Can gluten affect multiple sclerosis?

Transcription

Correspondencia: Ismael San Mauro Martín – Research Centre in Nutrition and Health (CINUSA group)
C/ Artistas 39, 2º-5 - 28020 Madrid – Teléfono: 910 114 113 – E-mail: info@cinusagroup.com
Revisión
13
18
Can gluten affect multiple sclerosis?
Ismael San Mauro Martín1, Elena Garicano Vilar2
Research Manager, 2Data Manager & Research.
Research Centre in Nutrition and Health (CINUSA group).
Madrid.
1
ABSTRACT. Introduction: Multiple sclerosis is a chronic inflammatory autoimmune disorder, characterized by the presence of disseminated demyelinating lesions in the central nervous system. Gluten not only affects the organism causing celiac disease, but it also
intervenes in other pathologies associated with glycoproteins. Gluten can cause neurologic damages through a combination of antibodies of crossed-reaction, complex immune diseases and direct toxicity. Some studies show the positive effect of removing gluten from
a patient’s diet. Aim: To review scientific literature related to gluten ingestion in multiple sclerosis, and to analyse the evidence that this
hypothesis supports. Methods: Bibliographic search in PubMed database. Several search strategies were designed, combining keywords
according to the studies that were sought in order to find the highest scientific evidence possible. Results: The cause of neurologic
symptoms are not known but it has been suggested that the autoimmunity resulting from the molecular mimicry between gliadin and
proteins from the nervous system have a relevant role. Some patients suffering from multiple sclerosis experienced a significant relief
of their symptoms after being on a gluten-free diet. Conclusion: There is a possible association between the disruption of the flow of
information within the brain and body and gluten. Studied patients may improve or stabilize their cognitive condition with the removal of
gluten. Studies reviewed have all shown low-medium evidence as a whole. More studies are needed, specially randomized clinical trials.
Key words: gluten, antigliadin, multiple sclerosis, neurologic disease.
RESUMEN. Introducción: La esclerosis múltiple es un trastorno inflamatorio autoimmune, caracterizado por la presencia de lesiones
desmielinizantes diseminadas en el sistema nervioso central. El gluten no sólo afecta al organismo causando la enfermedad celíaca, sino
que también interviene en otras patologías asociadas con glicoproteínas. El gluten puede ocasionar lesiones neurológicas por medio de
la combinación de anticuerpos cros-reactivos, enfermedades inmunes complejas y daño directo. Algunos estudios muestran el efecto
positivo de la eliminación del gluten de la dieta de los pacientes. Objetivo: revisar la literatura científica relacionada con el gluten y la
esclerosis múltiple, y analizar la evidencia que apoya esta posible relación. Métodos: búsqueda bibliográfica en la base de datos PubMed.
Se diseñaron varias estrategias de búsqueda, combinando palabras clave de acuerdo con los estudios que fueron hallados, con el fin de
obtener la evidencia científica de mayor calidad. Resultados: la causa de los síntomas neurológicos no se conoce, pero se ha sugerido
que un proceso autoinmune resultado de un proceso de mimetismo molecular entre la gliadina y las proteínas del sistema nervioso
podría tener un papel relevante. Algunos pacientes de esclerosis múltiple experimentan una reducción significativa de sus síntomas tras
seguir una dieta libre de gluten. Conclusión: hay una posible asociación entre la disrupción del flujo de información entre cerebro, cuerpo
y gluten. Los estudios revisados tienen un grado bajo-medio de evidencia en conjunto. Se precisan más estudios y especialmente ensayos clínicos aleatorizados.
Palabras clave: gluten, antigliadina, esclerosis múltiple, enfermedad neurológica.
