, nut, and fish [rich in Ω-6 and Ω-3 polyunsatu-
rated fatty acids, (PUFAs)] were associated with a
reduced risk of MS. In line with Arganoff et al.,
other epidemiological studies have supported evidence
of a detrimental association between the incidence of
MS and the intake of saturated animal fat, while
PUFA-rich foods have been inversely associated with
MS onset.12–14 These findings, however, have not
been unequivocally confirmed by the majority of
population-based case-control studies,15–21 probably
due to methodological caveats.22
Possible role of diet as a disease-modifying
factor
The experimental model and the type/amount of
selected food appear to influence the impact of diet
2 Nutritional Neuroscience 2017
on MS animal models. In experimentally induced T-
cell-mediated autoimmune diseases, essential fatty
acid-deficient diets, or Ω-3 fatty acid supplements,
appeared to worsen disease course, whereas Ω-6 fatty
acids appeared to prevent or ameliorate disease sever-
ity, probably exerting a cytokine-related immunomo-
dulatory effect.23 Further animal experiments and
clinical intervention studies have indicated some anti-
inflammatory properties of Ω-3 PUFA, including
effects on intracellular signaling pathways, transcrip-
tion factor activity, and gene expression.24 Choi
et al.25 reported that three cycles of a very low-
calorie and low-protein diet (fasting mimicking diet,
FMD), lasting three days every seven days, mitigated
demyelination, axonal damage, and disease severity
in EAE, promoting oligodendrocyte precursor acti-
vation and reducing Th1, Th17 cells, and the level of
pro-inflammatory cytokines. The authors suggested
that the alternation of FMD cycles and re-feeding
independently modulated both remyelination and
inflammatory response in animal model of MS.
A re-analysis of three double-blind trials26 showed a
positive effect (decrease of relapse duration and sever-
ity) of linoleic acid supplementation in MS patients
with mild disability and short disease duration. A 2-
year double-blind-controlled trial27 of long chain Ω-3
PUFA demonstrated beneficial trends in 145 relap-
sing-remitting (RR) MS patients receiving Ω-3 in
terms of reduction of MS relapses duration, frequency,
and severity, as compared to 147 RRMS patients of
the control arm. Nevertheless, none of the tested par-
ameters reached the 95% statistical significance. A
subsequent double-blind randomized 1-year trial28
showed a moderate positive effect on subjective
quality-of-life measures [assessed by the Short Form
Health Survey Questionnaire (SF-36), the Modified
Fatigue Impact Scale (MFIS), and the Mental
Health Inventory] in RRMS patients who underwent
a low-fat diet (15% fat) supplemented with Ω-3, com-
pared to those patients who observed a 30% fat diet
supplemented with olive oil. A recent multicenter
placebo-controlled clinical trial29 compared the effect
of daily treatment with concentrated Ω-3 fatty acids
versus placebo on radiological disease activity assessed
after 6, 9, and 24 months from baseline. Ω-3 fatty acids
were supplemented alone during the first 6 months of
trial and in association with subcutaneously 44 μg of
interferon beta-1a to all patients over the following
18 months. The study provided class 1 evidence that
Ω-3 fatty acid supplementation did not exert beneficial
effects on disease activity in RRMS as monotherapy
or in combination with a first-line immunomodulatory
treatment. Pantzaris et al.,30 in a randomized double-
blind placebo-controlled phase II proof-of-concept
clinical trial showed that an oral nutraceutical combi-
nation of PUFA (Ω-3 and Ω-6 at 1:1) and gamma-

tocopherol, versus placebo, significantly reduced at 2
years the annualized relapse rate and the probability
of disability progression [intended as an increase of
at least 1.0 point on the Expanded Disability Status
Scale (EDSS), confirmed after 6 months] in RRMS
patients, without any serious adverse events. The
study had two considerable limitations: the small
sample size (20 participants randomly assigned to
each intervention group) and the low adherence of
the participants (51% of patients completed the 30-
month trial).
Possible role of a metabolic hormone, i.e.
Leptin, in MS
Leptin is an adipocyte-derived hormone, regulating
energy expenditure and acute phase reactants, which
is emerging as a potential metabolic mediator involved
in the induction/progression of EAE31,32 and in the
pathogenesis of MS.33,34 In animal models, leptin
has shown a modulating role in cellular immune
response and in cytokines release; leptin deficiency,
related to acute starvation, has been associated with
decreased IFN-γ secretion ( pro-inflammatory cyto-
kine), reduced IL-4 and IL-10 levels (regulatory cyto-
kines), increased TGF-β values ( potent immune
regulator), reduction in circulating CD4+ T cells and
impaired T-cell proliferation.35 Fasting mice, with cir-
culating leptin shortage, have shown lower EAE
activity with delayed disease onset and attenuated
clinical symptoms.32 In humans, hyperleptinemia has
been correlated with pro-inflammatory conditions
Figure 1 Outline of molecular interaction between dietary habits and immunologic regulatory system (Riccio P, Autoimmune
Diseases 2010, modified).
