Special Article

Adverse effects of gluten ingestion and advantages of gluten

withdrawal in nonceliac autoimmune disease
Aaron Lerner, Yehuda Shoenfeld, and Torsten Matthias

In light of the coincident surge in overall gluten intake and the incidence of autoim-
mune diseases, the possible biological adverse effects of gluten were explored.
PubMed, MEDLINE, and the Cochrane Library databases were screened for reports

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published between 1964 and 2016 regarding the adverse effects of gluten as well
as the effects of a gluten-free diet on autoimmune diseases. In vitro and in vivo
studies describing gluten intake in animal models or cell lines and gluten-free diets
in human autoimmune diseases were reviewed. Multiple detrimental aspects of glu-
ten affect human health, including gluten-dependent digestive and extradigestive
manifestations mediated by potentially immunological or toxic reactions that in-
duce gastrointestinal inadequacy. Gluten affects the microbiome and increases in-
testinal permeability. It boosts oxidative stress and affects epigenetic behavior. It is
also immunogenic, cytotoxic, and proinflammatory. Gluten intake increases apo-
ptosis and decreases cell viability and differentiation. In certain nonceliac autoim-
mune diseases, gluten-free diets may help curtail the adverse effects of gluten.
Additional in vivo studies are needed to unravel the puzzle of gluten effects in
humans and to explore the potential beneficial effects of gluten-free diets in auto-
immune diseases.

INTRODUCTION Increased consumption of gluten

Gluten is the main protein in wheat, constituting ap-
proximately 80% of the total proteins in this grain. The
remaining 20%—albumins and globulins; multiple
enzymes such as b-amylases, uridine diphosphate
glucose pyrophosphorylases, peroxidases, and thiore-
doxins; amylase-trypsin inhibitors; puroindolines; heat-
shock proteins; and proteins involved in response to
stress— are outside the scope of this review. Wheat also
contains nonprotein components like fermentable,
oligo-, di-, and monosaccharides and polyols
(FODMAPs). Not surprisingly, gluten peptides are also
contained in other nonwheat cereals like barley, rye,
and oats.1
Wheat is an important food in human nutrition, and
wheat- or gluten-containing foods are common in
Western diets. Wheat grain is easy to stockpile and con-
venient to grind into flour, which improves its texture,
and palatability. According to the Food and Agriculture
Organization of the United Nations, worldwide produc-
tion of wheat increased from 711.4 million metric tons
in 2013 to 750.1 million metric tons in 2017 (as of
October 5, 2017).2 Gluten is a major food additive in
the processed food industry, with a net increase in usage
of 1.8 6 0.4% per year reported over the last 30 years1
Currently, both the prevalence and the incidence of
gluten-related disorders are surging in many countries

Affiliation: A. Lerner is with the B. Rappaport School of Medicine, Technion–Israel Institute of Technology, Haifa, Israel. Y. Shoenfeld is with
the Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center–Tel Hashomer, Ramat Gan, Israel, and the Sackler Faculty of
Medicine, Tel-Aviv University, Tel-Aviv, Israel. A. Lerner and T. Matthias are with the AESKU.KIPP Institute, Wendelsheim, Germany
Correspondence: A. Lerner, AESKU.KIPP Institute, Mikroforum Ring 2, Wendelsheim 55234, Germany. Email: aaronlerner1948@gmail.com.
Key words: adverse effect, autoimmunity, biological effects, celiac disease, gluten-free diet.
C The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute.
V
All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