❑❑Introduction
Multiple sclerosis (MS) is a chronic inflammatory
autoimmune disorder1, characterized by the presence
of disseminated demyelinating lesions in the central
nervous system (CNS)2. It has a multifactorial etiology, including environmental, immunological, and
genetic factors1. Activated, potentially autoimmune,
T cells cross the blood-brain barrier and produce
inflammatory plaques and axonal loss in the brain,
spinal cord or optic nerves. The result is the accumulation of gliosis and demyelination in areas of the
CNS. MS affects about 1% of the population worldwide, mainly young women2.
MS could be associated with other autoimmune
diseases, such us celiac disease (CD) and vice versa1.
The association of autoimmune disorders and CD is
REVISTA ESPAÑOLA DE ESCLEROSIS MÚLTIPLE
considered to be due to a shared genetic tendency3.
CD occurs in up to 11% of the patients, together with
MS4. When both occur in a patient, CD is frequently
silent, and the patient is initially diagnosed with the
autoimmune disease3. Arguments for the coexistence of both conditions are the cerebrospinal fluid
and magnetic resonance imaging (MRI) findings,
improvement of gastrointestinal manifestations and
polyneuropathy upon gluten-free diet (GFD), and
previous reports which refer to the collateral concurrence of both conditions4.
CD is a systemic immune-mediated intestinal
disorder with gluten sensitivity which is characterized with villus atrophy and crypt hyperplasia1. The
genetic basis for gluten intolerance are mainly attributed to the HLA class-II locus located on chromosome 6p213. A high level of Immunoglobulin A (IgA)
Nº 37 - Diciembre de 2015
Ismael San Mauro Martín, Elena Garicano Vilar
❑❑Objectives
The aims of this manuscript were to review scientific
literature related to the ingestion of gluten and GFD
in MS; to study the link between MS and CD; and
to analyse the evidence that these hypothesis are supported by.
❑❑Material and methods
Search strategy
The present text was a systematic review. It focuses on scientific literature about gluten (ingestion
and sensibility) and MS. Thus, a bibliographic search
has been made on PubMed data base and other scientific data bases.
The studies undertaken on gluten and MS were
systematically reviewed in September 2015. The
search was done by two independent researchers
who subsequently corroborated the results found.
The exact electronic search strategy is outlined in
Figure 1, below.
Identification
Search terms
In order to gather the most relevant studies,
several search strategies were designed, combining
keywords according to the study that was aimed for,
with the highest scientific evidence possible. There
was a limitation imposed in the year of publication
of the studies: not older than 30 years.
The search strategy was the following:
(“glutens”[MeSH Terms] OR “glutens”[All Fields]
OR “gluten”[All Fields] OR “triticum”[MeSH
Terms] OR “triticum”[All Fields] OR “wheat”[All
Records identified through
database searching
(n=48)
19
Eligibility
Screening
Records after duplicates removed (n=47)
Included
anti-tissue transglutaminase-2 (tTG-2) antibody in
the serum of the patients is an important serologic
marker for diagnosis3. There is prevalence in the general population is 1-2% worldwide2. Gluten is a glycoprotein formed by two other glycoproteins: gliadin
and glutenin. These glycoproteins are presented in
some cereals of usual consumption, such as wheat,
barley, rye and probably oat, and in other cereals of
less frequent consumption, like spelt (dinkel wheat)
or triticale (hybrid of wheat and rye)5. Gluten can
cause neurological damage through a combination of
antibodies of crossed-reaction, causing complex immune diseases and direct toxicity6. Although its relation to some toxicity and hiper-allergenicity, it is due
to broad use on food industry and due to its physical
and chemical characteristics, giving great viscosity
to food cooking6. The two major steps leading to diagnosis of CD are: 1) blood test for gluten autoantibodies (IgA, anti-endomysial, tTG, deamidated gliadin peptide) and 2) a small bowel biopsy to assess
gut damage. Gene test alone are not used to diagnose
CD, they can only exclude the probability of developing the disease7.
