46 Journal of The Association of Physicians of India Vol.

64 March 2016

Review Article

Non-celiac Gluten Sensitivity (NCGS)

Pravin M Rathi1, Vinay G Zanwar2

patients. 1 Gluten sensitivity (GS)

Abstract was originally described in the
There has been increasing interest in the entity Non-celiac gluten 1980s. 10 Number of papers have
come up in recent past after the
sensitivity in recent years which was first of its in 1980s. This re-
landmark work by Sapone and co-
discovered disorder is characterized by intestinal and extra-intestinal
workers on GS in the year 2010. 11
symptoms which occur after ingestion of gluten containing food. The
H o we ve r , m a n y a s p e c t s o f i t s
number of such patients who neither have celiac disease nor wheat
epidemiology, pathophysiology,
allergy, but appear to benefit from gluten withdrawal is increasing
clinical spectrum, and treatment
substantially. However it still remains a controversial and its pathogenesis are still unclear. Given the recent
is not well understood. Lack of biomarkers is a major limitation making increase in the patients consuming
it difficult to differentiate it from other gluten related disorders. Recent gluten-free diet, revenue in the
studies have raised the possibility that, beside gluten and wheat amylase- gluten-free market has increased
trypsin inhibitors (ATI), low-fermentable, poorly-absorbed, short-chain from $100 million in 2003 to $1.31
carbohydrates can contribute to symptoms (at least those related to IBS) billion (2011) to $1.68 billion by
experienced by NCGS patients. the year 2015 emerging as big
In this paper we will focus on the manifestations of NCGS and evidence business. 12 Hence, there is a need
for the condition. Also areas of controversy, major advances and future of separating the wheat from the
trends will be discussed. chaff. 13
In February 2011 at London,
p a n e l o f e x p e r t s d e ve l o p e d a
consensus on new nomenclature
Introduction epidemiological studies have
and classification of gluten-related
estimated the prevalence of the same

R eal existence of the non-celiac
gluten sensitivity has always
been debatable issue due to its
diagnosis of exclusion and lack of
concrete pathogenesis. In contrast,
Celiac disease (CD) is a heightened
immune response to ingestion of
wheat gluten and related cereal
proteins in genetically predisposed
individuals.1 The resulting
inflammatory response in the
small bowel leads to lymphocytic
infiltration, villous atrophy, and
crypt hyperplasia. Elimination
of the gluten proteins from diet
generally leads to clinical and
histological improvement. 2 CD is a
multigenic disorder, the HLA-DQ2
and HLA-DQ8 molecules confer
susceptibility for CD. 3 The gold
standard tool for the diagnosis of
CD is the demonstration of villous
atrophy on duodenal biopsies,
with celiac serology playing a
supportive role. 4,5 Contemporary
in the European adult population to
be 1%. 6,7 Some of the CD-associated
symptoms experienced in response
to ingestion of wheat are also
reported by individuals who are
n e g a t i ve f o r t y p i c a l s e r o l o g i c ,
histological, or genetic markers
of CD, and who also do not
experience the immunoglobulin E
(IgE) serologic response associated
with wheat allergy. These patients
have frequently put themselves
on Gluten-free diet (GFD) after
negative experiences from eating
gluten-containing foods and report
significant improvements on a
GFD. 8,9
The term nonceliac gluten
sensitivity (NCGS) has been
proposed to refer the spectrum
of conditions reported by such
1
Prof and Head, 2Resident, Department of Gastroenterology, TNMC & B.Y.L Nair Ch. Hospital, Mumbai
Received: 05.08.2014; Accepted: 12.03.2015
disorders, a first met. The panel
proposed a series of definitions
and a diagnostic algorithm that
has been recently published. 14 An
overlap between the irritable bowel
syndrome (IBS) and GS has been
suspected, requiring even more
stringent diagnostic criteria. 15
Here we reviewed the
international literature about this
new disease, consulting PubMed
and Medline, using the search terms
wheat allergy, wheat (hyper )
sensitivity, wheat intolerance,
gluten (hyper ) sensitivity, and
gluten intolerance; and we will
discuss current knowledge about
NCGS.

Gluten disease spectrum
Pathogenesis
Allergy Autoimmune
Wheat Allergy Celiac Disease/
disorders Dermatitis
herpitiformis
Classic food
Bakers asthma
allergy
Fig. 1: Proposed new nomenclature and classification of gluten-related
disorders
Wheat and Gluten: What
are they?