doi: 10.1093/nutrit/nux054
1046 Nutrition ReviewsV Vol. 75(12):1046–1058
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worldwide.3–7 The reasons most frequently suggested
include the spread of the Western diet,1 the increased
consumption of gluten-containing diets,8 the gradual
shift toward increased production and consumption of
wheat, which is replacing the traditional food of rice in
Asia and Africa,9 and the evolutionary development of
wheat with higher gluten content and cytotoxic proper-
ties.10,11 Even advanced food-processing technology,
which reduces dough fermentation time, can increase
gluten concentration in commercial bakery prod-
ucts.10,12 It is estimated that, in the 20th century, global
wheat output increased 5-fold, with most of the increase
occurring after 1955.4 In parallel, the prevalence of
celiac disease increased 5-fold in the United States be-
tween 1974 and 1989.13 On the other hand, in a 2014
US Consumer Reports survey, 63% of responders felt
that abstaining from bread and other gluten-containing
diets would enhance their physical or mental health.
Moreover, in a 2015 Gallup poll, 21% of Americans dis-
closed they tried to follow a gluten-free diet.14
Increased frequency of autoimmune disease
Increasing evidence demonstrates a continuous rise in
the incidence of autoimmune diseases.3 The incidence of
rheumatic, endocrinological, gastrointestinal, and neuro-
logical autoimmune diseases has increased annually, at
rates ranging from 3.7% to 7.1%, between 1985 and
2015.3 These observations, together with the fact that only
1% to 3% of the 30% of the general population that carries
the human leukocyte antigen DQ 2/8 allele will develop
celiac disease, strengthen the hypothesis that the environ-
ment plays a more important role than genetics, in the
development of autoimmune diseases, in the last
decades.3,4,15 The increased incidence of celiac disease has
been linked to increased gluten consumption.4,15 However,
some evidence indicates that gluten might be related to the
increased incidence of other, nonceliac autoimmune dis-
eases. The parallel surge in gluten consumption3,15 and the
increased incidence of autoimmune diseases prompted a
review of the current knowledge about the disadvantages
of dietary gluten and the role of gluten-free diets in the nu-
tritional therapy of autoimmune diseases.
METHODS
The first part of this review addresses the effects of glu-
ten on cell lines of human origin in vitro and on animal
models in vivo, since in vivo studies in humans are
scarce. The second part addresses the effects of gluten-
free diets in various autoimmune diseases. The litera-
ture search covered the period 1964–2016 and included
studies that describe the following: (1) effects of gluten
intake by animals, (2) in vitro effects of gluten on cell
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lines, and (3) effects of gluten-free diets on nonceliac
autoimmune diseases in humans.
Research studies, reviews, and case–control series
were included, while case reports were excluded. The liter-
ature search was performed using the PubMed,
MEDLINE, Embase, Scopus, and Cochrane Database of
Systematic Reviews databases to identify the most relevant
information.
The following search algorithm was used (“gluten
side effect” or “gluten adverse effects” or “gluten
treatment” or “gluten therapy” or “gluten application”)
AND (“human” or “animal” or “cell-line”) AND
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(“gluten”) or (“gliadin”) AND (“autoimmune disease”).
Type 1 diabetes, multiple sclerosis, psoriasis, rheu-
matoid arthritis, autoimmune hepatitis, celiac hepatitis,
autoimmune thyroiditis, and autoimmune diseases
were searched separately for gluten or gluten-free diets.
Additional studies were identified by examining the ref-
erence list of the retrieved articles. The search was lim-
ited to articles published in English. Altogether, 251
publications were identified. Relevant articles were se-
lected for full-text review on the basis of screened titles
and abstracts. Since primary data was not collected, eth-
ical approval was not mandatory.
DIRECT IMMUNE EFFECTS OF GLUTEN IN
ANIMAL STUDIES
Direct effects of gluten on dendritic cells and innate
immune systems in mice
The innate immune system plays a critical role in oral tol-
erance to nutritional antigens. In experiments with
BALB/c and nonobese diabetic (NOD) mice, gluten-free
diets increased both the percentage of macrophages in the
spleen of BALB/c mice and the percentage of CD11cþ
dendritic cells in the spleen of BALB/c and NOD mice.
Moreover, gluten-free diets increased the percentage of
CD103þ dendritic cells in BALB/c mice and decreased the
percentage of CD11bþ dendritic cells in their mesenteric
lymph nodes. Gluten-free diets in BALB/c mice attenuated
the exposure of dendritic cells to CD40, CCR7, and major
histocompatibility complex II in pancreatic lymph nodes.
These results help to explain the low incidence of diabetes
in gluten-free NOD mice, in which gluten might play a di-
abetogenic role. This pathway might be essential in the
progression of type 1 diabetes (T1D), celiac disease, and
nonceliac gluten sensitivity.16
Direct effects of gluten on cytokine production and
cytotoxicity of natural killer cells
Larsen et al.17 have shown that gluten-containing diets
drive an increased expression and cytotoxicity of
1047
natural killer cells toward pancreatic beta-cell line
MIN6 cells, higher expression NKG2D and CD71 on
NKp46(þ) cells in all lymphoid organs of BALB/c and
