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Non-Celiac Gluten Sensitivity: A Review

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: Background and objectives: Grain food consumption is a trigger of gluten related disorders: celiac disease, non-celiac gluten sensitivity (NCGS) and wheat allergy. They demonstrate with non-specific symptoms: bloating, abdominal discomfort, diarrhea and flatulence. Aim: The aim of the review is to summarize data about pathogenesis, symptoms and criteria of NCGS, which can be helpful for physicians. Materials and Methods: The PubMed and Google Scholar databases were searched in January 2019 with phrases: ’non-celiac gluten sensitivity’, non-celiac gluten sensitivity’, non-celiac wheat gluten sensitivity’, non-celiac wheat gluten sensitivity’, and gluten sensitivity’. More than 1000 results were found. A total of 67 clinical trials published between 1989 and 2019 was scanned. After skimming abstracts, 66 articles were chosen for this review; including 26 clinical trials. Results: In 2015, Salerno Experts’ Criteria of NCGS were published. The Salerno first step is assessing the clinical response to gluten free diet (GFD) and second is measuring the effect of reintroducing gluten after a period of treatment with GFD. Several clinical trials were based on the criteria. Conclusions: Symptoms of NCGS are similar to other gluten-related diseases, irritable bowel syndrome and Crohn’s disease. With Salerno Experts’ Criteria of NCGS, it is possible to diagnose patients properly and give them advice about nutritional treatment
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Medicina 2019, 55, 222; doi:10.3390/medicina55060222 www.mdpi.com/journal/medicina
Review
Non-Celiac Gluten Sensitivity: A Review
Anna Roszkowska
1,
*, Marta Pawlicka
1
, Anna Mroczek
1
, Kamil Bałabuszek
1
and Barbara Nieradko-Iwanicka
2
1
Medical University of Lublin, Radziwillowska 11 Street, 20-080 Lublin, Poland;
martamisztal991@gmail.com (M.P.); anna.mroczek94@wp.pl (A.M.); balkam@o2.pl (K.B.)
2
Chair and Department of Hygiene, Medical University of Lublin, Radziwillowska 11 Street,
20-080 Lublin, Poland; barbaranieradkoiwanicka@umlub.pl
* Correspondence: annros7@gmail.com
Received: 2 February 2019; Accepted: 22 May 2019; Published: 28 May 2019
Abstract: Background and objectives: Grain food consumption is a trigger of gluten related disorders:
celiac disease, non-celiac gluten sensitivity (NCGS) and wheat allergy. They demonstrate with non-
specific symptoms: bloating, abdominal discomfort, diarrhea and flatulence. Aim: The aim of the
review is to summarize data about pathogenesis, symptoms and criteria of NCGS, which can be
helpful for physicians. Materials and Methods: The PubMed and Google Scholar databases were
searched in January 2019 with phrases: ’non-celiac gluten sensitivity’, non-celiac gluten sensitivity’,
non-celiac wheat gluten sensitivity’, non-celiac wheat gluten sensitivity’, and gluten sensitivity’.
More than 1000 results were found. A total of 67 clinical trials published between 1989 and 2019 was
scanned. After skimming abstracts, 66 articles were chosen for this review; including 26 clinical
trials. Results: In 2015, Salerno Experts’ Criteria of NCGS were published. The Salerno first step is
assessing the clinical response to gluten free diet (GFD) and second is measuring the effect of
reintroducing gluten after a period of treatment with GFD. Several clinical trials were based on the
criteria. Conclusions: Symptoms of NCGS are similar to other gluten-related diseases, irritable bowel
syndrome and Crohn’s disease. With Salerno Experts’ Criteria of NCGS, it is possible to diagnose
patients properly and give them advice about nutritional treatment
Keywords: non-celiac gluten sensitivity; irritable bowel disease; gluten; FODMAP; wheat allergy
1. Introduction
Wheat, rice and maize are the most commonly consumed grains worldwide. These products are
rich sources of starch—the basic dietary component for the growing human population [1]. Wheat
contains gluten. In 1953 Dickie, van de Kamer and Weyers published a study confirming
malabsorption after wheat consumption in patients with celiac disease (CD) [2]. Nowadays, gluten
intake is considered to be the trigger of gluten related disorders (GRDs). In GRD, the gluten-free diet
(GFD) is principal, effective and yet the only treatment method. The gluten-free market is still rising,
not only because of growing interest and public awareness of GRDs, but also due to celebrities touting
this diet by for weight loss and athletes for improved performance [3], which is debatable as grains
should be the main source of energy in the human diet.