Gluten is the protein mixture of
glutelins and gliadins (prolamines),
which occurs in the endosperm of
wheat and other cereals (such as
barley, rye and spelt) and can be
fractionated to produce alpha, beta,
and gamma peptides. The ratio of
glutelins to gliadins in the protein
mixture is approximately 1:1.
Gliadins, a group of proteins that
are rich in proline and glutamine,
have been identified as the main
culprit gluten component that is
toxic. 16-18
Globally nowadays, gluten is one
of the principle dietary components
particularly in western population.
Mean daily gluten ingestion is
1020 g in the Mediterranean
a r e a a n d e ve n h i g h e r i n o t h e r
populations. 19,20
New variants of wheat have
Journal of The Association of Physicians of India Vol. 64 March 2016
? Innate Immunity
Gluten
Ataxia Non celiac gluten
spectrum sensitivity
WDEIA Contact urticaria
arisen as a result of agricultural
modernisation and the growing
use of pesticides and fertilizers,
which could have a leading role in
the adverse immunologic reactions
to gluten. Moreover, the process
of bread leavening has been
progressively shortened, resulting
in an increased concentration of
toxic gluten peptides in bakery
products. 21,22
Nomenclature
The term gluten-related
disorders is the umbrella-term
to be used to cover all conditions
related to ingestion of gluten-
c on t aining food. Based on t he
discussion and the current evidence
in literature, the panel generated a
series of definitions and created
the classifications and algorithms
summarized below in Figure 1. 14
WA (onset: minutes to hours
after gluten exposure) is defined as
47
an adverse immunologic reaction
to wheat proteins. WA is classified
into classic food allergy affecting
the skin, gastrointestinal tract or
respiratory tract; wheat dependent
exercise-induced anaphylaxis
(WDEIA); occupational asthma
(bakers asthma) and rhinitis; and
contact urticaria. Wheat specific
IgE antibodies play a vital role in
executing WA, however non-IgE-
mediated WA does exist 23 and make
difficult to distinguish from GS.
Celiac disease (onset: weeks
to years after gluten exposure)
is an autoimmune enteropathy
triggered by the ingestion of
gluten in genetically predisposed
individuals. The major antibody
responses are targeted against
deamidated gluten sequences,
and the transglutaminase 2 (TG2)
e n z y m e s o f g l u t e n p r o t e i n s . 24
However, the immunoglobulin A
(IgA) anti-TG2 antibody is currently
considered the most sensitive and
specific serologic marker of CD. 25,26
Diagnosis of CD is confirmed if
at least four of the following five
criteria are fulfilled: 27
1. Typical symptoms of CD
2. Positivity of serum IgA class
auto antibodies at high titre
3. HLA-DQ2 and/or HLA-DQ8
genotypes
4. Classic histological findings on
duodenal biopsy
5. Improvement on GFD
Dermatitis herpitiformis
is a skin manifestation of CD
presenting with blistering rash
and pathognomonic cutaneous
IgA deposits. 28 Since DH is the
cutaneous counterpart of CD (skin
CD), a proven diagnosis of DH in a
patient should be taken as indirect
evidence for the presence of small
bowel damage.
Gluten ataxia was originally
defined as otherwise idiopathic
s p o r a d i c a t a x i a w i t h p o s i t i ve
serological markers for gluten
sensitization. 29 Like CD, it is an
autoimmune disease characterized
48 Journal of The Association of Physicians of India Vol. 64 March 2016
by damage to the cerebellum
resulting in ataxia.
Gluten sensitivity (Immune-
mediated form with onset: hours
to days after gluten exposure) the
recent rise of the gluten-free market
in the USA, partially sustained by
individuals who undertake a GFD,
raises questions about possible
gluten reactions alternative.
These are generally defined as
non celiac GS (NCGS) or more
simply, GS in which neither allergic
nor autoimmune mechanisms
can be identified. Thus GS is
defined as those cases of gluten
reaction in which both allergic
and autoimmune mechanisms
have been ruled out (diagnosis by
exclusion).
The Uttering of this disorder
was a great deal among the panel
experts. In order to avoid confusion
with CD, sometimes defined as
gluten-sensitive enteropathy,
non celiac gluten sensitivity
appeared as an improved
definition. Doubtless this is still
too vague a terminology, simply
reflecting the poor knowledge
of the pathophysiology of this
condition. As triggering cereal
proteins could include fractions
other than gluten, some panellists
we r e i n f a v o u r o f n o n c e l i a c
wheat (protein) sensitivity, a
terminology that would however
conflict with the possibility that
other gluten-containing cereals
(rye, barley) may be offensive for
the gluten sensitive patient. 15
Bearing these limitations in mind,
the experts panel agreed that this
entity can provisionally be defined
as NCGS, a definition requiring
refinement in the future.