NOD mice. Gluten ingestion augments the secretion of
both IFN-c and IL-6 to a greater degree in BALB/c and
NOD mice than in mice fed gluten-free diets, suggest-
ing that gluten intake induces murine natural killer cell
activity toward pancreatic beta cells. This may reinforce
the progression of T1D and help explain the increased
incidence of disease associated with gluten consump-
tion in NOD mice.17
Direct effects of gluten on the Th17 pathway
and T regulatory cells
Cytokine-secreting Th17 cells are associated with auto-
immunity. The Th17 profile is substantially increased in
the pancreatic lymph nodes of BALB/c gluten-fed mice,
parallel to the increased populations of CD4þ,
CD45RBhighþ, and CD103þ T cells. This indicates that
gluten intake impacts multiple subsets of T regulatory
cells as well as Th17 cells in the mucosal lymphoid
tissue.18
Closure of ATP-sensitive potassium channels
and induction of insulin release
The incidence of diabetes is reduced by a gluten-free
diet in the NOD murine model.19 Gluten peptides, such
as gliadin, can cross the intestinal barrier and may di-
rectly affect the beta cells of the endocrine pancreas. In
INS-1E cells and in isolated rat islets, the application of
gliadin peptides induced a dose-related surge in insulin
delivery and decreased electrical currents through ATP-
sensitive potassium channels.19 This data may indicate
gliadin fragments as modulators responsible for the
activation of beta cells activity in the late stages of T1D.
Induction of neutrophil migration
Gliadin induces the secretion of interleukin (IL) 8, a
powerful neutrophil-activating and chemoattractant
chemokine. Recently, gliadin was shown to exhibit neu-
trophil chemoattractant capabilities similar to those of
the classical neutrophil chemoattractant, N-formyl-
methionyl-leucyl-phenylalanine (fMet-Leu-Phe), and
likewise uses the formyl peptide receptor 1 to induce
migration.20
Induction of expression of the activating receptor
natural killer group 2D and its ligands
Enteric expression of the activating receptor natural
killer group 2D (CD314) and its ligands is a marker of
1048
intestinal autoimmunity. In studies of enteric and pan-
creatic islets in BALB/c and NOD mice, gluten-free
diets decreased the expression of natural killer group
2D and its ligands.21 This immunological response may
lower T1D incidence associated with gluten-free diets
in animals and, potentially, in humans.
Induction of inflammation through Toll-like receptor 4
Animal and cell culture models have shown that gluten
peptides can induce inflammation by binding Toll-like
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receptor 4, thereby inducing the expression of proin-
flammatory cytokines such as IL-1, IL-6, and tumor ne-
crosis factor.22,23 Although these findings must still be
corroborated in humans, they suggest an intriguing hy-
pothesis, given the current trend toward increased use
of gluten-free diets. Table 116–18,20,21,24–38 summarizes
additional studies reporting in vivo and in vitro direct
effects of gluten intake on the immune system. Taken
together, the animal studies support the involvement of
gluten peptides in the innate and the regulatory im-
mune systems, on the Th17 and other proinflammatory
pathways and neutrophil migration. There are some
indications that gluten may be involved in the induction
of diabetes and autoimmune disorders. The following
section on adverse effects of gluten in humans might
shed additional light on the subject.
ADVERSE EFFECTS OF GLUTEN ON HUMAN HEALTH
The role of gluten in celiac disease is well established
and will not be described in this review. Yet gluten also
plays a role, though indirectly, in other nonceliac health
conditions.
Gliadin is an ideal substrate for endogenous tissue
transglutaminase and exogenous microbial transgluta-
minase, both of which belong to the extended transglu-
taminase family.39 Gluten is abundant in glutamine and
lysine and thus is a very attractive substrate for post-
translational modification of protein by both endoge-
nous tissue transglutaminase and exogenous microbial
transglutaminase. Both enzymes are able to deamidate
or cross-link gluten peptides to numerous other pepti-
des, thus turning naive, self-proteins into immunogenic
ones.40–44 Importantly, luminal microbial transglutami-
nase, derived from processed food or from the micro-
biome or, more specifically, from the dysbiome
(microbial imbalance), is a major cause of post-transla-
tional modification of gliadin or other naive proteins.45
Recently, it was hypothesized that the luminal transglu-
taminases, which originate in the dysbiome, are poten-
tial drivers of end-organ or systemic autoimmunity.46
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 Table 1 Direct in vivo and in vitro effects of gluten intake on the immune system
Reference Study Cell type or Effects of gluten intake
type animal model
Thomas et al. (2006),24 In vitro Macrophages Increases proinflammatory cytokine and nitric oxide
Tuckova et al. (2000),25 production
Tuckova (2002)26
Nikulina et al. (2004),27 In vitro Dendritic cells Upregulates MHC II, costimulatory molecules, Toll-like re-
Palova-Jelinkova et al. (2005),28 ceptor, cytokine, and chemokine production
Ciccocioppo et al. (2008)29
Larsen et al. (2014)17 In vitro Lymphoid organ Increases expression of NKG2D and CD71 on NKp46þ
cells
Gujral et al. (2015)30 In vitro Caco-2 Increases intestinal permeability, TNF-a, and IL-1b
production
Flohe et al. (2003),31 In vivo NOD mice Modifies Th1/Th2 intestinal cytokines