Many immunopathogenic mechanisms and different antibodies associated with gluten have been
described as capable of crossing the blood-brain
barrier and deposit at the level of the Purkinje cells,
where they produce a marked inflammatory response
followed by neuronal degeneration and cerebellar
atrophy2. Some patients with MS show high levels
of anti-tTG-2 antibodies, which was said before, it
seems to be an important serological marker in the
diagnosis of the disease2. MS and CD are considered
T-cell-mediated autoimmune diseases, and the involvement of Th1 cells in their pathogenesis has also
been suggested. However, in CD, activated HLA-restricted gliadin-specific T cells and antigliadin antibodies (AGA) are found systemically. AGA might be
responsible for white-matter abnormalities1.
As gluten sensitivity shows concurrence with
neurological manifestations like white-matter lesions, MS has been studied because of the association with gluten sensitivity, as it might be suggested
by the etiology of “atypical” primary progressive
MS8.
Based on the possible association of MS with
other autoimmune processes, we briefly review studies relating MS to CD and whether a GFD should be
considered or not in these patients.
Records
screened
(n=47)
Full text articles
assessed for
eligibility (n=22)
Titles excluded (n=25) due to:
-Not related to the topic (n=14)
-Older than 30 years (n=10)
-Studies in animals (n=1)
Full text articles excluded
(n=5) due to:
-Irrelevant focus (n=5)
Studies
included
(n=17)
Figure 1 PRISMA diagram demonstrating the search
strategy and its results.
Revisión
Fields]
OR
“gliadin”[MeSH
Terms]
OR
“gliadin”[All
Fields]
OR
“glutenin”[MeSH
Terms] OR “glutenin”[All Fields]) AND (“multiple sclerosis”[MeSH Terms] OR (“multiple”[All
Fields] AND “sclerosis”[All Fields]) OR “multiple
sclerosis”[All Fields]) AND (Case Reports[ptyp]
OR Randomized Controlled Trial[ptyp] OR
Overall[ptyp] OR Observational Study[ptyp]
OR Multicenter Study[ptyp] OR Comparative
Study[ptyp] OR Clinical Trial[ptyp] OR Clinical Trial, Phase I[ptyp] OR Controlled Clinical Trial[ptyp]).
13
Inclusion/Exclusion criteria:
The following types of studies were included:
related to the aims, studies that reported presence
of CD or non-celiac gluten sensivity (NCGS) in patients, cohort or case-control studies, case-reports,
crossover, controlled trials and randomized clinical
trials.
The exclusion criteria were as follows: duplicated studies or non-related with the topic, controversial
biomarkers to get and support results or conclusions,
reviews, opinions, expert’s opinions, letters, conference papers and editorial papers.
❑❑Results
20
Search results
A total of 48 articles were retrieved in this systematic review. After reading all the articles we were
led to the exclusion of 29 of them for not following
the proposed criteria or being duplicated. Thus, only
17 studies were considered legible for systematic review and have been included after a double revision.
The characteristics of those directly related with gluten and MS are described in Table I.
❑❑Discussion
A possible relationship between the presence of AGA
in gluten intolerance and the incidence of MS has
been debated since the 1960s9, 10. It’s been suggested
that antibodies directed against gluten and gliadin in
wheat may play a role in the pathogenesis of MS by
affecting the permeability of the blood-brain barrier11. Currently, controversial data are available about
efficacy of a GFD in alleviating MS manifestations,
which needs additional studies12.
Gluten-related disorders are a spectrum of systemic immune mediated conditions that occur at any
age in genetically susceptible individuals upon ingesting gluten13. Rodrigo L et al. found a high prevalence of CD (OR: 5.33; CI-95%: 1.07-26.45) among
MS patients (11.1%), 5-10 times higher than the frequency found in the general population2. NevertheREVISTA ESPAÑOLA DE ESCLEROSIS MÚLTIPLE
less, they have not found any differences between the
DQ2 and DQ8 genetic markers in patients and control groups. They also discovered several duodenal
lesions in 29% of MS patients and mild villous atrophy in 11.1% of them2. All of these findings, altogether with the high prevalence of CD in first-degree
relatives (32%)2 support that cryptic gluten sensitivity may be involved in the pathogenesis of MS14.