Epidemiology
The overall prevalence of
NCGS in the general population
is still unknown, mainly because
many patients are currently
self-diagnosed and start a GFD
without consultation. Whereas
the low-carb diet was widely
adopted in the years after 2000,
which now has been on decline.
On the other hand, the gluten-
free diet has gained popularity
and shown a steady rise since
2008 and is expected to increase
further. In US study Digiacomo
et al. reported a 0.55% prevalence
of persons on a self-reported GFD
who participated in the National
Health and Nutrition Examination
Survey (NHANES) 20092010. The
prevalence was higher in females
and older participants. 30 Many
of the NHANES subjects on a
GFD could indeed be affected by
NCGS. Because (a) the possible
relationship between gastro-
intestinal symptoms and gluten
i n t a k e wa s n o t s y s t e m a t i c a l l y
explored in this population sample,
and (b) the NHANES survey was
conducted before NCGS was
described in the medical literature,
this likely to underestimate the
original figure.
However, new data confirm that
this is not an uncommon disorder
at all. In a selected (and, therefore,
probably biased) series of adults
with IBS, the frequency of NCGS,
documented by a double-blind,
placebo-controlled challenge, was
28% 31 . According to an article
in The Wall Street Journal, some
experts think as many as 1 in
2 0 A m e r i c a n s m a y h a ve s o m e
form of NCGS. 32 The prevalence
of non celiac gluten sensitivity
was reported at 6% based on the
Maryland secondary care clinic
experience (where between 2004
and 2010, 5896 patients were seen
with 347 fulfilling gluten sensitivity
criteria). 14 High-quality genetic
studies on the NCGS population
have not been performed as yet.
There are no data suggesting that
the condition follows the same
HLA-DQ2/-DQ8 association as
CD. 33
Historical Review
The entity of non celiac gluten
intolerance has been regarded
a s a n e w d i a g n o s i s 34 b u t i t i s
better to consider it as an old
diagnosis which has been recently
rediscovered and embellished. A
study in 1980 described 9 female
subjects with abdominal pain
and chronic diarrhoea who had
dramatic relief on a gluten-free
diet and a return of symptoms on
gluten challenge. 10 CD was ruled
out by lack of villous atrophy on a
gluten-containing diet, but it was
noted that the gluten challenge
induced a jejunal cellular infiltrate.
The clinical description of these
patients is similar to that for
patients who are now frequently
found in clinical practice and are
thought to have NCGS. In a study
using rectal challenge of gluten
for investigation of CD, it was
shown that about half of nonceliac
siblings of CD patients respond
to gluten, with epithelial changes
and an increase in intraepithelial
l y m p h o c y t e n u m b e r s . 35 I t i s
interesting that this rectal response
was not dependent on the presence
o f H L A - D Q 2 . T h e o b s e r va t i o n
suggests that an immune response
to gluten can happen in the absence
of the HLA-DQ2 restricted,
gluten-specific T cells that are
c e n t r a l t o t h e d e ve l o p m e n t o f
CD. Kaukinen and colleagues 36
observed further that intolerance
to cereals is not specific for overt
or latent CD. Ninety three adults
reporting abdominal symptoms
in response to ingestion of cereals
were recruited. Only 8 patients
were found to have CD, 7 could
be said to have latent CD i.e. both
an increase IELs and the presence
of celiac disease-type HLA, and 19
were positive for allergy tests. In
non-celiac patients, serum EmA
(Endo myslia) and tTG tests were
negative in all, whereas AGA (Anti
gliad Ab) was seen in 40%.
Without villous atrophy,
patients with a symptomatic
response to a (GFD) that does not
show tTG serological responses
characterizing celiac disease are
diagnosed as IBS gluten sensitive,
particularly in the presence of
genetic markers for celiac disease.37
In a non-randomised, prospective
study of 41 patients who fulfilled

80%
70%
60%
50%
40%
30%
20%
10%
0%
Fig. 2: Symptoms presentation in NCGS
the Rome II diagnostic criteria for
irritable bowel syndrome but with
normal small bowel biopsies, a
gastrointestinal symptom score
decreased significantly in those
treated with a gluten-free diet for
six months, who were positive
for DQ2, IgG AGA/tTG or DQ2
and IgG AGA/tTG, than in those
who were negative for these
markers (p<0.05- <0.01).38 Diarrhoea
resolved more frequently in DQ2
positive patients with celiac disease
associated antibodies (p<0.05).