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Alam et al. (2010)32
Alam et al. (2010)32
Scott et al. (2002)33
Scott et al. (1997)34
Antvorskov et al. (2012)18
Antvorskov et al. (2012)18
Antvorskov et al. (2013),35
Bernardo et al. (2007) 36
Antvorskov et al. (2012)18
Larsen et al. (2015)16
Larsen et al. (2014)17
Adlercreutz et al. (2014)21
Palova-Jelinkova et al. (2013)37
Lammers et al. (2015)20
Stepankova et al. (1996)38
Abbreviations: IL, interleukin; IFN, interferon; KO, knockout; MHC, major histocompatibility complex; MLN, mesenteric lymph node; Th,
T helper; TNF, tumor necrosis factor.
In vivo NOD mice Increases counts of activated intestinal CD4þ T cells, den-
dritic cells, and Th17 cells
In vivo BB rats Modifies Th1 intestinal and MLN cytokines
In vivo BB rats Alters Th1 cytokine pattern in islet infiltrate
In vivo BALB/c mice Induces proportional changes in regulatory T-cell subsets
In vivo BALB/c mice Increases Th17 cell counts in peripheral lymph nodes
In vivo BALB/c mice Alters inflammatory cytokine pattern in FOX3 and
FOXP3þ T cells, activates innate immune response
In vivo BALB/c mice Increases Th17 cell counts, increases proportions of
CD4þCD45RBhighþ cells, increases CD103þ T-cell
counts
In vivo BALB/c and NOD mice Modulates dendritic cells and innate immune subsets in
mice
In vivo BALB/c and NOD mice Increases natural killer cell cytotoxicity and cytokine se-
cretion of IFN-c and IL-6
In vivo BALB/c and NOD mice Induces expression of NKG2D and ligands
In vivo NLRP/ ASC/ KO mice Induces IL-1b production in bone-marrow-derived den-
dritic cells
In vivo C57BL/6 and Lys-GFP mice Induces neutrophil migration
In vivo AVN Wistar rats Increases counts of pathogenic intraepithelial
lymphocytes

Immunogenicity of gluten immunoglobulin G (IgG), immunoglobulin A (IgA),

Antigliadin antibodies are age dependent and are found
in the normal population well as in patients with intesti-
nal and extraintestinal diseases.47–50 Antigliadin anti-
bodies may represent an epiphenomenon whereby the
immune system reacts against gluten peptides. Even in
the PreventCD intervention study, 30% of healthy
infants produced antibodies against gluten/gliadin with-
out anti–tissue transglutaminase antibodies shortly after
gluten introduction.51 In patients with rheumatoid ar-
thritis, a non–gluten-related condition, the intestinal
fluid and sera were significantly enriched with immu-
noglobulin M (IgM) antibodies against gliadin.44,52
When the immunogenicity of processed food products
vs their raw constituents was checked in normal sera,
titers of the specific corresponding immunoglobulins
were significantly higher against the processed prod-
ucts. When pizza, pasta, cereals, or bakery products
from supermarket shelves were checked, products con-
taining processed wheat provoked much higher
and IgM antibody responses than products containing
raw wheat. It is suggested that industrial processing of
wheat may enhance the immunogenicity of the protein
(gluten).53
Microbial transglutaminase docked by gluten pepti-
des is immunogenic in celiac disease.40 Microbial
transglutaminase–modified gluten proteins react with
IgA antigliadin antibodies in the sera of patients with
celiac disease. Microbial transglutaminase–treated glu-
ten peptides cultured with intestinal biopsies from
patients with celiac disease induced a substantial release
of interferon-! accompanied by a surge in anti–tissue
transglutaminase and antiendomysial autoantibodies,
suggesting that those gluten peptides are proinflamma-
tory and immunogenic, at least ex vivo. Interestingly, in
sera from celiac patients, IgA antibodies were higher
against wheat from microbial-transglutaminase-treated
breads than against gluten-free breads not treated with
microbial transglutaminase. Moreover, microbial-
transglutaminase-deamidated gluten peptides react with

