American Journal of Lifestyle Medicine
Ashok Philip, PhD and
Gluten, Inflammation, and
Neurodegeneration
Abstract: Growing evidence
supports a potential link between
dietary gluten intake and
neurodegenerative disease in
susceptible populations.
Observational data supporting this
link are described along with
interventional study data
evaluating the effects of restricting
gluten from the diet in patients with
neurologic disorders. Suggested
underlying mechanisms between
gluten intake and
neurodegeneration are discussed.
Keywords: gluten; inflammation;
neurodegeneration; neurologic
disorders; celiac disease; Nonceliac
gluten sensitivity
Gluten plays an established role in
the pathogenesis of celiac disease
(CD) and nonceliac gluten sensitivity
(NCGS).1 Interestingly, a number of
neurodegenerative conditions have
been associated with grain intake or
respond favorably when gluten is
restricted from the diet.2-4
Additionally, rates of comorbid CD/
NCGS and neurodegenerative
disorders, including bipolar, major
depressive disorder, anxiety, and
autism spectrum disorders (ASD),
have been observed in unusually
high rates.5-8 These findings raise the
DOI: 10.1177/15598276211049345. Director of Assessment and Professor of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, AR, USA (AP);
Department of Pharmacy Practice, School of Pharmacy and Health Professions. Creighton University, Omaha, NE, USA (NDW). Address correspondence to: Ashok Philip, Director
of Assessment and Professor of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, College of Pharmacy 4301 W. Markham | Little Rock, AR 72205, USA. e-
mail: aephilip@uams.edu.
For reprints and permissions queries, please visit SAGE’s Web site at http://www.sagepub.com/journalsPermissions.nav.
Copyright © 2022 The Author(s).
32
Nicole D. White, PharmD, CDCES, NBC-HWC, DipACLM
question as to whether gluten may
be implicated in the pathogenesis of
neurodegenerative conditions.
Gluten, primarily comprising
gliadin and glutenin proteins
(8085%), is a member of the
prolamin superfamily and is
commonly found in wheat, barley,
rye, and oats. The prolamin
superfamily of proteins is
characterized by a repetitive
sequence of the amino acids
glutamine and proline and is
‘“...dietary gluten-induced chronic
inflammation is linked to dysbiosis and
a permeable gut...”
suspected to be responsible for
gluten’s water insolubility. Gluten
within grains is confined to the cells
of the starchy endosperm where it
supports germination. In food
production, gluten proteins are
valued for their cohesiveness and
viscoelasticity, which allows for ideal
dough and bread consistency.9,10 As
a result, gluten is highly prevalent in
a variety of common foods (bread,
pasta, bakery items, and cereal) as
well as used for sauce thickeners,
fillers, and stabilizers.
Jan • Feb 2022
Gluten consumed through the diet
has been linked to a pathological
immune response in susceptible
populations.10-13 Upon
consumption, gluten is partially
hydrolyzed by proteases in the
gastrointestinal tract to peptides of
∼1030 amino acids in length that
cross the intestinal barrier via trans or
paracellular transport. These
peptides undergo deamidation by
intestinal tissue transglutaminase-2
(tTG2) which increases their affinity
’
for major histocompatibility complex
II (MHC II) molecules and triggers an
inflammatory response. In
individuals with celiac disease (CD)
who carry human leukocyte antigen
class II with DQ2 and/or DQ8
molecules on antigen-presenting
cells (HLA-DQ2 or DQ8 haplotype),
these partially digested peptides are
recognized by the DQ cell receptor
and presented to T lymphocytes,
resulting in an immune response. In
patients with nonceliac gluten
sensitivity (NCGS), who are DQ2
 vol. 16 • no. 1
and DQ8 negative, it is suspected
that gluten proteins in concert with
other components of wheat activate
an innate immune response in the
body. Wheat germ agglutinin and
amylase-trypsin inhibitors of wheat
have also been shown to illicit an
innate immune response.10-13 As
a result, due to loss of tolerance to
gluten proteins, individuals with CD
and NCGS experience gastrointestinal
distress, fatigue, and pain including
inflammation and increased
permeability of the intestinal mucosa.1
These inflammatory effects of
gluten may not be limited to the
gastrointestinal system. Increased
intestinal permeability leads to entry
of toxic digestive metabolites,
bacteria, and bacterial toxins into the
bloodstream which may eventually
reach the central nervous system.1
Neurological issues like cerebellar
ataxia, peripheral neuropathy,
cognitive impairment, and
neuropsychiatric diseases have been
associated with CD, suggesting the
possibility of gluten-mediated
inflammation playing a role in loss of
bloodbrain barrier (BBB)
integrity.1,14-16 Furthermore,
increased BBB permeability
attributed to inflammation or
bacteria is linked to other
neurological disorders including
ASD, dementia, Alzheimer’s disease,
Parkinson’s disease (PD),
depression, anxiety, and
schizophrenia.15,17 The following
describes observed relationships
between gluten and
neurodegenerative conditions as
well as potential mechanisms by
which dietary gluten may lead to
neurodegeneration.