This investigation has identified
a subgroup of patients with
diarrhoea predominant irritable
bowel syndrome who are likely to
respond to a gluten-free diet. The
most concrete evidence for NCGS
existence comes from two recent
double blind placebo controlled
trials in patients with self-reported
sensitivity to gluten 31 or wheat. 39
The first study was a rechallenge
trial. It included 34 patients with
IBS, who met the ROME III criteria
and were self-controlled on a GFD
over a 6-week period. CD was
excluded based on negative celiac
serology plus either a HLA genotype
incompatible with CD or a normal
duodenal biopsy while on gluten
c o n t a i n i n g d i e t . Pa t i e n t s we r e
then subjected to either gluten or
placebo in the form of muffins and
bread that were low in fermentable
oligosaccharides, disaccharides,
Journal of The Association of Physicians of India Vol. 64 March 2016
percentage
monosaccharide, and polyols
(FODMAPs). Those in the gluten
containing group demonstrated a
significant worsening of symptoms
as compared to those on a GFD
(p=0.001). There was no difference
between the groups in tests that
served as biomarkers of intestinal
injury in the form of faecal
lactoferrin, C-reactive protein and
the dual sugar test for intestinal
permeability. There was no change
in celiac serology including
gliadins antibodies on gluten
challenge. This study indicates that
gluten does trigger symptoms in
individuals without celiac disease.
The gluten used in this study did
not contain FODMAPs which it
is speculated cause symptoms in
patients with IBS. 40 The authors
were therefore unable to elucidate
a mechanism for the difference
between the groups.
The second study was a larger
study of 920 patients suffering from
IBS. 39 After a 4-week elimination
diet, patients were rechallenged
using a crossover double blind
placebo control challenge DBPCC
of wheat or placebo capsules. A
total of 276 patients were identified
as having wheat sensitivity of
w h o m , 2 0 6 we r e i d e n t i f i e d a s
suffering from multiple food
sensitivities. However, there is
confusion in this terminology.
There is still uncertainty as to
49
whether it is gluten withdrawal
that benefited patients or another
component of wheat (fructans and
poorly absorbed carbohydrate).
The subjects with wheat sensitivity
alone had features more in keeping
with celiac disease. Three quarters
carried the DQ2 or DQ8 haplotypes,
30% produced EMA from
culture of biopsies, and almost
a l l h a d e l e va t i o n o f d u o d e n a l
intraepithelial lymphocytes. Some
of these may well go on to develop
overt celiac disease if they remain
on gluten containing diet. 41 It is
possible therefore that some of
the patients enrolled in the study
may have had CD without villous
atrophy, particularly as some
patients had reduced wheat on
enrollment in the study, which
may have led to some improvement
i n h i s t o l o g y . H o we ve r , w h e a t
sensitivity also affected those who
did not have celiac disease in any
form and will not develop it because
the necessary HLA markers were
absent. Those with multiple food
sensitivity had features more in
keeping with food allergy.
What these studies point
towards? Clearly, gluten sensitivity
do exists as an entity beside overt
celiac disease. Some patients fall
into the spectrum of celiac disease,
b e c a u s e t h e y h a ve t h e g e n e t i c
predisposition, necessary HLA
markers and also celiac disease
associated antibodies, although
a macroscopically normal small
bowel mucosa and fall in as having
potential or latent celiac disease.
About half of patients do not have
celiac disease in any of its forms
b e c a u s e t h e y d o n o t h a ve t h e
necessary HLA profile.
Clinical Features
As name implies NCGS
symptoms usually occur soon
after gluten ingestion, disappear
with gluten withdrawal and
relapse following gluten challenge,
with varying symptom interval.
The classical presentation of
NCGS is a combination of IBS-like
symptoms, including abdominal
50 Journal of The Association of Physicians of India Vol. 64 March 2016
Table 1: Clinical comparison of gluten related disorders.
Celiac disease
Gastrointestinal Abdominal pain
Diarrhoea
Constipation
Neuropsychiatric Headache
Musculoskeletal pain
Brain fog
Tingling, numbness
Fatigue
Ataxia
Others Dermatitis herpitiformis
Weight loss
pain (68%), altered bowel habits
(33%), and systemic manifestations
such as, dermatitis (eczema or
skin rash 40%), headache (35%),
foggy mind (34%), fatigue
(33%), depression (22%), leg or
arm numbness (20%), and anaemia
(20%), joint and muscle pain
(11%) (Figure 2). 14,42 In children,
NCGS manifests with typical
gastrointestinal symptoms, such
as abdominal pain and chronic
diarrhoea, while the extra-
intestinal manifestations seem to
be less frequent, the most common
extra-intestinal symptom being
tiredness. 43 In recent years several
studies suggested a relationship
between NCGS and occurrence
of neuropsychiatric disorders
like schizophrenia, Cerebellar
ataxia and autism spectrum
disorders (ASD). 44 Table 1 lists
the most commonly reported
symptoms associated with NCGS
in comparison with those of CD
and wheat allergy. 33
No major complication of
untreated NCGS has so far been
described; especially autoimmune
comorbidity, as observed in CD.