2. Materials and Methods
Standard up-to-date criteria were followed for review of the literature data. A search for English-
language articles in the PubMed database was performed. The PubMed and Google Scholar
databases were searched in January 2019 with phrases: ’non-celiac gluten sensitivity’, non-celiac
gluten sensitivity’, non-celiac wheat gluten sensitivity’, non-celiac wheat gluten sensitivity’, and
gluten sensitivity’. More than 1000 results were found. A total of 67 clinical trials published between
Medicina 2019, 55, 222 2 of 18
1989 and 2019 was scanned. After skimming abstracts, 66 articles were chosen for this review
including 26 clinical trials.
2.1. Gluten Related Disorders (GRDs)
The term “gluten intolerance” includes three different conditions: CD, allergy to wheat (WA)
and non-celiac gluten sensitivity (NCGS) [4]. To date, CD and WA comprise for the best known and
studied entities, which are mediated by immune system [1]. WA—classified as a classic food allergy
is induced by wheat (not only gluten) intake that leads to type I and type IV hypersensitivity. The
crucial role in WA disorder play IgE immunoglobulins [1,5]. CD is an autoimmune disease occurring
in genetically susceptible individuals with HLA-DQ2 and/or HLA-DQ8 genotypes. CD is
characterized by the presence of specific serological antibodies such as: anti-tissue transglutaminase
(tTG) IgA, anti-endomysium IgA (EMA) and anti-deamidated gliadin peptides IgG (DPG) [1]. There
were reported cases of patients with gluten sensitivity in which allergic and autoimmune
mechanisms could not be identified. They were collectively described as NCGS [1]. The NCGS or
“non-celiac wheat sensitivity’’ (NCWS) has been a topic of interest in recent years. This trend is
associated with a large number of studies concerning the syndrome [6,7]. The term NCWS is more
adequate because of components other than gluten, that may contribute to intestinal and extra-
intestinal symptoms [6]. In 1980, Cooper et al. described intestinal gluten-sensitive symptoms in 8
patients in whom CD was ruled out [8]. Further studies led to the definition of NCGS. NCGS is a
condition characterized by clinical and pathological manifestations, related to gluten ingestion in
individuals in whom CD and WA have been excluded [1,6,9,10]. Leccioli et al. described NCGS as a
multi-factor-onset disorder, perhaps temporary and preventable, associated with an unbalanced diet
[11].
Interestingly, II MHC haplotype HLA-DQ2 and HLA-DQ8 typical for CD is present only in
about 50% of NCGS patients [1]. The main features of GRDs are summarized in Table 1.
Table 1. Comparison of prevalence, pathogenic, and diagnostic features of gluten related disorders
(GRDs); non-celiac gluten sensitivity (NCGS), IgA anti-EMA (IgA antibodies against endomysium),
IgA anti-tTG (IgA antibodies against transglutaminase), IgG anti-DGP (IgG antibodies against
deamidated gliadin peptides).
Celiac Disease NCGS Wheat Allergy
Prevalence 0,5–1,7% no population studies 0,5–9% in children
Pathogenesis autoimmune non-specific immune response IgE mediated response
DQ2-DQ8 HLA
haplotypes positive in 95% cases positive in 50% cases negative
Serological
markers
IgA anti-EMA, IgA anti-tTG,
IgG anti-DGP, IgA anti-gliadin IgA/IgG anti-gliadin in 50% cases
specific IgE antibodies
against wheat and
gliadin
Duodenal biopsy * Marsh I to IV with domination
of Marsh III and IV
Marsh 0-II, but according to some
experts Marsh III might also be in
NCGS
Marsh 0-II
Duodenal villi
atrophy present absent might be present or
absent
* Marsh classification.
2.2. Epidemiology of Gluten Related Disorders (GRDs)
CD morbidity, based on serological results, is estimated to be 1.1% to 1.7% worldwide [12,13].