These two diseases, MS and CD, share some
human leukocyte antigens (HLA)15. The structural and functional properties of HLA-DQ and -DR
molecules that confer susceptibility to several common autoimmune diseases, such as MS, have been
defined. The relevant polymorphisms directly affect
interaction with peptides, which provides strong support for the hypothesis that these diseases are peptide-antigen driven15. Several studies indicate that
structural modifications of peptides can affect major
histocompatibility complex class II binding and/or Tcell receptors recognition and should be considered
in the analysis of T-cell responses in autoimmune
diseases16.
The cause of neurological manifestations regarding gluten is still unclear, but it has been suggested
that the resulting autoimmunity of the molecular
mimicry between gliadin and proteins on the nervous
system has an important role17, 18.
Multiple changes in antibodies against various
antigens are found in MS19. Patients with neurological disease sometimes present with antigliadin and
anti-tTG antibodies9, 20. The association between
these antibodies and MS has been previously suggested: Shor DB et al.9 found a highly significant
increase in IgG antibodies against gliadin and tissue
ansglutaminase titers in MS patients. A study from
Norway has reported significantly higher serum levels of AGA in the MS group compared to a control
group19. IgA antibodies against casein were significantly increased, while anti-endomycium and tTG
antibodies were negative19. Pengiran Tengah CD et
al.21 found IgA anti-endomysial antibody in 2% of
MS patients. IgG anti-gliadin antibody was found in
12% of patients and 13% of blood donors, concluding that anti-gliadin antibody (especially IgG isotype) can be a non-specific finding.
Contrary to the studies mentioned above, in a
study conducted by Borhani A et al., no significant
differences in serum levels of AGA were detected
between MS patients and normal controls22. None of
the 217 patients with MS of Nicoletti A et al.23 study
presented IgG and IgA anti-gliadin, anti-endomysial
antibodies, anti-tissue transglutaminase and antireticulin; therefore data did not show an increased
frequency of celiac disease among patients with MS.
Finally, in a study performed by Rodrigo L et al.2,
HernándezLahoz C,
Rodríguez S,
Tuñón A,
et al.31
2009
2011
Rodrigo L,
HernándezLahoz C,
Fuentes D, et al.2
2013
Case report
Prospective
observational
study
Case report
72 RRMS
Clinical Trial
Batur-Caglayan
HZ, Irkec C,
Yildirim-Capraz
I, et al.1
1
Case report
Azizi Z, Ebrahimi 2014
Daryani N,
Rezaii Salim M,
et al.12
2014
Rodrigo L,
HernándezLahoz C,
Fuentes D,
et al.30
1
72 MS
126 first-degree
relatives
123 healthy controls.
1
1
Case report
2014
Finsterer J,
Leutmezer F.4
N Sample
Methodology
Year
Authors
TABLE I
MS and CD are considered
T-cell-mediated autoimmune
diseases, and the involvement
of Th1 cells in their pathogenesis
is suggested. Gluten sensitivity
might be the etiology of “atypical”
primary progressive MS.
Prevalence of gluten intolerance
is 5.5 to 11 times higher in MS
patients than in the general
population. A GFD should be
considered for any MS patient.
Is it a CD with secondary CNS
lesions that are confused with those
of EM and responds favorably to the
GFD, or, rather, we are facing the
neuroprotective effect of GFD on a
RRMS, which also has an associated
CD remitting under GFD?
CD may mimic MS and may be
present despite the absence of
AGA, endomysial or tTG
antibodies. Authors end up
referring the patient has CD
not a MS.
The patient improved secondary
clinic of CD (digestive and clinical
iron deficiency). No mention of the
course of MS is made.
GFD has shown a neuro-protective
effect in RRMS patients.
Conclusion
Quantification of tTG-2 by commercial
ELISA. Genetic markers HLA-DQ2
and HLA-DQ8, by PCR using specific
primers and a commercial kit.