Esposito et al. The role of diet in multiple sclerosis: a review
and autoimmunity.36 In naïve-to treatment MS
patients, increased levels of leptin have been observed
in serum and cerebrospinal fluid (CSF). Leptin levels
have also been found to correlate directly with CSF
IFN-γ secretion and inversely with the percentage of
circulating regulatory T cells (T-reg),34 a subset of T-
Lymphocytes with a critical role in suppressing auto-
reactive T-cells and in maintaining peripheral toler-
ance.37 Overexpression of leptin receptor (LEPR) has
been detected in CD8+ T cells and in monocytes of
MS patients during clinical exacerbation, in contrast
to patients in remission or healthy controls, suggesting
an involvement of LEPR in MS relapses.38 Based on
this evidence, Matarese et al.39 have proposed the
role of leptin as mediator between metabolic status
and MS pathogenesis/activity: a diet-related increase
in adipocyte mass, through the hypersecretion of
leptin, might impair the balance between effector T
cells (T-eff) and T-reg cells, promoting a pro-inflam-
matory status and a cell-mediated autoimmunity tar-
geting antigens involved in MS.
Molecular impact of diet on MS-related
autoimmune inflammation
In recent years, we have witnessed a remarkable inter-
est in nutrients and special diets, such as saturated and
‘trans’ fatty acids, α-lipoic acid, polyphenols, high-fat
diet, and high-carbohydrate diet that operating at the
molecular level, may modulate the components of
inflammatory cascade (Fig. 1). There is some evidence
that nuclear factor-kB (NF-κB) and Activator Protein-
Nutritional Neuroscience 2017 3
Esposito et al. The role of diet in multiple sclerosis: a review
1 (AP-1) – two main pro-inflammatory transcription
factors involved in T-cell induction – are activated in
MS,40,41 determining overexpression of pro-inflamma-
tory products such as: tumor necrosis factor alpha
(TNF-α), interleukin 1 beta, high-sensitivity C-reac-
tive protein (hs-CRP), receptor activator of NF-κB
ligand,42 IL-6,43 matrix metalloproteinase-9 (MMP-
9),44 prostaglandins, and leukotrienes.45,46 As a conse-
quence, inflammation, extracellular-matrix degra-
dation, angiogenesis, and oxidative stress may be
aroused and/or enhanced.
NF-κB is also protagonist of a mutual modulation
with nuclear factor erythroid-2-related factor 2
(Nrf2), an important transcriptional activator of cyto-
protective genes, whose activity is associated with
specific dietary molecule intake.47 Nrf2 activation
reduces NF-κB pathways and the release of cytokines,
chemokines, adhesion molecules, cyclooxygenases-2,
MMP-9, and inducible nitric oxide synthase;48–50 con-
versely, recent experimental evidence has indicated
that NF-κB may directly interfere with Nrf2 signaling
at the transcriptional level.47
Peroxisome proliferator-activated receptor (PPARα,
β/δ, and γ) represents another cluster of nuclear recep-
tors that regulate the inflammatory process by inter-
acting with NF-κB, AP-1, and nutrients.51 Each
member of the family, being a modulator of energy
homeostasis, plays a distinct role in lipid metabolism
(they are activated by fatty acids, fatty acid derivatives,
and synthetic compounds) and down-regulates both
NF-κB and AP-1 activities,52 integrating metabolic
and inflammatory signaling at transcriptional level
(Fig. 1).
Besides evidence of indirect influences, several
studies have shown that saturated and ‘trans’ fatty
acids and lipopolysaccharide (LPS) may up-regulate
NF-κB and AP-1 activities, promoting inflammation,
Figure 2 Putative mechanisms connecting diet, local, and systemic inflammation and autoimmunity processes.
4 Nutritional Neuroscience 2017
while calorie restriction, polyphenols, Ω-3 PUFA,
butyrate, and physical exercise would exert the oppo-
site effect.41,53
Therefore, an increasing body of evidence seems to
highlight the influence of diet on inflammatory and
autoimmune processes implicated in MS, supporting
the hypothesis of close interplay between dietary mol-
ecules and key transcription factors likely involved in
both metabolic and immunological homeostasis
(Fig. 1).