Gluten and
Neurodegenerative
Conditions
Despite the paucity of evidence
establishing a causal relationship
between dietary gluten intake and
neurological disorders, a number of
studies demonstrate an association
between the 2 and/or a beneficial
effect on neurological symptoms
when gluten is restricted from the
diet. One example is the reduction
in observed incidence of
schizophrenia in populations who
consume little to no grains
compared to those consuming
grain-rich diets.2 Patients with
schizophrenia have markedly high
levels of inflammation, and
a gluten-free diet (GFD) has been
shown to improve both psychiatric
and gastrointestinal symptoms in
these patients.3,18,19 Likewise, GFD
has been associated with
improvements in ASD.4,5,20,21
Unusually high rates of chronic
diarrhea, constipation, and bloating
have been observed in children with
ASD.5 Interventional studies have
demonstrated improvements in both
the prevalence of gastrointestinal
symptoms and ASD behaviors in
children with ASD who followed
GFD.4 Mood disorders (bipolar
disorder, major depressive disorder,
and anxiety) are commonly observed
in individuals with CD and NCGS,
with bipolar disorder 17 times more
likely to affect individuals with CD
relative to the general population.6,7
Increased levels of gluten-related
antibodies are found in individuals
with bipolar disorder, depression,
anxiety, hyperactivity, as well as
schizophrenia suggesting the
correlation between gluten
consumption and mood disorders.6-8
Putative Mechanisms
As stated earlier, intestinal tissue
transglutaminase-2 (tTG2) is
a calcium-dependent enzyme that
mediates deamidation of glutamine
residues present in gluten proteins,
triggering gluten’s inflammatory
response.16,22 tTG2 not only
mediates the post-translational
modification/deamidation of the
gluten protein gliadin, but was
shown to act as an autoantigen and
due to its ability to induce the
production of tTG2
American Journal of Lifestyle Medicine
autoantibodies.22,23 The presence of
tTG2 autoantibodies were detected
in almost 100% of patients diagnosed
with CD and in a minor fraction of
NCGS patients.23 Tissue
transglutaminase is also involved in
multiple neurodegenerative
diseases. The neural isoform of
tissue transglutaminase, tTG6, is
implicated in the pathogenesis of
Alzheimer’s disease (AD),
Huntington’s disease (HD), and
movement disorders like gluten
ataxia and multiple sclerosis.24-28
Increased levels of circulating anti-
tTG6 antibodies are also present in
adult patients with
schizophrenia.16,29
Overall, increased levels of tTG6
antibodies in CD patients with gluten
ataxia and peripheral neuropathy
suggest a plausible role for tTG6 in
contributing toward these central
and peripheral symptoms of CD.26,29
With regards to NCGS patients, it is
suggested that loss of integrity of the
intestinal barrier facilitates access of
partially hydrolyzed immunogenic
gluten peptides to both the systemic
circulation and the brain. Access of
these toxic gluten peptides and HLA-
DQ2/DQ8 restricted CD4 T cells to
the brain may contribute to the
neurological issues observed in
NCGS patients.30-33 It is also
proposed that loss of intestinal
barrier’s integrity aka leaky gut
promotes increased access for
circulating or gut-derived
extracellular structures like
biomolecular condensates (BMC)
and extracellular vesicles (EV) to the
brain of CD and NCGS patients.16
Given the critical role of tTG in
mediating gluten metabolism, its
autoantigen properties, its ability to
cause central β-amyloid
accumulation, and foster
inflammation and cancer, tTG is
being pursued as a molecular target
for a variety of disease states.16,34
Additional mechanisms have been
postulated to contribute to gluten
sensitivity and neuronal dysfunction.
One of them is the identification of
33
 American Journal of Lifestyle Medicine
a strong correlation between specific
HLA haplotypes and dysregulation
of the gut-brain axis in CD and NCGS
patients diagnosed with ASD and/or
Down’s syndrome (DS).16,35,36 Also,
in NCGS patients with neurological
issues, antibodies for glutamic acid
decarboxylase (GAD), a key enzyme
involved in the biosynthesis of the
primary inhibitory neurotransmitter
gamma-aminobutyric acid, were
detected.16,37
The potential role of epigenetic
mechanisms in regulating
inflammatory responses has
prompted focused attention toward
micro-RNAs (MiRNAs) and CD.16
The MiRNAs are ∼20–23 nucleotides
in length, small RNA molecules that
mediate a number of cellular
processes like cell proliferation,
differentiation, apoptosis, cell
signaling, and immune, including
inflammatory, responses.16
Specifically, downregulation of miR-
192-5p due to inflammation is
suggestive of its role in maintaining
intestinal homeostasis.16,38,39
Moreover, chronic inflammation of
the intestine combined with a leaky
gut results in gut dysbiosis, which
may in turn promote microbial entry
into systemic circulation. Especially,
loss of intestinal barrier’s integrity
has the potential to allow increased
access of lipopolysaccharides (LPS)
across the BBB, activate microglial
cells, and ultimately cause neuronal
inflammation and damage in CD
patients.16,40
In CD and NCGS individuals, it is
established that dietary gluten-
induced chronic inflammation is
linked to dysbiosis and a permeable
gut.16 This in turn affects factors that
regulate neuronal inflammation,
cognition, and neurodegeneration.
For example, at the molecular level,
the genetic expression of
peroxisome proliferator activated
receptor gamma (PPARγ) is reduced
in patients diagnosed with ulcerative
colitis and CD. Because PPARγ is an
anti-inflammatory and anti-dysbiotic
molecule, it may serve as a potential
34
molecular target for the management
of gluten-induced intestinal
inflammation and dysbiosis.16,41
Conclusion
While data supporting the direct
link between gluten consumption
and neurodegeneration is limited,
available evidence highlights the
relationship between gluten
consumption, tTG antibody
production, and disruption of the
microbiota-gut-brain axis.1,16 The
beneficial effects of GFD in patients
with CD, schizophrenia, and ASD,
especially in mitigating
gastrointestinal and neurological
symptoms, highlight the need for
more exploration and identification
of definitive evidence.42
Declaration of Conflicting
Interests
The author(s) declared no potential conflicts of interest
with respect to the research, authorship, and/or
publication of this article.
Funding
The author(s) received no financial support for the
research, authorship, and/or publication of this article.
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