However, natural history data on
NCGS are still lacking. Therefore it
is difficult to draw firm conclusions
on the outcome of this condition.
Laboratory Evaluation
Serology
At present, there are no known
specific serologic markers for
NCGS. Wahnschaffe and colleagues
Wheat sensitivity NCGS
Abdominal pain Abdominal pain
Vomiting Diarrhoea
Diarrhoea Constipation
Nausea
Vomiting
Dizziness Headache
Headache Musculoskeletal pain
Brain fog
Tingling, numbness
Fatigue
Ataxia
Eczema, itching Rash
Asthma, Rhinitis Weight loss
reported that a high proportion
of NCGS patients have increased
levels (56.4%) of IgG antibodies
to gliadins. 38 The prevalence of
IgG AGA detected in NCGS,
although lower than that found in
CD (81.2%), was much higher than
other pathologic conditions such
as connective tissue disorders (9%)
and autoimmune liver diseases
(21.5%) as well as in the general
population and healthy blood
donors (2%8%). 15
More recently, Volta and
colleagues studied 78 patients
with NCGS and 80 patients with
untreated CD in a tertiary referral
setting. 42 The prevalence of IgA
AGA in GS patients was very low
(7.7%). Noteworthy, the gold
standard CD markers, namely
IgG deamidated gliadins peptide
(DGP) antibodies, IgA tTG, and
IgA EMA, were always negative
in NCGS patients, except for an
isolated positivity at a very low
titre for IgG DGP. The consistent
negativity for IgG DGP-AGA,
whose synthesis in vivo is an
expression of the interaction
between tissue transglutaminase
a n d g l i a d i n s p e p t i d e s , 45 i s
particularly interesting because the
absence of these antibodies seems
to ex c lude t he involvement of
adaptive immunity. 11 Interestingly
enough, ELISA activities of IgA
t T G i n G S p a t i e n t s we r e ve r y
low with 30% of them displaying
values <1AU (none of them had IgA
deficiency).
In Majamaa et al study serum
total IgE concentration and wheat-
specific IgE antibodies (RAST) were
used to rule out wheat allergy with
specificity of 93% but with poor
sensitivity of 20%. 46
Haplotypes
CD-predisposing HLA-DQ2 and
DQ8 genotypes were found in 50%
of NCGS patients, a prevalence
that was lower than CD (95%)
and only slightly higher than
the general population (30%). It
was statistically not significant. 42
HLA-DQ2 and HLA-DQ8 has an
excellent negative predictive value
for CD. 47
Duodenal Biopsy
In a study done by Sapone and
co-workers11 all subjects (11 patients
with NCGS, 13 with CD, and 7
controls), underwent endoscopy
for duodenal biopsy. Those with
NCGS revealed normal to mildly
inflamed mucosa (Marsh 0 to 1),
w h i l e a l l C D p a t i e n t s s h o we d
partial or subtotal villous atrophy
with crypt hyperplasia. Also, CD
patients had increased numbers of
CD3+ IELs (>50/100 enterocytes)
compared to controls, while NCGS
patients had a number of CD3+
IELs intermediate between CD
patients and controls in the context
of relatively conserved villous
architecture. Recently, activation of
circulating basophils and increased
infiltration of duodenal lamina
propria with eosinophils 39,48 have
been described.
Skin Testing
Skin-prick testing is an additional
tool for ruling out wheat allergy.
Diagnosis
In western countries, it is
typical to find people who have
commenced a gluten-free diet
GFD on their own without formal
evaluation for food sensitivity.
Various reasons to adopt this diet
include suggestions from family
members and relatives who may
have CD. Others have received
advice from dieticians. Physicians
may then concur if there has been
the exclusion of other forms of
 Journal of The Association of Physicians of India Vol. 64 March 2016 51

with symptoms of CD to a large

1. Suspect gluten sensitivity degree. The need for performing a
(DBPCC) is a controversial issue.