Pro-inflammatory role of diet-related dysbiosis
The growing interest in understanding the role of gut
Microbiome in human health prompted the investi-
gation of the microbial repertoire in the framework
of autoimmune and inflammatory diseases such as
MS. Unicellular eukaryotes, viruses, archaeas, and
two major bacterial phyla (i.e. Bacteroidetes and the
Firmicutes) characterize the mammalian intestinal
microflora community, also known as gut
Microbiota. It regulates many metabolic pathways
(carbohydrate, lipid, and aminoacid metabolism),54,55
and interferes with host immune system development56
and with immune tolerance modulation.57 Alteration
in its composition (dysbiosis) may depend on a
number of factors including dietary habits, especially
the high-fat/high-sugar Western diet (Fig. 2).58,59
Long-term diets may modulate the microbial entero-
types,60 but a drastic short-term consumption of pro-
teins and animal fats versus vegetable products may
also induce a change in gut biodiversity.61 Moreover,
dysbiosis influences many immunological and meta-
bolic pathways and correlates with a variety of inflam-
matory and metabolic diseases.57,62–64 Given a
possible relationship between gut microbiota and
inflammation, many authors have also been encour-
aged to investigate the microbiota in experimental

models of MS. An extensive review by Mielcarz and
Kasper,65 examining the role of gut microflora in
EAE, has provided evidence that commensal and pro-
biotic bacteria play an important role in modulating
mice immune system, thus reducing the clinical sever-
ity of EAE. One of the underlying mechanisms may
depend on the regulation of T-reg/T helper (Th) 17
balance, notoriously impaired in autoimmune dis-
eases.66,67 It has been described that specific gut com-
mensals can lead to developing IL-10
(immunoregulatory cytokine produced by Foxp3+ T-
Reg cells and implicated in immune tolerance of the
gut microbiota)68 and complex glycans-consuming
bacteria may exert an anti-inflammatory effect produ-
cing butyrate.69,70 Over the last few years, gut
microbial composition has been investigated in MS
through case–control studies that, although limited
in sample size, have shown interesting results. A sig-
nificant increase in pro-inflammatory species and a
reduction of organisms with anti-inflammatory prop-
erties have been observed in MS patients. In particular,
in their gut microbiota, there is an increase of Archae
(whose lipid membrane may induce local and systemic
inflammatory process in the host);71,72 of Shigella,
Escherichia Coli, and Clostridium, commonly associ-
ated with infections;73 and a decrease in
Butyricimonas and Lachnospiraceae, butyrate produ-
cers.71,74 Collectively these findings suggest that gut
dysbiosis, mostly induced by nutrition, may indirectly
alter T-reg/Th17 balance and trigger an inflammatory
pathway – through molecular mimicry mechanisms or
microbial antigen presentation – contributing to the
pathogenesis of MS.75
LPS and low-grade inflammation
LPS is a component of the outer cellular wall in Gram-
negative bacteria, detectable at low concentrations in
the plasma of healthy people (metabolic endotoxe-
mia).76 Levels of circulating LPS are influenced by
changes in intestinal microbiota, modulated, in turn,
by food content, high-fat feeding,77,78 and high-
energy intake,79 by raising the Gram-negative/
Gram-positive ratio, leading to an increase of post-
prandial endotoxemia. Conversely, dietary fibers nor-
malize the gut microbial ratio and LPS plasma con-
centrations.80 High endogenous LPS levels are
increasingly considered as a potential key mediator
of a low-grade inflammatory state, characterized by
the elevation of circulating humoral factors, such as
TNFα, interleukins, adipokines,81 and hs-CRP.82
This low-grade systemic inflammation has been corre-
lated with the risk of chronic immune-mediated dis-
eases,62,68 metabolic syndrome,80 obesity, diabetes
mellitus,83 atherosclerosis, cardiovascular dis-
orders84,85 and, more generally, to a wide spectrum
of inflammatory diseases.86 These conditions seem to
Esposito et al. The role of diet in multiple sclerosis: a review
share a loss of gut epithelial barrier function, with a
consequent translocation of intestinal LPS into the
bloodstream, especially during fat absorption,79
which may induce the release of cytokines favoring a
chronic inflammatory state.87 These observations
strongly suggest that the increased LPS, related to
diet-driven dysbiosis, might be responsible for
chronic intestinal inflammation, low-grade endotoxe-
mia, and systemic inflammation, promoting inflam-
matory and autoimmune diseases (Fig. 2).
Nevertheless, the exact causative mechanisms linking
dietary habits, endotoxemia, and immunological dis-
orders, in particular in MS, are still debated and diffi-
cult to ascertain.
As discussed above, experimental data suggest that
the pathogenesis of MS might involve specific mechan-
isms linking the immune system with metabolic status.
Some dietary lifestyles and metabolic mediators may
exert a direct or indirect pro-inflammatory effect,
developing systemic and intestinal micro-environ-
mental conditions that might contribute to the
initiation and/or promotion of the inflammatory
cascade and the loss of immune self-tolerance (Fig. 2).