WA among children occurs with a frequency of 0,4–9% [5,14]. Due to an absence of diagnostic
markers and population studies, the prevalence of NCGS is not well established [5,6]. Although
studies have been conducted by several authors, this problem is still insufficiently explored. Previous
data were based primarily on questionnaires for self-reported gluten sensitivity SR-GS/self-reported
NCGS. According to several authors, the NCGS prevalence is from 0.6% up to 13% of the general
population [15–19]. NCGS was reported more often among women [16–18], adults in the fourth
decade of life [19,20] and individuals coming from urban area [18]. Among intestinal symptoms the
Medicina 2019, 55, 222 3 of 18
most frequent in NCGS are: bloating, abdominal discomfort and pain, diarrhea and flatulence. The
most common extra-intestinal symptoms were: tiredness, headache and anxiety [15,16,18,20].
Differentiation between NCGS and functional gastrointestinal (GI) disease—mainly irritable bowel
syndrome (IBS)—may be difficult as some of the above-mentioned symptoms overlap with IBS
manifestations. Van Gils et al. pointed that 37% of self-reported gluten sensitivity individuals (SR-
GS) fulfilled the Rome III criteria for IBS, in contrast to 9% prevalence in the control group [18].
Similar findings were reported by Carroccio et al. IBS symptoms were reported in 44% self-reported
NCWS [15]. According to research conducted by Cabrera et al., IBS, eating disorders and lactose
intolerance were present more often in SR-GS individuals than in non-SR-GS group (14.3% vs. 4.7%)
[16]. Herein, discussed studies indicate that SR-GS/SR-NCGS may correlate with more frequent
occurrence of IBS, comparing to the general population. However, the German Society of Allergology
and Clinical Immunology emphasized that the publications about NCGS suffer from certain
weaknesses: absence of validated diagnostic criteria, suitable biomarkers, frequent self-diagnosis and
unconfirmed etiology of reported symptoms. Thus, the prevalence of NCGS cannot be clearly
established [21].
2.3. Gluten
Gluten is defined as a family of proteins found in grains (wheat, rye, barley, oats). It includes
two main proteins: gliadin and glutenin. Also, similar proteins such as secalin in rye, harden in barley
and avenues in oats contribute to the definition of ‘gluten’ [22]. Gluten proteins are characterized by
high proline and glutamine content, moreover, they are resistant to proteolytic enzymes in the
gastrointestinal tract. In some individuals these peptides can cross the epithelial barrier and activate
immune system: trigger an allergic (WA) or autoimmune response (CD) [5]. Incomplete digestion
leads to significant changes in human gut and causes intestinal or extra-intestinal symptoms. Gliadin
and other gluten proteins stimulate T-cells. Some authors suggested that amylase-tripsin inhibitors
(ATIs) and fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) may be associated
with NCGS [11]. Another wheat constituent, known as agglutinin-carbohydrate binding protein and
exorphins seem to influence immune system and induce damage of intestinal epithelium [11,22].
2.4. Amylase-Tripsin Inhibitors (ATIs)
ATIs are albumin proteins found in wheat representing up to 4% of total proteins in grains [1].
They are highly resistant to intestinal proteases [1] and may induce release of pro-inflammatory
cytokines from monocytes, macrophages and dendritic cells through activation of a toll-like receptor-
4 in CD and NCGS patients [1,22]. ATIs may provoke activation of innate immune cells and intestinal
inflammation [21]. ATIs activate immunological system through effect on toll-like receptor-4 in CD,
that was confirmed in the research conducted by Junker et al. on mice deficient in TLR4 or TLR
signaling [23]. Authors observed, that their mice models were protected from intestinal and systemic
immune responses during oral ATIs intake [23]. Scientists also confirmed, that ATIs stimulate
monocytes, macrophages and dendritic cells in vitro to produce IL-8, IL-12, TNF, MCP-1 and
Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) [23].