A single-day DBPCC with capsules
containing wheat flour has been
2. Serologic tests used and is recommended, but
has been disappointing in the
authors hands (Rudihaugen J,
A) CD specific serology (IgA anti-TG2
unpublished results, 2006). The
antibody, IgG/IgA anti-DAG antibody* American Gastroenterological
Association technical review from
B) Wheat allergy tests
Positive 2001 recommended a DBPCC, 50
and this was also recommended in
CD serology#
a recent review 51 and a workgroup
C) IgG/IgA anti-gliadin antibody tests
report. 51 Others have emphasized
the limitations and impracticality
of the DBPCC and consider it
unsuitable in clinical setting. 52
Negative CD antibodies Virtually none of these publications
Evaluate for CD
Negative wheat allergy tests
have addressed the investigation
of NCGS as the clinical entity
Positive IgE and/or prick tests encountered today.
3. Gluten free diet
The authors generally perform an
Work up for food allergies open challenge with 4 slices of white
Symptom improvement sandwich bread (approximately 4 g
gluten per slice). As this challenge
4. Provisional diagnosis of NCGS is not blinded, one could expect a
substantial placebo effect. However,
the clinical responses picked up by
5. Gluten challenge this method seem to overlap with
those seen after blinded challenge.31
Appearance of symptoms There is no clear agreement on how
to perform symptom evaluation
6. Definitive diagnosis of NCGS after challenge. The authors have
used symptom scoring with the
Fig 3: Diagnostic flowchart for NCGS * HLA typing may also be particularly following questionnaires: Short
useful here, as the absence of HLA-DQ2 and -DQ8 has an excellent Form (36) Health Survey (SF-36),
negative predictive value for CD. # Clinician may proceed with the work- S c o r i n g S y s t e m f o r S u b j e c t i ve
up for CD in the less common cases of negative serology but high clinical Health Complaints (SHC) and
suspicion Gastrointestinal Symptom Rating
Scale for IBS (GSRS-IBS), 53 100
gluten-induced disease (CD and serologic tests performed, even if m m v i s u a l a n a l o g u e s c a l e . 31,39
WA) by appropriate serological the patient is on a gluten-free diet None of the validated CD-specific
and/or biopsy tests. already. 49 In other cases, a short symptom questionnaires have been
The clinical workup for diagnosis gluten challenge may be necessary. applied to NCGS investigation.
of NCGS usually focuses initially The finding that symptoms A consensus among clinicians on
on the exclusion of CD and wheat disappear after gluten elimination how to diagnose NCGS is urgently
allergy. The task of exclusion is adds weight to the diagnosis of needed. Figure 3 shows a proposed
difficult in the case of a patient NCGS, which is definitely proven algorithm for the diagnosis of
already on a strict gluten-free diet by a double-blind (or open) oral NCGS.
GFD. If the patient in fact has CD, gluten challenge performed after at Pathophysiology
the mucosa may have recovered least three weeks of GFD. 15 Gluten
Although many questions about
and the serology could also be challenge is initiated once patients
the mechanism of CD remain
negative. However, in many cases symptoms are reasonably under
unresolved, the disease is one of
the mucosal damage persists for good control. The clinical response
the best understood autoimmune
a definite diagnosis, so a small after gluten challenge might be
disorders. By contrast, little is
intestinal biopsy can be taken and va r i a b l e b u t u s u a l l y o ve r l a p s
known about the pathophysiology
52 Journal of The Association of Physicians of India Vol. 64 March 2016
Poorly absorbed carbohydrate
Excess Fructans
Fermentation
Gas production and
short chain fatty acid
production
GASTROINTESTINAL SYMPTOMS
Fig. 4: Proposed mechanisms of non-celiac wheat sensitivity
of NCGS and it is still under
scrutiny.
Sapone and colleagues studied
42 patients with CD and 26 with
NCGS 11 . NCGS subjects showed
a normal intestinal permeability
and claudin-1 and ZO-1 expression
compared with celiac patients, and
a significantly higher expression
of claudin-4. This up-regulation of
claudin-4 was associated with an
increased expression of toll-like
receptor-2 and a significant
reduction of T-regulatory cell
marker FoxP3 relative to controls
and CD patients. Additionally, an
increase in IELs of the classes
and , but no increase in adaptive
immunity-related gut mucosal gene
expression, including interleukin
( I L) - 6 , I L - 2 1 , a n d i n t e r f e r o n -
(IFN-), was detected in NCGS.
These changes suggested an
important role of the intestinal
innate immune system in NCGS,
without any involvement of the
Wheat ingestion
Gluten
Fermentation
Microbiome Spectrum of Immune
changes celiac disease activation / food
allergy variant
adaptive immune response.