Dietary habits in MS patients
Although the impact of diet on MS pathogenesis is still
debated, it is rather evident that some disease-related
symptoms may interfere with nutrition. In particular,
fatigue, depression, cognitive decline, swallowing pro-
blems, mobility restrictions, and high disability level
may impinge on adequate nourishment, impairing
meal preparation, and eating.88–90 This may lead to
a higher consumption of energy-dense fast foods or
‘convenience’ foods, thus increasing the risk of
chronic metabolic diseases and affecting overall
quality of life.91,92 Dietary and lifestyle behaviors
have not been extensively examined in the MS popu-
lation, for the anticipated difficulties in collecting
reliable retrospective data and for the rarity of pro-
spective and sufficiently large sample studies.93 In a
case–control study performed in Croatia,20 a high-
risk zone for MS, the consumption of nonskimmed
milk, animal fat, and smoked meat resulted more fre-
quently in MS patients than in controls. A case–
control study conducted by Pekmezovic et al.94 on
110 MS patients, using a food frequency approach,
showed higher consumption of beef, chicken, lamb,
butter, and ice-cream in MS patients than in controls;
conversely, the ingestion of cabbage, lettuce, pepper,
potatoes, cauliflower, and beet was significantly
higher in the control group. An international cross-sec-
tional study by Hadgkiss et al.95 investigated health
and lifestyle behaviors in a sample of 2519 MS patients
enrolled by on-line resources. A substantial number of
participants reported meat- or dairy-free diets, a high
intake of Ω-3 and vitamin D supplements. As
Nutritional Neuroscience 2017 5
Esposito et al. The role of diet in multiple sclerosis: a review
discussed by the authors, these results are not generally
applicable to the whole MS community, as they prob-
ably reflect a subgroup of motivated patients more
inclined to technology, as well as to self-directed learn-
ing of innovative practices.
Alternative diets and complementary medical
therapies
Complementary and alternative medicine (CAM) use
is widely diffused among persons with MS, despite
the lack of evidence-based guidelines. Some recent
surveys5,96 suggested that up to 70% of people with
MS have tried one or more CAM treatments, includ-
ing special diets, vitamins/minerals, essential fatty
acids, and anti-oxidant supplements. An Australian
self-administered survey97 among 1230 MS patients
identified, as the most used alternative diets, the low-
fat, low/no sugar, and gluten-free diets. The Swank
diet98,99 is a popular example of a food regimen
based on strict reduction of saturated fat and dairy
products, frequent intake of seafood, vegetable oil,
and cod liver oil supplements. Its pathophysiological
rationale derives from a 34-year qualitative prospec-
tive study on 144 MS patients observing the diet.
The results showed a positive impact of the low satu-
rated fat diet on disease clinical activity and pro-
gression of disability, but the validity of the study is
limited by a number of methodological issues:
absence of blindness, control arm, and randomization.
Based on these premises, it should not be surprising
that the Cochrane Collaboration systematic review,
among dietary interventions in MS, failed to confirm
the benefits of the Swank and other alternative
diets.100
Health implications of unbalanced diet
Nutritional imbalances might justify widespread
vitamin deficiencies,101 reduced control of body
weight,102,103 prevalence of atherosclerosis,104 hyper-
tension, hyperlipidemia, diabetes, and an increased
risk of vascular comorbidities, observed in MS
patients as compared to the general population.105
Emerging evidence of an increased risk of disease pro-
gression in MS patients with vascular and metabolic
comorbidities106 makes it reasonable to assume the
existence of a dangerous vicious circle.
Malnutrition
Malnutrition can be defined as a pathological state
resulting from inadequate nutrition, including under-
nutrition, over-nutrition (overweight and obesity),
and deficiency of one or more specific nutrients
(such as vitamins or minerals).107 To date, its exact
prevalence in MS patients is unknown, but some
studies have demonstrated that malnutrition may
occur more frequently in MS than in other chronic
6 Nutritional Neuroscience 2017
diseases,101,108 being more relevant in severely disabled
patients.109,110 The detrimental consequences on func-
tional abilities, mental activity, immune system, and
muscle strength may contribute to worsen pre-existing
MS symptoms,89 impacting negatively on patients’
quality of life.111
Obesity and body composition
General strategies to ensure body weight control,
including physical activity, are not always feasible for
moderate-severely disabled MS patients.112 In such
cases, diet plays a key role in maintaining an adequate
energy balance and in reducing the risk of comorbid-
ities and mortality associated with weight
excess.113,114 However, findings regarding the body
composition and the prevalence of obesity in MS
patients are conflicting. As evidenced by a systematic
review of Wens et al.,115 the best designed studies
investigating body composition looked at three
anthropometric measures: body mass index (BMI),
lean body mass (LBM), and body fat amount. BMI
data have shown inconsistent results between studies,
with slightly elevated, normal, or slightly lowered
BMI values in MS patients. Similarly, most LBM
studies have shown no significant differences in LBM
between MS and controls, with only a few of them
indicating regional differences (lower LBM in the
lower limbs of female patients) and an influence of dis-
ability level. Finally, small studies, comparing body fat
percentage between MS and matched controls,
reported either similar or lower fat amount in MS
patients. Nevertheless, a recent study103 on 130 dis-
abled MS patients compared to the general population
showed that despite the lower percentage of obesity
(evaluated according to BMI), the MS group had
higher rates of increased waist circumference. Its
known relationship to cardio-metabolic compli-
cations116,117 suggests that abdominal obesity might
be a better index to evaluate health risk in MS
population.