2.5. Fermentable Oligo-, Di- and Mono-Saccharides and Polyols (FODMAPs)
FODMAPs are short-chain sugars with less than 10 carbon atoms in the molecule [24]. The
attention of scientists in recent years was drawn to the potential contribution of FODMAPS to
pathogenesis of gastrointestinal disorders [25]. The scientists from Monash University in Australia
conducted thorough analysis of a group of carbohydrates, which, despite their different structures,
produced similar postprandial effects. The most prevalent forms of FODMAP include:
fructooligosaccharides (FOS), galactooligosaccharides (GOS), lactose, fructose, polyols, sorbitol and
mannitol. Barrett et al. created a list of food products that are good sources of FODMAP (Figure 1)
and poor in short chain sugars (Figure 2) [24].
Medicina 2019, 55, 222 4 of 18
Figure 1. List of products being the source of fermentable oligo-, di-, and mono-saccharides and
polyols (FODMAPs).
Figure 2. List of products low in FODMAPs.
Compounds belonging to the FODMAP group are not digested nor absorbed in the
gastrointestinal tract. They have a strong osmotic effect and undergo rapid fermentation in the
intestines, resulting in intestinal liquefaction, excessive gas production, bloating and pain. They may
cause or exacerbate symptoms in susceptible patients with inflammatory bowel disease and irritable
bowel syndrome (IBS) [24,25]. Numerous studies have confirmed the improvement in patients
suffering from ulcerative colitis, Crohn’s Disease and IBS following the elimination of short-chain
sugars from the diet [26].
Wheat is a rich source of gluten and also contains large amounts of FODMAPs, which play a key
role in NCGS development [27]. Some researchers suggest that diet low in FODMAP is beneficial for
NCGS patients [25].
Considering the above research results, scientists are leaning towards renaming NCGS to a more
recent NCWS [2 7]. It should be emph asized that a diet poor in FODMAPs should not be used without
medical indications, as healthy people do not benefit from such diet [24]. Moreover, it was proven
that FOS and GOS, compounds belonging to FODMAPS, alike prebiotic, favor proper colonization of
intestines with Bifidobacteria and Lactobacilli bacteria and limit the proliferation of Bacteroides spp.,
Clostridium spp. and Escherichia coli. There is evidence that short-chain fatty acids (SCFA)—the
product of FODMAP fermentation—have protective properties against colorectal cancer [24,27].
FODMAPs are believed to have a positive effect on lipid metabolism by lowering serum cholesterol,
triglycerides and phospholipids [27]. In addition, this diet leads to calcium absorption disorders,
lowering its serum levels. People resigning from products that are the source of FODMAP are at risk
of vitamin and antioxidants deficiency [27,28]. Therefore, it is suggested to supplement vitamins, pro-
and prebiotics when switching to the low FODMAPs diet [24,27].
2.6. The Salerno Experts’ Criteria of NCGS
As long as the NCGS biomarker is not available, certain limitations are included in two-step
diagnostic protocol introduced in 2015. However, up to date The Salerno Experts’ Criteria constitute
the only accessible recommendations for diagnosis of NCGS. It should be emphasized that according
to currently used criteria, NCGS should not be based only on exclusion diagnosis, which is new in
Medicina 2019, 55, 222 5 of 18
comparison to the former practice [29]. Thus, the guidelines indicate the need of a standardized
procedure: 6-week course of gluten-free diet—with the simultaneous, continuous assessment of
symptoms and their intensity, followed by measuring the effect of reintroducing gluten after a period
of treatment with GFD. A modified version of the Gastrointestinal Symptom Rating Scale (GSRS) was
found to be applicable in terms of symptoms evaluation. Although limited, double-blind-placebo-
controlled (DBPC) procedure remains to be the golden standard in NCGS investigation, yet, single-
blinded procedure is allowed for the purposes of clinical practice [29–31]. The guidelines stress the
importance of patient compliance, especially when it comes to shift to GFD, which should be
discussed with a dietitian before implementation [29].
Back to the limitations—it is recommended to use gluten in the form of commonly consumed
food products, during gluten challenge, rather than in the form of gluten capsules. Nevertheless,
there is presumption that ATIs and FODMAPS—as the constituents of grains—interfere with the
DPBC results [6,30,32]. Moreover, since the study on patients complaining about IBS-like symptoms,
it was revealed that almost two-thirds of questioned patients presented nocebo effect after
elimination diet, which seems to have same significant influence on performing DBPC during gluten
challenge [29,33].