Upper gastrointestinal endoscopy with
multiple biopsies from the first and
second portion of the duodenum.
No
Serological and CD genetic markers,
together with an upper GI endoscopy
with multiple duodenal biopsies.
tTG levels. HLA-II typing.
Duodenal biopsy.
Yes
Yes
Yes
No
Upper endoscopy with small
bowel biopsy
No
Was CD and NCGS
diagnosed?
Yes
CD and
NCGS
included
No
Characteristics and results of gluten and MS related studies
No
Yes
Yes
Yes
No
No
3
2+
3
2++
3
3
Association
study
Prospective
study
Association
study
Prospective
study
Association
study
Association
study
Positive Evidence Objective and
results
characteristics
21
Descriptive
study (Selfadministered
postal survey)
A- Case Report
B- Cross-sectional study
Cross-sectional
study
Case report
Cross-sectional
study
2009
2008
2007
2007
Leong EM,
Semple SJ,
Angley M,
et al.33
Frisullo G,
Nociti V,
Iorio R,
et al.26
Nicoletti A,
Patti F, Lo
Fermo S, et al.25
Trucco Aguirre
E, Olano
Gossweiler C,
Mendez Pereira
C, et al.15
Alaedini A,
Okamoto H,
Briani C,
et al.17
Cross-sectional
study
2009
Shor DB,
Barzilai O,
Ram M,
et al.9
2008
Methodology
Year
9 CD patients and
elevated levels of
IgG and/or IgA AGA
9 patients with
neurologic disease
(3 with MS) without
AGA 4 healthy
subjects.
1
217 MS
200 controls
A- 1 MS-CD
B- 30 relapsingremmiting MS (15
in the acute (relapse)
and 15 in the stable
phase (remission)
of disease)
20 controls.
416
161 MS
166 controls
N Sample
AGA response in immunized animals
and CD patients can cross-react with
the synapsin I protein. Such
cross-reactivity may provide clues
into the pathogenic mechanism of
the neurologic deficits that are
associated with gluten sensitivity.
In the MS-CD patient the cognate
interactions that occur between
T-bet expressing B and T cells
during the exacerbation of
neurologic symptoms may enhance
type1 immunity and increase
pathology. Thus, the interaction
between MS- and CD-related
inflammatory processes may
result in an amplification of Th1
immune response.
Data did not show an increased
frequency of CD among patients
with MS.
SSc and CD share some HLA
antigens.
Neither IgG nor IgA AGA showed
significant differences between
MS patients and controls. Gluten
sensitivity is not associated with
MS in Iran.
The majority of people with MS
reported using dietary interventions
(64.7%), including GFD (16.4%).
Conclusion
Yes
Yes
Yes
Yes
No
CD and
NCGS
included
Yes
Biopsy-proven, IgG / IgA
Serology and biopsy
IgG and IgA AGA, anti-endomysial
antibodies, tTG and anti-reticulin
No
IgG and IgA AGA by enzyme immuno
assay (EIA). The test of IgA tTG and
duodenal biopsy were carried out in
patients with either IgA or IgG AGA
positive sera.
No
Was CD and NCGS
diagnosed?
Yes
Yes
No
Yes
Yes
No
2-
3
2+
2-
2-
2+
Intervention
study
Association
study
Intervention
study
Intervention
study
Association
study
Intervention
study
results
characteristics
13
Authors
Characteristics and results of gluten and MS related studies (continuation)
22
TABLE I
Revisión
Cross-sectional
study
Cross-sectional
study
1998
1996
Hadjivassiliou
M, Gibson A,
Davies-Jones
GA, et al.10
Descriptive
study
2002
Volta U, De
Giorgio R,
Petrolini N,
et al.32
Pratesi R,
Gandolfi L,
Friedman H,
et al.11
Cross-sectional
study
2004
Reichelt KL,
Jensen D.19
Methodology
Cross-sectional
study
Year
Pengiran Tengah 2004
CD, Lock RJ,
Unsworth DJ,
et al.21
Authors
TABLE I
4 active CD on a
gluten-containing
diet (3 F, 1 M)
11 biopsy proven
CD on a GFD
(9 F, 2M)
52 non-coeliac
controls (26 F,
26 M)
53 neurological
dysfunction of
unknown cause
94 specific
neurological
diagnosis
(12 with MS)
50 healthy
blood donors.