Pressure ulcers and malnutrition
Pressure ulcers – which represent a major cause of hos-
pitalization118 – occur more often in MS than in the
general population, especially in the presence of mobi-
lity decline (in advanced stages of the disease), older
age, male sex, lower socio-economic status.
Decreased albumin and hemoglobin levels, but also a
low mid-arm circumference, seem to be related with
pressure sores.119 An inadequate nutritional status
characterized by a low intake of calories, iron, folate,
vitamin D,109 zinc, arginine, and anti-oxidants,120 in
combination with the use of medications, such as glu-
cocorticoids, may contribute to delaying the healing
process of pressure ulcers in MS patients, increasing
costs for medical care and hospitalization.121

Osteoporosis
Osteoporosis, a major cause of morbidity and mor-
tality due to fractures,122 occurs frequently in MS in
association with decreased vitamin D/calcium levels,
physical inactivity, reduced bone mechanical loads,
and use of medications such as steroids and anticon-
vulsants.123 In particular, dairy produce restriction
and insufficient sunlight exposure, frequent conditions
among MS patients, may favor calcium deficiency.124
In addition to evidence of decreased bone mineral
density,125 an increased risk of fractures has been
detected in MS subjects,126 because MS-symptoms
(i.e. muscle weakness, postural instability, impaired
vision, dizziness) may induce falls; therefore osteo-
porosis is a major but modifiable risk factor in the
MS population.
Bowel and bladder dysfunctions
Up to 70% of MS patients complain about bowel dys-
functions (constipation and/or fecal incontinence)
with discomfort and debilitating effects on their
quality of life.127 In addition to neurological reasons,
unbalanced diet, decreased food/water intake,
impaired mobility, and adverse effects of the drugs,
concur to their pathogenesis.128 Bowel management
is mainly empirical and, despite limited evidence,129
some lifestyle recommendations may be drawn: a
high-fiber diet (a gradual increase until reaching 25–
30 g per day, through wheat bran and bran cereals,
whole grain foods, fruits and vegetables), high fluid
intake (approximately two liters daily), and regular
bowel movement may be advantageous.127
Constipation and encopresis may also contribute to
the development of urologic dysfunctions, experienced
by up to 90% of MS patients,130 especially overactive
bladder symptoms131 and recurrent urinary tract infec-
tions (UTIs).132 A full rectum may indeed displace the
bladder leading to incomplete voiding133 and to sub-
sequent UTIs; on the other hand, encopresis may
favor urinary tract colonization leading to UTIs,
exacerbation of bladder instability, and enuresis.
UTIs have also been related to an increased risk in
relapses.134 Nutritional attempts to prevent their
onset have shown limited effectiveness, although no
definite conclusions can be drawn. Small
studies135,136 failed to show significant benefits of pro-
biotics and cranberry juice – compared with placebo –
in preventing UTIs. On the other hand, it is advisable
to ensure bowel regularity and a proper water supply.
Evaluation of nutritional status in MS
The evaluation of nutritional status in MS is a step-
wise, time-consuming procedure, often neglected in
clinical practice, although the early identification of
patients at risk of developing malnutrition or nutri-
tional imbalances has important health implications.
Esposito et al. The role of diet in multiple sclerosis: a review
Many nutritional screening questionnaires are avail-
able: the Subjective Global Assessment;137 the
Nutritional Risk Screening 2002;138 the Mini
Nutritional Assessment (in elderly subjects);139,140
and the Malnutrition Universal Screening Tool141
(for adults). Once ‘at-risk patients’ are identified, a
comprehensive nutritional evaluation is indicated to:
(i) assess the level of malnutrition, (ii) detect the
major contributing factors, such as dysphagia or anor-
exia, and (iii) provide an accurate and multidisciplin-
ary program to ensure an adequate diet. As
suggested by Pasquinelli et al.,142 the following steps
should be observed:
• Evaluation of nutritional status through some key
points. Nutrition ‘history’ (through diet diaries, ques-
tionnaires, and weekly monitoring) assessing lifestyle
and types/quantities of consumed food; clinical
examination: weight loss history, actual height/
weight, skin integrity, muscle strength, changes in
body temperature; anthropometric evaluation: age,
gender, BMI, non-dominant arm circumference,
waist circumference, skinfold thickness; hematologi-
cal parameters: albumin, transferrin, prealbumin,
retinol-binding protein, lymphocyte count, comp-
lement C3 fraction, IgM.
• Calculation of nutritional needs; the Harris–Benedict
equation is the most used formula for daily calorie
requirement, with corrections for coefficients of phys-
ical activity and illness state.
• Evaluation of dysphagia and potential interfering
conditions with nutrition (through a multidisciplinary
approach).