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1049
gluten-selected T cells, thus boosting the immunogenic-
ity of gluten.40 It appears that commercially available
products contain certain quantities of microbial trans-
glutaminase, implying that microbial transglutaminase
used during food processing is eaten by consumers and
eventually finds its way to the gut lumen.54
Immunogenicity of gliadin when docked on tissue
transglutaminase or microbial transglutaminase
Even in celiac disease, neoepitopes generated by the
docking of gliadin onto tissue transglutaminase and
microbial transglutaminase are more immunogenic than
undocked gliadin. Compared with conventional tissue
transglutaminase isotypes, the tissue transglutaminase
neoepitope IgA þ IgG isotype (detected by AESKULISA,
CeliCheck New Generation, Wendelsheim, Germany)
has a higher optical density value, more accurately
reflects intestinal injury, has higher sensitivity and specif-
icity, and targets different autoantigens.55,56 The same
was found for the microbial transglutaminase
neoepitope.57
Pathogenicity of gluten in HCT116 cells
When applied to HCT116 cells, gliadin reduced cell via-
bility by 50% (P < 0.05), induced lactic dehydrogenase
secretion over time (P < 0.01), and increased apoptosis
significantly (A.L. and T.M., unpublished data, 2016).
These effects of gliadin are supported by multiple stud-
ies in cell lines of human origin. Decreased viability,58,59
necrosis and/or lactic dehydrogenase release,59 and in-
duction of apoptosis59–61 have been described.
Ability of gliadin to increase intestinal permeability
Tight-junction integrity is breached in multiple autoim-
mune diseases, including celiac disease.62,63 Numerous
in vitro, ex vivo, and in vivo studies have confirmed that
gliadin, the main antigen of gluten, increases intestinal
permeability.64,65 After binding to its chemokine receptor
CXCR3 on epithelial cells, gliadin activates the MyD88-
pathway, resulting in the release of zonulin. Gliadin has
agglutinating activity, polymerizes soluble G- and F-
actins, inhibits cell proliferation, is proapoptotic,
decreases redox potential, affects the rearrangement of
the enterocyte cytoskeleton, and induces zonulin secre-
tion, resulting in increased gut leakage.63,65
Most recently, studies of epithelial transit of immu-
nogenic and toxic gliadin peptides have shown en-
hanced luminal degradation of the peptides,
highlighting the importance of the epithelial barrier
against shorter gliadin peptides.66 In summary, gluten
and gliadin induce multiple adverse effects, owing to
1050
their capacity as substrates for enzymatic post transla-
tional modification of proteins their immunogenicity
(whether alone or complexed), their ability to reduce
cell viability, their necrotogenic and apoptotic proper-
ties, and their ability to breach tight-junction integrity.
Effects of gluten on the microbiome
Human beings are host to a multiform but host-specific
gut microbial population along the proximal-to-distal
axis of the intestine. Analysis of the microbiota in the
large intestine has shown that nutrition affects the lumi-
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nal bacteria, and together affect the host’s well-being.
Does gluten affect the intestinal ecosystem? The answer
is yes.
When NOD mice were fed a gluten-free diet, num-
bers of cecal microbes and gram-positive bacteria were
lower than those in mice fed a standard gluten-
containing diet.67,68 Recently, Antvorskov et al.67 and
Marietta et al.69 showed that gluten-containing diets in-
creased the numbers of Bifidobacterium, Tannerella,
and Barnesiella species in the intestinal flora of NOD
mice, whereas gluten-free diets resulted in increased
counts of Akkermansia species. It appears that the
microbiome is altered in celiac disease, as a richer,
more diverse microbiome has been observed.70 As
stated recently by Sanz,70 “disease-associated alterations
in microbiome-derived metabolites could not only re-
flect intestinal dysbiosis but also contribute to dysfunc-
tion of the immunoregulatory mechanism.” However,
in celiac disease, the situation is more complex, since
crosstalk between the host genome and members of the
microbiota related to the development of celiac disease
was recently observed.44,71
The precise pathomechanisms that determine how
gluten impacts the intestinal ecosystem are not well un-
derstood, but several potential mechanisms, described
below, have been offered.
Gluten-induced dysbiosis is accompanied by a
breach in the tight-junction barrier and the induction
of several inflammation-associated microRNAs.72 In
addition, the crosstalk between the enteric microbiota
and the intestinal epithelium is mediated by receptors
shared with the innate immune system. Thus, gluten-
induced dysbiosis may contribute to the activation of
this inflammatory pathway. Patients with celiac disease
are known to have fewer beneficial gut species and a
greater number of potentially pathogenic ones com-
pared with healthy controls. Gluten-free diets reduce
this dysbiosis, although it is not eliminated.73
Additionally, dietary factors, such as meat-containing
or vegetarian diets or the presence or absence of gluten
in the diet, can affect a number of taxa in the lumen
and influence multiple bacterial pathways, especially
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those involved specifically in carbohydrate and starch
metabolism. Variation in the diet, including the intro-
duction of gluten-free diets, could affect the composi-
tion of the microbiome, even in normal volunteers.74
There are also other potential mechanisms by which
gluten might impact luminal conditions. Compared with
healthy controls, untreated and treated patients with celiac
disease showed evidence of gluten-induced dysbiosis at the
duodenal and/or the fecal level.74,75 The ratio of protective
antiinflammatory microbes such as Lactobacillus and
Bifidobacterium to potentially harmful microbes like
Bacteroides and Enterobacteriaceae was lower in untreated
children than in children treated with a gluten-free diet.
Similar to observations in dysbiotic microbiota, serum, fe-
cal, and urinary metabolomes from patients with celiac dis-
ease showed abnormal levels of free amino acids and
volatile organic substances that may convey messages to
the mucosal wall. There is no consensus across studies with
regard to the specific microbes and/or metabolites in indi-
viduals with untreated or treated celiac disease.75 Finally, it
should be emphasized gluten affects the microbiome, but
the microbiome also affects gluten and might play a role in
the breakdown and immunogenicity of gluten.76
Induction of oxidative stress by gluten
Hudson et al.77 were the first to report the suppressed
growth and morphological alterations induced by appli-
cation of gliadin peptides to cell lines of human origin.
Gliadin induces agglutination of K562 cells, decreases
F-actin expression in intestine 407 cells, attenuates cell
viability and growth, is proapoptotic and affects redox
homeostasis in Caco-2 cells, alters the morphology of
LoVo cells and of cells in 2- and 3-dimensional cultures,
and induces restructuring of the cytoskeleton in intesti-
nal epithelial cell line 6.59 Glutathione is a crucial low-
molecular-weight molecule that affects redox status. Its
depletion perturbs cell homeostasis, triggering cytotox-
icity. In fact, the oxidative stress induced by gliadin was
demonstrated in multiple cell lines, including Caco-2,
HT29, SH-SY5Y, T84, and LoVo, and was reviewed ex-
tensively.59,78–80 The compromised antioxidant defense
mechanisms may exacerbate mucosal inflammation, po-
tentiating tissue damage and delaying the return of epi-
thelial cell layer integrity, not only in celiac disease but
also in other inflammatory conditions.
Effects of gluten on epigenetic programming
Epigenetic programming, including methylation and
histone modification, is affected by numerous environ-
mental factors, including nutrients.78,79 Altered expres-
sion of genes involving methylation homeostasis,
induced by gluten-derived peptides, was recently
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observed.78,79 Several aspects of the relation between
gliadins and epigenetics were observed not only in ce-
liac disease but also in nonceliac cells like SH-SY5Y, a
cell line of neuroblastoma origin, and Caco-2 cells.79
These results indicate the potential of gliadin peptides
to trigger antioxidant and epigenetic alterations that
may be crucial during the postnatal transition from
breastfeeding to gluten consumption.78,79 Most recently,
the involvement of the proinflammatory cytokine inter-
feron-c and the microbiota metabolome in switching
epigenetic behavior was described in celiac disease.81
Reduced antioxidant capacity and the epigenetic conse-
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quences of the gliadin-induced opioid activities may
predispose genetically susceptible individuals to inflam-
mation or autoimmunity, partially explaining the bene-
fits of gluten-free diets. In a more holistic way, the
oxidative stress, gene expression, and inflammation in-
duced by gluten-derived peptides during progression of
the autoimmune and inflammatory cascade are closely
related and interconnected.
Effects of gluten on cellular metabolism
In the 1990s, wheat-derived peptides were shown to af-
fect cell metabolism in Caco-2 cell lines. One study
reported that cell proliferation was inhibited by 50%,
colony-forming ability was decreased by 20%, and alka-
line phosphatase activity during cell differentiation was
decreased.82 Furthermore, peptic/tryptic digests from
wheat inhibited DNA and RNA synthesis by almost
80% and glycoprotein synthesis by close to 60%.83
Apoptosis induced by gliadin peptides was demon-
strated in several cell lines, including Caco-2, LoVo,
Hep-2, and MRC-5.59,61,84 The effects of prolamin-
derived antinutritional gliadin peptides, which include
antiproliferation, antidifferentiation, cellular agglutina-
tion, and synthesis of nucleic acids, can disturb cellular
metabolism and intestinal recovery in various enteric
inflammatory conditions and gluten-related diseases.
Effects of gluten on cognitive function
Gluten initiates an immune reaction and decomposes,
during luminal digestion, to peptides with opioid activ-
ity, which has multiple consequences on mental func-
tion and behavior in humans.85 Gluten-derived
peptides that exhibit strong opioid activities are called
exorphins. Exorphin receptors are widely scattered
throughout the body, at locations that include the gut,
the brain, and the nervous system. If the intestinal and
blood–brain barriers are disrupted by stress, dietary
components,40,63 alcohol, or over-the-counter drugs,
gluten-derived exorphins can impact cognitive
function.85
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 The ability of gluten to affect mental function is not
merely a hypothesis. Multiple studies have shown a high
prevalence of antigliadin antibodies in patients with
schizophrenia.86 Patients with autistic spectrum disor-
ders are affected by gluten intake. Gluten-free diets are
efficient in modulating both gastrointestinal symptoms
and behavior in patients with autistic spectrum disor-
der.87 Various risk factors for the progression of schizo-
phrenia can be related to a common pathway in the
intestinal tract. It is increasingly recognized that bidi-
rectional communication, involving neural, hormonal,
and immunological routes, exists between the brain and