The fact that numerous symptoms manifested by active NCGS can be either vague or simply
mimic other medical conditions, makes the diagnostic process long lasting and complex. For instance,
bloating, abdominal pain, and irregular bowel movements are typical symptoms seen in IBS [20]. The
overlapping symptoms of IBS, Crohn’s disease and GRD are shown in Figure 3.
The similarity between symptomatology of IBS and NCGS may lead to a wrong diagnosis and
ineffective treatment [6]. The clinical case described by Vojdani and Perlmutter, presented a 49-year-
old woman formerly diagnosed with IBS. The patient complained about abdominal pain,
constipation, acid reflux and headache. Following conditions were contemplated and finally
excluded: autoimmunological disorders, abnormal level of thyroid hormones, H. pylori infection [34].
Consequently, in the course of inappropriate therapy, the patient developed symptoms imitating
systemic lupus erythematosus. Furthermore, the patient showed some improvement after
corticosteroids administration, which appeared to be confusing for making right diagnosis as well
[34]. Ultimately, after years of inappropriate treatment, the NCGS turned out to be the reason for
patient’s affliction. In addition, a few studies indicate that NCGS can be primary trigger for
developing IBS. Virtually, as NCGS and IBS-like symptoms tend to overlap, the diagnostic process is
particularly challenging [20,35,36].
Even though the diagnosis within the wide spectrum of bowel diseases was made, in the case of
continuous therapy failure, it is crucial to reconsider NCGS as the possible cause. A clinical case of a
patient with NCGS overlapping Crohn’s disease has been reported. The onset of Crohn’s disease is
characterized mainly by unspecific symptoms, including diarrhea, weight loss, right lower quadrant
abdominal pain, which proceed in a gradual way, with very harmful effects [37]. In the above-
mentioned case report, the patient suffered from refractory Crohn’s disease for 14 years and elevated
IgG class antibodies directed against native gliadin (AGA) were detected, which shed a light on
gluten related disorder. Introduction of GFD ceased diarrhea and enabled the patient to gain weight
[34]. It is worth highlighting that NCGS patients are twice as likely to have AGA positivity [38].
At present, the linkage between gluten sensitivity, such as CD, and neurological disorders seems
to be obvious. So far, numerous studies have unveiled extra intestinal symptoms affecting the
peripheral and central nervous system due to celiac sprue. Although not fully understood yet, a wide
range of NCGS neurological complications has been reported too. The state-of-the-art knowledge on
NCGS revealed its association with transient and subtle cognitive impairment, being called “brain
fog” [39]. Some scientists suggest NCGS to worsen symptoms in the context of depression but further
examination must be performed to comprehend and determine NCGS relation with depressive
disorders [32]. Busby et al. in their meta-analysis pointed out that standardization of methods
measuring dietary adherence and mood symptoms is vital in terms of future research. Nevertheless,
they admit that the gluten elimination diet may be an applicable treatment for mood disorders in
patients suffering from gluten-related diseases [40].
Medicina 2019, 55, 222 6 of 18
It has not been until recently, when researchers explored that NCGS may be associated with
gluten ataxia (GA), as the patients with typical GA symptoms did not meet criteria for CD diagnosis
[41]. NCGS symptoms are believed to originate from an innate immune response. Interestingly,
autoimmune diseases are reported to be more frequent in this group of patients, comparing to sheer
IBS patients [42].
Figure 3. Overlapping symptoms in Crohn’s disease, IBS and gluten-related disease.
3. Results
Comparison of selected clinical trials concerning NCGS is shown in Table 2. In the study by
Capannolo et al. patients with CD and WA were excluded while in the study by Elli et al. patients
without CD, WA, IBS were enrolled. The prevalence of NCGS, CD and WA among patients with
functional GI symptoms in the study of Capannolo et al. was estimated to be 6.88%, 6.63% and 0.51%.