• Schedule of nutritional intake.
• Plan for the eventual occurrence of complications.
To accurately assess body composition, in addition to
skinfold thickness measurement (biceps, triceps, sub-
scapular, and sovra-iliaca skinfold), many advanced
techniques have been implemented (i.e. bioelectrical
impedance analysis, dilution techniques, air displace-
ment plethysmography, dual energy X-ray absorptio-
metry, three-dimensional photonic scanning,
magnetic resonance, spectroscopy, etc.), but they
have limited use in routine clinical practice, being
expensive and dependent on skilled/trained
personnel.143
Dietary recommendation and specific nutrients
in MS
Until now, a specific dietary model has not been estab-
lished for MS patients; therefore, balanced and healthy
nutrition – as advised to the general population – is
recommended. Current healthy dietary guidelines
indicate a daily calorie intake between 20 and
35 kcal/kg (actual weight) as ‘proper’ for MS
people.142 In MS subjects, respecting the proportions
between macro- (lipids, proteins, and carbohydrates)
and micronutrients (vitamins and minerals), the diet
Nutritional Neuroscience 2017 7
Esposito et al. The role of diet in multiple sclerosis: a review
should increase plasma levels of essential fatty acids,
unrefined carbohydrates (to alleviate symptoms such
as fatigue and weakness), anti-oxidants, vitamin D
and B12; it would also be appropriate to ensure an
adequate supply of proteins, zinc (for tissue trophism),
fibers, and fluids (to maintain regular gut function). In
the presence of swallowing disorders (affecting more
than one-third of MS patients),90 to prevent aspiration
and dehydration, it may be useful to modify bolus
rheology144 and to use a thickening agent (commercial
or natural such as cream, peanut butter, fish glue,
flour, and cornstarch) or diluents. In case of under-
nutrition, high-energy oral supplements are rec-
ommended (in the form of drinks, puddings, or
powders) to increase calorie intake.145 When nutri-
tional status is severely compromised, or dysphagia
has reached a critical level, naso-gastric/naso-duode-
nal tube or percutaneous gastrostomy, respectively
short-and long-term enteral nutrition procedures,
should be considered after careful evaluation with
both patient and caregiver.146,147
Saturated fats and PUFAs
Lipids are the basic components of cellular mem-
branes.148 As formerly elucidated (see section ‘The
impact of diet on MS pathogenesis’), many investi-
gations suggested the detrimental effect of saturated
fatty acid (in meat, butterfat, coconut, and palm oils)
abuse on health, encouraging their replacement with
unsaturated fatty acids.149 PUFA include two classes
of essential acids: Ω-3 (alpha-linolenic acid, derived
from ocean fish, shellfish, fish and cod liver oils,
tofu, almonds, walnuts, green leafy vegetables,
legumes, soybean, linseed, and hazelnut oils) with
anti-inflammatory effects150 and Ω-6 (linoleic acid, in
vegetable oils extracted from sunflower, corn,
soybean, and sesame) resulting in the biosynthesis
of arachidonic acid, precursor of inflammatory
cascade.151 The Western diets are characterized by
increases in saturated fatty acids and in Ω-6/Ω-3
ratio (15/1-16.7/1).152 Although available scientific
data are insufficient to assert a real benefit of PUFA
supplements in MS,100 some evidence suggests that
the dietary inversion of the competitive and oppos-
ing153 relationship between Ω-6 and Ω-3 (with ↑ of
Ω-3 and ↓ of Ω-6) may reduce the synthesis of pro-
inflammatory prostaglandins exerting beneficial
effects on health.154–156 With the purpose of evaluat-
ing the influence of nutritional intervention on inflam-
matory and clinical status in MS patients, Riccio
et al.157 recently conducted a 7-month pilot study.
They investigated the effects of a fixed dietary
regimen, mainly based on the Mediterranean model,
combined with vitamin D and additional dietary sup-
plements (fish oil containing Ω-3 PUFA, alfa-lipoic,
resveratrol, and a multivitamin complex) on three
8 Nutritional Neuroscience 2017
groups of RRMS patients [10 subjects with only
disease-modifying therapy (DMT) + vitamin D, 11
patients with DMT + vitamin D + diet, and 12
patients with DMT + vitamin D + diet + sup-
plements] and one group of primary-progressive MS
patients (10 subjects with vitamin D + diet + sup-
plements). After 3 months of treatment, serum concen-
trations of Ω-3 PUFA increased in all groups under
dietary regimen, with or without the administration
of dietary supplements. This effect was associated
with an improvement of systemic inflammatory
status (expressed by a reduction of active MMP-9
serum levels) despite the lack of significant ameliora-
tion of quality of life (measured by SF-36 question-
naire and the Hamilton Rating Scale for
Depression), clinical outcomes (EDDS score), and
fatigue (assessed by Fatigue Severity Scale) in any
group, after 3 and 6 months.