160 (120 F, 40 M),
1 with MS.
36 MS (21 F, 15 M)
26 controls
49 (33 F, 16 M)
30 anonymous blood
donors (15 female)
used as serologic
controls.
N Sample
Biopsy proven
Serum IgG and IgA antigliadin antibodies,
using ELISA
Yes
Yes
Yes
CD can sometimes present
in the guise of a neurological
disorder, which may
greatly improve when
a GFD is started
promptly.
Sera from patients with active
CD contain IgA antibodies that
react with human brain vessel
structures. These antibodies
are not present in sera from
CD patients on a GFD or
non-coeliac controls.
Gluten sensitivity is common
in patients with neurological
disease of unknown cause and
may have aetiological significance.
No positive results were explicitly
reported for MS patients.
No
Yes
IgA antibodies were measured in serum
Yes
against gluten, gliadin, lactoglobulin, lactalbumin, casein and ovalbumin in patients with
MS and controls using ELISA technique.
IgG was likewise measured for gluten
and gliadin.
CD-related antibodies (AGA, anti-endomysial Yes
and anti-human recombinant tissue
transglutaminase (h-tTG). Diagnosis
of CD was confirmed by endoscopic
duodenal biopsy.
2-
2-
2-
2-
Intervention
study
Intervention
study
Association
study / Intervention study
Intervention
study
Intervention
study
No
AGA (IgG and IgA) and IgA anti-tTG were
detected by ELISA
2-
results
characteristics
Was CD and NCGS
diagnosed?
Yes
CD and
NCGS
included
Yes
There may be a possible
moderately increased uptake of
some specific proteins from the
gut in MS compared with controls.
16% of MS patients and 17% of
blood donor controls had AGA,
mainly IgG isotype, reflecting the
long-established poor disease
specificity for IgG AGA.
Conclusion
Characteristics and results of gluten and MS related studies (continuation)
23
Revisión
13
24
high serum levels of anti-tTG-2 antibodies were observed in relapsing-remitting MS patients and their
first-degree relatives compared to health controls.
This study failed to report the role of serological gluten markers in the pathogenesis of MS2.
All this findings support the associations between AGA and tTG to MS; although the specific
role of these antibodies in the pathogenesis of MS
remains uncertain and requires additional research.
The following mechanism is suggested to explain
the neuronal connection which could affect MS:
High AGA levels and have been associated with idiopathic neuropathy. It has been demonstrated that
serum given to patients suffering from neurological symptoms and AGA attach to the neural tissue,
which implies that the antibody has a crossed-reaction with auto-antigens. The crossed-reaction doublet was identified as a “synapsin I”, a member of
a neuronal phosphoprotein´s group involved in the
regulation of neurotransmitter´s release17. The same
authors found out that human and animal AGA can
have a crossed-reaction with synapsin I, a cytosolic
phosphoprotein found in the majority of neurons of
the central and peripheral neural systems. The similarity between synapsin I and gliadin is based on the
fact that both have high frequency regions of proline
and glutamine residues. The presence of this amino
acids sequences could be responsible for the crossreactivity observed in AGA. The interruption of the
activity of synapsin I indicates that it is necessary
for the formation and maintenance of the reserve of
synaptic vesicles and, therefore, the regulation of
neurotransmitter´s release. More specifically, the
union between anti-synapsin I and antibodies has
proved to reduce the post-tetanic potentiation and to
increase the speed and extension of the synaptic depression17.