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the gut. An increased incidence of gastrointestinal bar-
rier dysfunction, food antigen sensitivity, inflammation,
and the metabolic syndrome is seen in patients with
schizophrenia.86 These findings may be influenced by
the composition of the gut microbiota. A significant
subgroup of patients may benefit from adherence to a
gluten-free diet. Antimicrobial agents and probiotics
have therapeutic potential to attenuate the metabolic ab-
normalities and immune dysfunction encountered in
patients with schizophrenia.88 A form of gluten Figure 1 Autoimmune diseases that improve following gluten
psychosis—a clinical psychosis clearly related to gluten withdrawal. Abbreviations: AT, autoimmune thyroiditis; AH, auto-
immune hepatitis; MS, multiple sclerosis; PS, psoriasis; RA, rheuma-
consumption, which completely resolved after a gluten-
toid arthritis; T1D, type 1 diabetes.
free diet was implemented—has been described.89 Food
proteins, including gluten, affect the rates of synthesis of
non–human leukocyte antigen genes, it is conceivable that
amino acids and brain neurotransmitters in rats.90
this genetic load transfers some gluten-dependent toxicity
Prolonged gluten intake impairs cognitive performance
to other autoimmune diseases.99–104 Since celiac disease
in elderly patients with celiac disease,91 many of whom
and other autoimmune diseases share common genetic,
benefit from gluten-free diets.92 Multiple behavioral and
environmental, and immunological pathways, it would be
peripheral or central neurological manifestations have
interesting to investigate the possible therapeutic effects of
been described in patients with celiac disease, some of
gluten-free diets in patients with nonceliac autoimmune
whom respond to gluten-free diets.93–96
conditions. At least in celiac disease, the additive risk of
Gluten exorphin B5 is an opioid peptide identified
subsequent autoimmune disease was decreased in patients
after wheat gluten digestion. It stimulates prolactin se-
who adhered to a gluten-free diet vs those who did not.105
cretion and affects brain neurotransmitter discharge,
It was concluded that a gluten-free diet has a protective ef-
even without crossing the blood–brain barrier, in rats.97
fect. The effects of gluten in non–gluten-sensitive popula-
The scientific and medical communities are wit-
tions were recently reviewed.106,107 The protective effect of
nessing a major era in which the relationship between
gluten withdrawal has been observed in several autoim-
the gut and the remote organs, including the gut–brain
mune diseases (Figure 1). Moreover, the ingestion of glu-
axis, is under intense investigation.98 The beneficial or
ten seems to be related to disease progression. It should be
partial response to gluten withdrawal suggests some de-
stressed, however, that the Speculation about the benefits
gree of cause-and-effect relationship between gluten
of gluten-free diets is based on a limited number of clinical
and neurological manifestations.
trials that investigated gluten-free diets as either a causal
To provide support that gluten intake may have ad-
factor in the pathogenesis of disease or in association with
verse effects in patients with nonceliac autoimmune disease,
the improvement of symptoms.
the next section describes various autoimmune diseases in
which gluten-free diets had some beneficial effect.
Type 1 diabetes mellitus
ROLE OF GLUTEN-FREE DIET IN NONCELIAC
AUTOIMMUNE DISEASES Multiple findings suggest a connection between T1D and
gluten or celiac disease: shared genes, coexistence of TID
Since celiac disease and many autoimmune diseases share and celiac disease in some patients, increased celiac disease
some human leukocyte antigen genes and multiple prevalence in patients with T1D, increased selective T-cell