Capannolo et al. indicate that high frequency of visits due to gluten-related symptoms is not
associated with high prevalence of GRDs. Ellie et al. established that 14% of patients, suspected to
have NCGS because of responding to gluten withdrawal showed a symptomatic relapse during the
gluten challenge. It was highlighted that GFD can have a beneficial effect even in the absence of CD
or WA. However, there are certain limitations seen in both of compared above research papers. The
research of Capannolo et al. was lacking blindness in GFD challenge and missing evaluation of
possible influence of other food components. Besides it was conducted before Salerno Criteria were
introduced (2015). A choice of timing and gluten dosage shown in the research of Elli et al. was not
in line with the timing suggested by Salerno criteria. In addition, the protocol did not make use of a
scheduled diet besides GFD. Moreover, a nocebo effect may be presumed, in consistence with
symptomatic deterioration observed in the placebo group. Other diet variables in both studies cannot
be excluded (ATIs) [43,44].
Medicina 2019, 55, 222 7 of 18
Table 2. Comparison of selected researches on NCGS.
References Study Group Exclusion Criteria Methods Findings Comments
Biesiekierski et
al. 2013
IBS patients fulfilling
Rome III criteria in NCGS
criteria, on GFD for 6
weeks
CD, IBD, age < 16, serious GI disease (cirrhosis),
psychiatric disorders, alcohol abuse, NSAIDs and
immunosuppressive treatment
GFD for 6 weeks, next 2-weeks diet low in FODMAPs, then 3 days
one of the groups—high gluten 16 g, low gluten 2 g gluten or 14 g
whey protein, control for 2 weeks washout period and crossover to
another group for 3 days. The primary outcome: GI symptoms
measured by using 100-mm VAS scoring. The secondary outcome:
Fatigue measured by Daily-Fatigue Impact Scale (D-FIS), gliadin-
specific T-cell response, biomarkers.
The primary outcome: Gluten-specific
responses only in 8% of patients, 16% had
worsening of overall GI symptoms in high
gluten diet Limitations: The nocebo effect was
present independent of substances
which was delivered
The secondary outcome: Fatigue
measured by D-FIS was lower in the low
FOTMAPs diet, no significant difference
in biomarkers , physical activity or sleep
was observed, only one patient had
gliadin-specific T-cell response.
Capannolo et
al. 2014
Individuals with gluten
related symptoms CD and WA NCGS finding: on the basis of the disappearance of the symptoms
within GFD 6 month, followed by 1month GD.
CD patients: 26 (6.63%); WA patients: 2
(0,51%); NCGS patients: 27 (6.88%).
Patients with no change of symptoms
after GFD 337 (85.9%)
Limitations: Lack of blindness in
GFD challenge
Missing evaluation of possible
influence by other food components
Symptoms in 74% NCGS patients:
Intestinal: abdominal pain, diarrhea,
constipation, alternating bowel function,
epigastric pain
Extra intestinal: malaise, chronic fatigue,
headache, anxiety, confused mind,
depression, joint/muscle pain, resembling
fibromyalgia, weight loss, anemia,
dermatitis, rash
Related disorders in NCGS patients:
lactose intolerance, autoimmune
thyroiditis, type 1 diabetes, psoriasis,
sarcoidosis
Zanini et al.
2015
Individuals on gluten-free
diet (GFD) on their own
initiative
CD, non-strict adherence to a GFD, symptomatic on
GFD
The primary outcome: the ability of the participants to correctly
identify flour containing glute n. GSRS questionnaire was performed
Only 34% (12 participants) correctly
identified gluten- containing flour
fulfilling the clinical diagnostic criteria for
NCGS.
The gluten-free flour used in this
test contained FODMAP
Hollon et al.