Other authors, such as Frisullo G et al.24 found
in MS-CD patients that the interaction between MSand CD-related inflammatory processes may result
in an amplification of Th1 immune response. They
showed in their patients a strong increased expression of T-bet, the key transcription factor for the
development of Th1 cells, in circulating T, B cells
and monocytes. Conversely, no difference of T-bet
expression was observed in B cells from relapsingremitting MS patients, neither in relapse or in remission, nor in controls24.
concluding that high consumption of bread and pasta
correlated positively with MS. A study from Croatia also reported more frequent wheat and rye bread
consumption among MS cases, although this difference was not statistically significant. However, one
study found no significant difference in the intake
of gluten-containing products between MS subjects
and controls, and another small case-control study
observed no difference in bread and cereal intakes
between cases and controls. Yet another case-control
study found a protective effect of higher cereal and
bread intake on risk of MS. Bowling AC et al.26 sustaining there are no diets, specifically GFD, or dietary supplements that are definitely effective in altering the disease course in MS.
On the contrary, it is suggested that treatment
with a GFD can provide considerable benefits to the
patients having both a gluten-related disorder and demyelinating diseases of the CNS12, 27.
The response of the GFD was excellent, both
from the digestive and the neurologic point of view
in the average follow-up period of three years long
in Rodrigo L et al. study2. Similar results were obtained in other studies of the same author28, 29: a
GFD has a neuroprotective role in the majority of
MS patients, especially improving the physical capacity and the activity of lesions seen on MRI.
Volta U et al.30 investigated neurological symptoms
in 160 consecutive patients (120 female, 40 male)
with biopsy-proven CD. Neurological symptoms
improved or disappeared in 7 patients who started a
GFD within 6 months after neurological onset, and
in none of 4 patients who began later. MS patients
from Leong EM et al.31 study reported using dietary
interventions (64.7%) including GFD (16.4%) to alleviate ‘general’ as well as specific MS symptoms
such as muscle weakness, urinary or memory problems and mobility, besides looking for better general health and well-being. This suggests that neurological disorders may greatly improve when a GFD
is promptly started.
It is worth mentioning that the included studies
show, overall, a low-medium degree of evidence32,
due to their designs. Furthermore, in some studies,
authors did not report clearly the presence or absence
of CD or NCGS (and the procedures for diagnosis),
which can distort the associations suggested by the
authors.
❑❑Gluten intake
❑❑Conclusion
Evidence is torn between the fact that higher gluten
consumption is a risk factor for MS25: one study reported significantly higher intake of cereal-derived
products by MS subjects when compared to controls,
Based on the present review, there is low-medium
evidence relating MS, CD and gluten intake, with
not enough harmony in the results. Low grade of evidence was also found in the study’s designs.
Studies have found an increased incidence of immunoglobulin A and G antibodies from exposure to
both gluten and gliadin among MS patients, sometimes highly significant, compared with controls,
while others have found no association.
Evaluating if any specific diet benefits a particular MS patient is difficult due to the unpredictable
nature of flare-ups and the long-term progression of
the disease. But in MS-CD patients, treatment with
GFD should be considered, given that it has not been
shown to be harmful.
Continued studies, specially randomized clinical trials, of these individuals with multiple autoimmune disorders are necessary to help identify shared
genetic susceptibility and to apply for the appropriate
treatment strategies for patients.
Ethical standards
Conflict of interests: authors declare they have no conflict of interest.
Abbreviations
AGA: Anti-gliadin antibodies; CD: Celiac disease; CNS: Central nervous system; GFD: Gluten-free diet; HLA: Human leukocyte antigens; IgA: Immunoglobulin A; IgG: Immunoglobulin G; NCGS: non-celiac gluten sensivity; MRI: Magnetic resonance imaging; MS: Multiple sclerosis; RRMS: relapsing-remitting form of MS; tTG: anti-tissue transglutaminase.
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Can gluten affect multiple sclerosis?

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