Vitamin D
It is a steroid hormone, mainly synthesized by human
skin after exposure to UV-B, whose receptor is a tran-
scription factor widely distributed across many tissues.
Increasing evidence has shown vitamin D deficiency in
many chronic diseases, supporting the hypothesis that
vitamin D has several non-skeletal functions158 and in
particular an immunomodulatory effect.159,160
Epidemiological studies have suggested a beneficial
effect of higher vitamin D and/or sun exposure
levels on MS risk, disease activity, and progression.161
Nevertheless, a Cochrane meta-analysis162 classified
the evidence from studies suggesting supplementations
of vitamin D in MS as not reliable. Anyhow, in case of
demonstrated deficiency – a very common occurrence
in MS population163 – oral supplements of vitamin D
are strongly and unanimously recommended.
According to the guidelines of the Italian Society for
Osteoporosis, Mineral Metabolism, and Bone
Diseases164 – considering that the daily requirement
of vitamin D ranges from 1500 to 2300 IU, depending
on age, sunlight exposure, BMI, fat mass, calcium
intake, clinical circumstances, and diet (the major
sources of vitamin D are fatty fish, milk, and dairy
products and the Italian diet provides only 300 IU/
day) – a cumulative dose of 300 000–1 000 000 IU,
over 1–4 weeks, is recommended, followed by a main-
tenance dose of 800–2000 IU/day (or weekly
equivalent).
Other vitamins in MS
Cobalamin (B12) is produced by microorganisms and
is mainly present in dairy and animal products
( poultry, lamb, sardines, salmon, tuna, cod, scallops,
shellfish, eggs, etc.) with a Recommended Dietary
Allowance (RDA) for adults of 2.4 μg/day, largely
supplied by a varied diet.165 B12-deficiency can lead

to demyelination and axonal injury.166 Most likely, on
the basis of a shared autoimmune pathogenesis
between some forms of B12-deficiency and MS, or
because in demyelinating disorders an increased
demand of B12 may be evoked for remyelination
process, the association between B12-deficiency and
MS has been investigated. So far, reported results are
conflicting.167,168 With regard to vitamin supplemen-
tation trials in MS, in 2012 a Cochrane meta-analy-
sis100 has rejected all interventional studies for lack
of compelling methods.
Biotin (vitamin H) is widely distributed in natural
foodstuffs (especially in liver, egg yolk, and cow’s
milk), with a recommended daily intake of 30 μg in
adults. Biotin serves as a coenzyme in carboxylation
reactions involved in energy metabolic pathways.165
The results of an open-label pilot study169 suggested
that high doses (300 mg/day) of biotin, administered
for a mean duration of 9.2 months, might exert
benefits on disability progression in MS. Treatment
efficacy was evaluated on progressive MS patients by
assessing changes in EDSS, Timed 25-foot walk
(TW25) test, walking distance, muscle strength, and
videotaped clinical examination (in 18 patients with
spinal cord damage); visual acuity, Goldmann perime-
try, visual evoked potentials, and Humphrey auto-
mated perimetry (in five patients with prominent
visual involvement). Due to the small sample size,
results were reported for each parameter in each
single patient; over 90% of participants exhibited
some significant benefit (qualitative or quantitative)
on clinical and/or electrophysiological examinations
after high-dose biotin treatment. Fatigue, swallowing
difficulty, and urinary dysfunction improved in 5, 4,
and 2, patients respectively. Positive results were also
reported in a randomized, double-blind, placebo-con-
trolled trial170 where 154 patients with spinal progress-
ive MS, and no evidence of clinical–radiological
disease activity, showed significant decrease in EDSS
score or ≥20% improvement in TW25, after 12
months of treatment with high doses of biotin.
Despite these encouraging results, the putative
mechanism of biotin action should be elucidated in
pre-clinical studies and the efficacy and safety of
high-dose biotin in progressive MS need to be con-
firmed in larger cohorts of patients.
Vitamin A includes retinoids and carotenoids
(dietary precursors of retinol, with an intestinal caro-
tenoid-to-retinol conversion ratio of 12:1). It is not
synthesized by humans and therefore must be provided
through diet. The RDA is 900 and 700 μg retinol
activity equivalents/day, for men and women, respect-
ively. Preformed vitamin A is available in some
animal-derived foods (liver, milk, cheese, eggs, or
foods fortified with vitamins), while carotenoids are
abundant in dark green leaves, red palm oil, orange-
Esposito et al. The role of diet in multiple sclerosis: a review
yellow vegetables and fruits (carrots, mangos,
papaya, etc.). Five rations of fruits and vegetables
per day could contribute approximately to 50–65%
of the men’s RDA.171 Vitamin A is needed to
support normal vision, immune functions, and main-
tenance of epithelial integrity, red blood cell synthesis,
and reproduction.172 There is evidence for a role of
vitamin A in modulation of both humoral and cell-
mediated immunity.171 A number of studies demon-
strated that retinoic acid in vivo inhibited inflamma-
tory responses and improved a variety of
autoimmune diseases in animal models, including
EAE,173 probably suppressing Th17 differentiation
and inducing T-reg cells.174 Bitarafan et al.,175 in a
recent randomized placebo-controlled clinical trial
showed benefits in 101 RRMS patients of high doses
(25 000 IU daily for 6 months and 10 000 IU for the
following 6 months) of Vitamin A supplements on
fatigue and depression (evaluated by MFIS and Beck
Depression Inventory-II, respectively).