1052 Nutrition ReviewsV Vol. 75(12):1046–1058

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response and high concentration of wheat antibodies in
both T1D and celiac disease, the dependency of animal
models of T1D on diet, with gluten being a major potent
diabetes-inducing protein, and, recently, the identification
of T1D-related proteins from wheat, showing that cDNA
clones of diverse wheat storage globulins were associated
with islet damage.108,109 Moreover, a partial depletion of
regulatory T cells before gliadin sensitization induced se-
vere insulitis in a mice model. The presence of gliadin-
responsive T cells in the pancreatic lymph nodes of mice
that develop insulitis suggests that gliadin-specific T-cell
clones have a role in the induction of insulitis in this ani-
mal model.110
Gluten-free diets delayed and prevented diabetes in
NOD mice that had never ingested gluten.111 The intesti-
nal immune system plays a primary role in the pathogene-
sis of T1D, since diabetogenic T cells are initially primed
locally in the gut, islet-infiltrating T cells express gut-
associated homing receptors, and mesenteric lymphocytes
passively transfer diabetes from NOD mice to mice with
NOD or severe combined immunodeficiency.67 During
infancy, the amount, timing, and mode of gluten intro-
duction have been shown to affect the diabetogenic poten-
tial of gluten, and it is now suggested that a gluten-free
diet may preserve beta cell function.67 A subset of patients
with T1D had an abnormal immune reaction to gluten,
manifested by a positive reaction to rectal gluten challenge
that resulted in lymphocyte infiltration of the rectal mu-
cosa, increased proliferative T-cell response to wheat pro-
teins, with production of proinflammatory cytokines, and
an elevated T-cell response to gluten in one-fourth of
patients with newly diagnosed T1D. All of these effects oc-
curred in patients without celiac disease–associated hu-
man leukocyte antigen haplotype, suggesting a direct,
diabetes-specific effect of gluten.67
Notably, the benefits of a gluten-free diet in
patients with symptomatic celiac disease and T1D are
supported by the literature, though it is unclear whether
these benefits occur in asymptomatic patients. In a 6-
month study of a gluten-free diet in individuals at high
risk for T1D, autoantibody levels did not change, but
insulin secretion was reduced.112 Other studies did not
substantiate the benefit of gluten-free diets.113,114 Taken
together, gluten consumption may play a substantial
role in the progression of T1D, but additional studies
are warranted to explore whether gluten withdrawal
could prevent disease in susceptible individuals or be
applied in newly diagnosed patients to stop or attenuate
disease progression.
Rheumatoid arthritis
Multiple studies have described shared domains be-
tween rheumatoid arthritis and celiac disease.44 Thus,
Nutrition ReviewsV Vol. 75(12):1046–1058
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the partial response of celiac disease–associated rheu-
matic manifestations to gluten-free diets is logical.
Additionally, there is a protective effect of gluten with-
drawal on the cumulative incidence of additional auto-
immune diseases in patients with celiac disease.78,105 In
fact, dietary modifications, like gluten-free vegan diets,
had clinical benefits in certain patients with rheumatoid
arthritis that may result from reduced immunoreactiv-
ity to food antigens that are eliminated by a restrictive
diet.115 A gluten-free vegan diet in patients with rheu-
matoid arthritis drives changes that are potentially athe-
roprotective and antiinflammatory.116 Of note, human
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leukocyte antigen DQ2/8-restricted gluten-specific T
cells were noticed to migrate from the enteric mucosa
into peripheral blood upon gluten challenge, thus indi-
cating an additional mechanism of articular pathology
in celiac disease and suggesting a basis for the benefit of
gluten-free diets.
Multiple sclerosis
Numerous neurological manifestations that mimic mul-
tiple sclerosis have been described in patients with ce-
liac disease.93,94 A certain percentage of patients with
multiple sclerosis show high levels of IgA anti–tissue
transglutaminase autoantibodies.117 It has been recom-
mended that gluten-free diets be considered in patients
who test positive for antigliadin antibodies. More re-
cently, an increased prevalence of antibodies associated
with celiac disease was found in a population of patients
with relapsing-remitting multiple sclerosis (odd ratio,
5.33),118 and 11% of that population was diagnosed as
having celiac disease. This is 5 to 10 times greater than
the prevalence in the normal population. Furthermore,
32% of first-degree relatives of this population had posi-
tive serology for celiac disease. More relevant to the pre-
sent review, however, is the finding that “the response
of the gluten-free diets was excellent in all of them, both
from the digestive and the neurologic point of view in
the average follow-up period of three years long.”
Several other small series and case reports observed
clinical improvement in patients on gluten-free diets,
but further research is needed to evaluate the response
of patients with multiple sclerosis to nutritional
changes.119,120 Many immunopathogenic pathways and
various celiac disease–associated antibodies have been
described. These antibodies can cross the blood–brain
barrier and deposit at the level of the Purkinje cells,
producing a remarkable inflammatory reaction fol-
lowed by neuronal damage and cerebellar atrophy.118
The isoenzyme of tissue transglutaminase subtype 6 was
demonstrated in the cerebellum of patients with celiac
disease ataxia. Nutritional factors and positive
1053
anti–transglutaminase 6 autoantibodies might explain
the pathogenesis of the gut–brain axis.121
Psoriasis
Psoriasis and celiac disease share genetic and inflamma-
tory features. The connection between psoriasis and ce-
liac disease was examined in a review of studies of
gluten-free diets in patients with psoriasis.122 Of 33
patients with psoriasis who were positive for antigliadin
antibodies and were treated with a gluten-free diet, 24
showed a reduction in their psoriatic severity index
when compared with patients who had psoriasis and
were negative for antigliadin antibodies.123 In another
28 patients, gluten withdrawal was shown to reduce the
expression of tissue transglutaminase in patients with
psoriasis who were positive for antigliadin antibod-
ies.124 Several additional case reports were published in
which patients with psoriasis experience rapid lesion
resolution following adherence to a gluten-free
diet.125–127 There is limited evidence to suggest that
gluten restriction may benefit some patients with pso-
riasis, but additional controlled studies in defined
patient populations are needed.
Autoimmune hepatitis and celiac hepatitis
Forty percent of individuals have abnormal liver tests
upon the diagnosis of celiac disease, but tests will nor-
malize in the majority who adhere to a gluten-free
diet.128 Celiac disease is twice as common in patients
with cirrhosis as in the normal population, and a
gluten-free diet is known to improve liver function
tests. Abnormally high levels of antiendomysial anti-
bodies and high levels of tissue transglutaminase raise
suspicion of celiac disease in patients with cirrhosis and
may prompt physicians to recommend a gluten-free
diet.129 Several hepatic and biliary diseases are associ-
ated with celiac disease: autoimmune hepatitis, primary
sclerosing cholangitis, and primary biliary cirrhosis.
These liver diseases are less prevalent than celiac hepati-
tis and are associated with increased morbidity and
mortality, which requires they be treated with appropri-
ate immunosuppressive therapy, rather than just
gluten-free diets.130 However, a significantly increased
proportion of patients with coexisting autoimmune
hepatitis and celiac disease show sustained remission
when compared with patients with autoimmune
hepatitis without celiac disease. The improvement in
liver function following dietary intervention suggests a
possible long-term beneficial effect of a gluten-free
diet.131,132
1054
Autoimmune thyroiditis
In an Italian multicenter study, thyroid function was
studied in 241 consecutive untreated patients with
celiac disease and 212 controls. Thyroid disease was 3-