A more recent study by Brottveit
et al further supports the presence
of mucosal immune activation
in NCGS, but one that may also
involve the adaptive response. 54
NCGS patients displayed an
increased density of intraepithelial
CD31 T cells before initiation
of challenge. Following gluten
challenge there was a significantly
increased expression of interferon-
gmRNA in duodenal biopsies. These
findings raise the possibility of an
adaptive component as well in the
pathogenesis of. It can be concluded
that although the pathophysiology
of NCGS is currently far from
clear, the available data suggest
immune activation to be a common
denominator in both CD and NCGS.
The triggers of mucosal events
leading to NCGS are not necessarily
represented by the same array
of gluten peptides responsible
for CD development. Unlike the
duodenal mucosa from patients
with CD, upon incubation with
gliadins, mucosa from patients with
NCGS does not express markers of
inflammation, and their basophils
are not activated by gliadins. 55 In
vitro studies suggest that wheat
ATIs (amylase-trypsin inhibitors)
could play a major role as triggers
of the innate immune response in
intestinal monocytes, macrophages
a n d d e n d r i t i c c e l l s e ve n t u a l l y
leading to NCGS. Wheat ATIs are a
family of five or more homologous
low-molecular-weight proteins
highly resistant to intestinal
proteolysis. They are known to
be the major allergen responsible
for bakers asthma. ATIs engage
the TLR4-MD2-CD14 complex and
lead to up-regulation of maturation
markers and elicit release of pro-
inflammatory cytokines in cells
from celiac and non-celiac patients
and in celiac patients biopsies. 56
Despite the selected terminology
for NCGS, there is no clear evidence
pointing that gluten proteins are
the sole culprit molecules for the
condition. It is also possible that
non-gluten proteins of wheat
are partially responsible for
the associated symptoms in at
least a subset of patients. Better
characterization of the trigger
molecules in NCGS will be a
major step toward gaining a better
understanding of the pathogenic
mechanism of the condition,
identifying specific biomarkers,
and devising more effective
treatment strategies. Figure 4
depicts proposed mechanisms of
nonceliac wheat sensitivity.
NCGS and IBS: A Complex Relationship
Irritable bowel syndrome
(IBS) ranks among functional
gastrointestinal disorder, in the
sense that the patients complaints
cannot be explained by laboratory
or biopsy testing. However, the
Rome criteria emphasize pain as a
dominant and necessary feature of
IBS. 57 The experience with NCGS,
however, shows that while some
of these patients may have pain,
bloating, flatulence, and diarrhoea

are much more prominent. Thus
it is difficult to give such patients
a diagnosis of IBS. In addition,
the diagnosis of IBS in patients
who experience full recovery after
withdrawal of gluten from their
diet raises a semantic question: do
they suffer from food intolerance
with IBS-like symptoms or do they
suffer from food-induced IBS? It is
likely that careful investigations
of NCGS patients would reveal
subgroups both with and without
IBS.
Vazquez-Roque and co-workers
demonstrated gastrointestinal
symptoms after gluten ingestion
in subjects affected with the D
variant (diarrhoea-predominant)
of IBS recently. 58 Subjects on a
gluten containing diet (GCD) had
more bowel movements per day,
particularly those with HLA-DQ2
and/or DQ8 genotypes. The GCD
was associated with higher small
bowel permeability. Patients on
the GCD had a small decrease in
expression of zonula occludens
1 i n s m a l l b o we l m u c o s a , a n d
significant decreases in expression
of zonula occludens 1, claudin-
1, and occludin in recto sigmoid
mucosa; again the effects of the GCD
on expression were significantly
greater in HLA-DQ2/8positive
patients. On the other hand, the
GCD vs. GFD had no significant
effects on gastrointestinal transit
or histology. It was concluded
that gluten alters bowel barrier
functions in patients with IBS-D,
particularly in HLA-DQ2/8
positive patients. Another reason
why a GFD would have a positive
effect in IBS is because a GFD is
deficient in dietary fibre, making
it more easily digestible, even
in patients without any gluten
sensitivity. 59 These data provided
mechanistic explanations for the
observation that gluten withdrawal
may improve patient symptoms
in IBS.
In addition, subsets of NCGS
and IBS patients could have
somatisation disorders as a
common denominator. It has been
Journal of The Association of Physicians of India Vol. 64 March 2016 53
found that the IBS population the data published by Biesiekirski
suffers from substantial psychiatric et al. it is also possible that there are
comorbidity. 60 In a study of CD IBS cases entirely due to FODMAPs
and HLA-DQ21 NCGS patients, that, therefore, cannot be classified
however, the authors found that as affected by NCGS.
the NCGS patients did not exhibit a Natural History, Prognosis and
tendency for general somatisation.61 Treatment for NCGS
In addition, the psychometric Knowledge of natural history
p r o f i l e s o f t h e 2 c o h o r t s we r e and progression of NCGS is still
completely overlapping, as was lacking.