Minerals
Some authors have speculated about the relationship
between the dysregulation of certain minerals and
MS.176–178 It has been reported that selenium
deficiency (contained in cereals, beef, white bread,
pork, chicken, fish, and eggs), and that of zinc (in
oysters, sardines, meat turkey, beef, lamb, poultry,
pumpkin seeds, eggs, cereals, nuts, legumes, dark cho-
colate), magnesium (in green leafy vegetables, dried
fruit, legumes, cereals, and bananas), and iron (in
beef, pig, horse, poultry, and fish), probably associated
with malnutrition and/or to an increased demand,
may worsen some aspects of the disease (especially
pressure sores and fatigue).109,179 Given their multiple
biological roles180–182 and the lack of association
between serum concentrations and homeostasis at
tissue level,183 in the nutritional assessment of MS
patients, it seems appropriate to evaluate the individ-
ual risk factors of mineral dysregulation and
deficiencies, in order to promptly correct them accord-
ing to the RDA.171,184,185
Anti-oxidant compounds
Oxidative damage, mostly related to the inflammatory
process, is known to be involved in MS pathogen-
esis,186,187 thus gaining interest as a new therapeutic
target. Recently, Plemel et al.,188 conducted a systema-
tic review of animal and clinical studies investigating
the effects of dietary anti-oxidant compounds on
EAE/MS. In particular, they focused on polyphenols
(luteolin, quercetin, curcumin, epigallocatechin-3-
gallate, and resveratrol), anti-oxidant vitamins (A, C,
and E), alpha lipoic acid and Ginkgo biloba. The
most significant results were observed with epigalloca-
techin-3-gallate (contained in dried leaves of white tea,
Nutritional Neuroscience 2017 9
Esposito et al. The role of diet in multiple sclerosis: a review
green tea, apple, plums, onions, hazelnuts, etc.), alpha
lipoic acid (in grass-fed red meat, liver, heart, potatoes,
broccoli, spinach, etc.), resveratrol (in peanuts, grape-
vines, and red wine) and vitamin E (in oil from plants,
almonds, hazelnuts, sunflower seeds, peanuts, etc.). In
animal models of MS, these compounds seemed to
exert anti-oxidant/anti-inflammatory effects, with
reduced demyelination and axonal injury, probably
through an active induction of myelin regeneration
and neuroprotection from inflammatory damage (in
the case of resveratrol independently of any anti-
inflammatory benefits). Some EAE experiments with
curcumin (main component of the Indian spice tur-
meric)189 showed consistent anti-inflammatory
effects. Therefore, although pre-clinical studies are
encouraging, the real neuroprotective/neurotrophic
action of dietary anti-oxidants in MS will need to be
tested through well-designed clinical trials.
Conclusions and future perspectives
To date, epidemiological studies have shown a link
between diet and incidence of MS. Pre-clinical exper-
iments and theoretical considerations have suggested
the role of nutrition as one of the environmental
factors involved in MS pathogenesis. This review
reports the most relevant evidence on the emerging
role of diet as a possible co-factor conditioning the
inflammatory cascade, by acting on both molecular
pathways and composition of gut microbiota.
Dysfunction of the inflammatory homeostasis might
be the trigger event as well as affecting the progress
of a cluster of chronic immune-mediated disorders,
also including MS.
Despite the limited number of large-scale prospec-
tive studies and well-designed clinical trials providing
MS-nutritional guidelines, an overall healthy lifestyle
profile, with balanced nutrition – to provide an ade-
quate intake of unsaturated fats, unrefined carbo-
hydrates, fibers, anti-oxidants and to correct
hypovitaminosis – is recommended.
Furthermore, because diet-related comorbidities,
such as malnutrition, metabolic syndrome, and cardi-
ovascular disease, seem to be related to a decline in
physical condition and quality of life in MS patients,
an accurate nutritional counseling should be encour-
aged in clinical practice.
Future studies, exploring the role of a healthy and
specific diet on MS onset and/or evolution, should
be strongly encouraged in order to move toward a hol-
istic management of MS.
Disclaimer statements
Contributors None.
Funding None.
Conflicts of interest None.
10 Nutritional Neuroscience 2017
Ethics approval None.
ORCID
Gioacchino Tedeschi http://orcid.org/0000-0002-
3321-1125
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