fold higher in patients with celiac disease than in con-
trols. In most patients who adhered to gluten-free diet
for 1 year, a normalization of subclinical hypothyroid-
ism was noticed,133 suggesting that, in some patients, a
gluten-free diet may, by itself, reverse abnormal thyroid
levels. Recently, however, an additional study could not
repeat those results.134 In thyroid-associated orbitop-
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athy, celiac disease is the only autoimmune disease in
which symptoms and tissue transglutaminase levels
usually improve if patients adhere to a gluten-free
diet.135 In a study of the role of gluten in the induction
of antiendocrine autoantibodies and organ dysfunction
in adolescent patients with celiac disease, at least 1 anti-
body was positive in 10 of 19 untreated patients but in
only 5 of 25 patients treated with gluten-free diets.136 A
recent review described the similarities and differences
between celiac disease and Hashimoto thyroiditis as
well as the potential gut–thyroid interrelated path-
ways.137 The concept of a gut–thyroid relationship was
supported by the fact that these 2 autoimmune diseases
are related and that tissue transglutaminase antibodies
were described to bind to thyroid follicles and to the ex-
tracellular matrix in patients with celiac disease.
Furthermore, anti–tissue transglutaminase titers corre-
late with anti–thyroid peroxidase antibody titers. These
findings suggest that celiac-associated autoantibodies
could contribute to the progression of thyroid dysfunc-
tion in celiac disease, thus establishing some logical ba-
sis for the beneficial effects of gluten withdrawal in
patients with autoimmune thyroid disease.137
Immunoglobulin A nephropathy
Like other autoimmune diseases, IgA nephropathy
shares multiple characteristics with celiac disease,138
and several animal and human studies documented a
beneficial effect of gluten-free diets in this disease.139,140
DISCUSSION
This is the first comprehensive review to address the ad-
verse effects of gluten application or ingestion, in vitro
or in vivo, and the effect of gluten-free diets in multiple
autoimmune diseases: T1D, rheumatoid arthritis, multi-
ple sclerosis, psoriasis, autoimmune hepatitis, and auto-
immune thyroiditis. Basic science and translational and
clinical research were reviewed to clarify the adverse
effects of gluten and the mechanisms underlying the
beneficial effects of gluten withdrawal. Summarizing
Nutrition ReviewsV Vol. 75(12):1046–1058
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Figure 2 Adverse effects of gluten on the human cellular, immune, intestinal, and systemic compartments. Abbreviations and symbols:
NKG2D, natural killer group 2D costimulatory molecule; PTMP, post-translational modification of proteins; TH-17, T-helper 17 lymphocytes;
TLR4, Toll-like receptor 4 signaling pathway; Treg, regulatory T cells; 䉱, increased; 䉲, decreased.
the evidence from studies that explore the adverse
effects of gluten in vitro or of uptake in vivo can help
guide the decision to recommend restriction of dietary
gluten to improve the well-being or clinical manage-
ment of patients with nonceliac chronic conditions.
However, it should be stressed that the lack of studies in
normal human populations devoid of any inflammatory
or autoimmune condition limits any recommendation
to attenuate or prevent gluten consumption worldwide.
Since wheat is the most important staple crop in
the West, and wheat consumption in countries un-
dergoing urbanization, industrialization, and
Westernization is steadily increasing,3,4,15,63 further
investigations are needed to clarify the drawbacks and
benefits of gluten ingestion. The enigma is further rein-
forced by the gains attributed to gluten, being a major
source for starch, energy, proteins, vitamins, fiber, and
phytochemicals. It should be clearly stated that the
above-described response to gluten-free diets in noncel-
iac autoimmune diseases does not replace the corre-
sponding disease-specific therapies of these disease. The
mechanisms of gluten-free diets as nutritional therapy
are far from being elucidated, but this review sheds new
light that might clarify some of the pathways underlying
the reduction in adverse effects sometimes observed
after gluten withdrawal.
There are, however, some limitations to this review.
The quality of evidence may be limited because of the
Nutrition ReviewsV Vol. 75(12):1046–1058
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small number of randomized clinical studies and animal
studies, or because studies may have included patients
with high heterogeneity and varying medical pheno-
types, disease activities, and morbidity. There is always
the possibility that some studies were not captured by
the keywords used in the literature search. Since the
search screened for autoimmune diseases, and not non-
celiac gluten sensitivity, some information could have
been missed. Furthermore, the gluten used in the stud-
ies might have been contaminated with other soluble
proteins, such as amylase-trypsin inhibitors or yeasts
used in commercial bakeries, which could have affected
the results. Finally, evidence of the adverse effects of
gluten was generated mainly in in vitro cell lines and
animal models. There are not yet enough in vivo animal
studies or human studies to support a recommendation
of gluten withdrawal in clinical practice.
CONCLUSION
Wheat, along with its main storage protein, gluten, is a
staple nutrient. Increasing evidence shows that gluten
may have multiple detrimental effects on human health.
Figure 2 summarizes the possible detrimental effects of
gluten on the intestinal luminal compartment, on the
immunological pathways, and on cellular as well as
systemic domains. A word of caution is needed before
conclusions are drawn and recommendations are
1055
suggested. Evidence of the detrimental effects of gluten
is limited to several in vitro and animal studies. Well-
designed, controlled studies in humans are lacking.
Thus, no practical clinical recommendations can be
suggested until further clinical trials are performed.
Implementing gluten-free diets in certain individuals af-
fected by nonceliac autoimmune disease might be in-
strumental in minimizing the adverse effects of gluten
in humans, but for now, the use of such nutritional
therapy is not based on adequate human investigations.
Considering the effects of gluten on the microbiome,
the role of gluten in oxidative stress and epigenetics,
and the relationship of gluten to the induction and pro-
gression of autoimmunity, a gluten-free diet might have
multiple indirect consequences.42,63,141–143
Currently, there is no clear indication to withdraw
gluten in non–gluten-related conditions. However,
since there is an increased prevalence of celiac disease
in multiple autoimmune diseases and vice versa, it is
suggested that patients with autoimmune disease be
screened for antibiodies associated with celiac disease.
In view of the central role played by the human
intestine in inducing autoimmunity in peripheral
organs,44,98,99,137,138,144,145 there is a need to elucidate the
pathways, the molecules, or the messengers involved in
the interplay between gluten and nonceliac autoimmune
conditions. It is hoped that the detrimental effects of glu-
ten summarized here will encourage the clinical and the
scientific communities to explore the underlying mecha-
nistic pathways and verify whether observations in ani-
mals and ex vivo can be substantiated in humans.
Acknowledgments
The authors would like to acknowledge Mr Neu Alf,
medical illustrator, for providing the figures and
Dr. Ramesh Ajay for editing the manuscript.
Author contributions A.L. wrote the manuscript and
was responsible for the study concept, the study design,
and the literature review. Y.S. supervised and was re-
sponsible for the study concept, the interpretation of
data, and the editing and critical revision of the manu-
script. T.M. was responsible for the study design and
the critical revision of the manuscript and provided ad-
ministrative, technical, and material support. All
authors approved the final version of the manuscript,
including the list of authors.
Funding/support. No external funds supported this
work.
Declaration of interest. The authors have no relevant
interests to declare.
1056
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