their quality of life as measured
Whether intestinal lymphoma
by SF-36.
or other gastrointestinal neoplasm
Questions Still to be Answered Despite
can complicate NCGS is yet to be
Increasing Awareness
determined. Same commercially
How specific the effect of gluten available gluten-free products used
withdrawal from the diet of patients by CD patients can be prescribed
with IBS is, still remains to be to NCGS patients. Considering the
elucidated. Besides gluten, wheat, lack of knowledge as to whether
and wheat derivatives contain NCGS is a permanent or a transient
other constituents that could play condition, periodic reintroduction
a role in triggering symptoms in of gluten (? yearly) on GFD might
IBS patients, e.g., amylase-trypsin be an advise. 8,9,14,42,63
inhibitors (ATIs) and fructans.
Current and Future Trends
Biesiekirski et al 62 studied IBS/
We are now with NCGS where
self-reported NCGS patients and
we probably were with CD forty
investigated by a double-blind
years ago indeed. In the 1980s
crossover trial. Study subjects
we k n e w t h a t C D e x i s t e d , b u t
were randomly allocated to groups
we had little information on the
given a 2-week diet of reduced
mechanisms of enteropathy,
FODMAPs and then placed on
immunological response involved
gluten or whey protein for 1 week,
in the pathogenesis of the disease,
followed by a washout period of
the genetic component of the
at least 2 weeks. In all participants
disease, its multifaceted clinical
symptoms consistently improved
presentation, and its complication.
during reduced FODMAP intake,
We dont have robust screening
but significantly worsened on
tools and lack understanding on
gluten or whey protein. FODMAPS
the most appropriate management
list includes fructans, galactans,
of the disease. The confusion
fructose, and polyols that are
about NCGS stems from the few
contained in several foodstuffs,
facts, and the many fantasies,
including wheat, vegetables, and
currently available on this topic.
milk products. These results raise
The best testimonial of this concept
the possibility that the positive
is the comparison of the literature
effect of the GFD in patients with
published on both conditions
IBS is an unspecific consequence of
during the past six decades. The
reducing FODMAPs intake, given
publications on CD doubled every
that wheat is one of the possible
20 years from approximately 2500
sources of FODMAPs. However, it
in the period of 195070 to ~9500
should be stressed that FODMAPs
in the period 19912010, with
cannot be entirely attributed for
already more than 2000 papers
the symptoms scenario, since these
published between 2011 and 2013.
patients experience a resolution of
Conversely, there were almost no
symptoms while on a GFD despite
scientific reports on NCGS before
continuing to ingest FODMAPs
1970 and only a handful number
from other sources, like legumes
of papers have been published
(a much richer source of FODMPs
ever since, most of them after 2005.
than wheat). Nevertheless, based on
54 Journal of The Association of Physicians of India Vol. 64 March 2016
Table 2: Number of research papers
on NCGS in last couple of
years
Timeline CD NCGS NCGS/CD ratio
1951-70 2632 6 1:438
1971-90 4915 118 1:43
1991-2010 9498 733 1:13
2011-13 2014 188 1:10
The increase interest in NCGS is
testified by the decreased. NCGS/
CD publication ratio that dropped
from 1:438 in the period 195070
to 1:10 in the period 201013 15
(Table 2).
Recent studies raised the
possibility that, beside gluten 42
and wheat ATIs, 56 low-fermentable,
poorly-absorbed, short-chain
c a r b o h y d r a t e s 62 c a n l e a d t o
symptoms overlap experienced by
NCGS patients. These new findings
need corroboration through
additional studies involving
larger numbers of subjects. If
these studies will confirm these
new findings, they will probably
prompt a change in nomenclature
from NCGS to wheat sensitivity to
reflect the fact that, beside gluten,
other components of wheat may
be responsible for the symptoms
reported by NCGS patients.
To surprise there are still lists of
questions about NCGS that should
be addressed.
1. I s N C G S p e r m a n e n t o r
transitory?
2. How frequent is NCGS?
3. Is the threshold of sensitivity
the same for everybody, or
change from subject to subject
and in the same subject over
time?
4. Is any reliable biomarker for
NCGS diagnosis
There is need of dedicated input
and ample of fund to explore the
pearls in the world of NCGS. High
yield research fields for NCGS
overshadowing next couple of
years would be
1. D o u b l e - b l i n d p l a c e b o -
controlled studies testing whole
wheat in one arm against to its
single component to assess real
Table 3: Common foodstuffs having 5. Hopper AD, Cross SS, Hurlstone DP et al.
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