2015
Individuals with Active
CD, CD in Remission,
Gluten Sensitivity (GS)
Positive CD serology, abnormal duodenal
histopathology, unresponsive to gluten open challenge
GS finding: on the basis of th e disappearance of the sympto ms
within GFD; non-blinded gluten challenge (10 g) for a minimum of 2
months before endoscopy
Increase of gut permeability after PT-
gliadin ex-vivo administration in all three
study groups, and in control group
Limitations: Lack of blindness in
GFD challenge—possible placebo-
response; Lack of GFD challenge in
the control group—possible
individuals with undiagnosed
GS/CD
Shahbazkhani
et al. 2015
Individuals with newly
diagnosed IBS based on
the Rome III criteria
Patients with CD, GFD introduced ever in medical
history, self-exclusion of wheat from the diet, IBD,
diabetes, concurrent drugs for depression/anxiety,
NSAI drugs intake, abnormal levels of: glucose, urea,
creatinine, sodium, potassium, hemoglobin,
erythrocyte sedimentation rate, thyroid function tests
GS finding: IBS diagnosed patients responding to gluten challenge
by means of statistically significant worsening of symptoms after
gluten meal packet. Patients previously following strict GFD,
continued gluten challenge for 6 weeks
Significant increase for following
symptoms after gluten-containing meal
challenge: bloating, abdominal pain, stool
consistence, tiredness, nausea
Limitations: Packets containing
gluten meal in t he form of
powder—not recommended
according to Salerno criteria
Pros: double-blind randomized
placebo-controlled trial
Di Sabatino et
al. 2015
Suspected NCGS
individuals CD, WA
Individuals were randomly assigned to groups given gluten or
placebo for 1 week, each via gastro-soluble capsules. After a 1 week
of gluten-free diet, participants crossed over to the oth er group.
Gluten group: significantly increased
overall symptoms (intestinal symptoms:
abdominal bloating and pain, extra-
intestinal symptoms: foggy mind,
depression, aphthous stomatitis) vs.
placebo group.
Limitation: small study group
Medicina 2019, 55, 222 8 of 18
Elli et al. 2016
Individuals with functional
gastroenterological
symptoms with enrolled
on 3-week-long GFD
CD, WA, IBS psychiatric disorders, major abdominal
surgery, diabetes mellitus, systemic autoimmune
diseases, previous anaphylactic episodes, any systemic
disorders, pregnant, breast feeding women, GFD in
previous 6 months, patients on pharmacological
therapy
Phase 1. GFD response in dividuals: questionnaire and next 3-week
GFD. Patients with significantly improvement carried on to next
phase.
Phase 2. 98 subjects. GFD response patients—maintain strict GFD
and underwent placebo-controlled double-blind gluten challenge
with crossover. Patients were randomized to take gluten in capsules
or placebo (rice starch) for 7 days. Total duration: 21 days: 7 days on
gluten or placebo, 7 days wash-out, 7 days on gluten or placebo.
28 individuals from phase 2 reported a
symptomatic relapse and deterioration of
quality of life. 14 patients responded to
the placebo ingestion. About 14 patients
responding to gluten withdrawal showed
a symptomatic relapse during the gluten
challenge—they are suspected to have
NCGS.
Strengths: The blinding of patients
and doctors, and the crossover
design.
Weaknesses: arbitrary choice of
timing and gluten dosage, the
protocol did not make use of a
scheduled diet besides GFD, other
diet variables cannot be excluded
(ATIs). Symptomatic deterioration
was also observed in placebo group.
Rosinach et al.
2016
Individuals with clinical GI
symptoms and clinical and
histologic al remission after
GFD
Age < 18, CD, NSAIDs and Olmesartan
immunosuppressive treatment in last month,
immunosuppressive therapy, parasitic or H. pylori
infection, AD, pregnant or breastfeeding women,
participation in other randomized controlled trials in
the last 4 weeks, serious GI diseases and GI surgery,
severe comorbidities, failure to comply with the
protocol requirements
Patients were randomly assigned to gluten group (20 g/day, n = 11)
and placebo (n = 7). Clinical symptoms were measured by VAS,
quality of life using GIQLI. Scientists examined the presenc e of
gamma/delta+ cells and transglutaminase deposits.
91% of patients with clinical relapse
during gluten challenge compared to
28.5% after placebo. Worsening results in
clinical scores and GIQLI was observed in
patients on gluten diet, but not in the
placebo
Limitations: a small study group
primary end-point: disease relapse after 6 months
Carroccio et al.
2017 Induviduals with NCWS Data collecting from a previous study of NCWS.
88% subjects improved after a diagnosis of
NCWS; 145 of 148 patients on strict GFD
(98%) had reduced symptoms, compared
to 30 of 52 patients who was not on GFD,
20 (from 22) subjects who repeated DBPC
challenge reacted to wheat. NCWS is a
persistent condition.
Limitations: not thoroughly
discussed exclusion criteria
Skodje et al.
2018
Individuals self-reported
NCGS on gluten-free diet
(GFD) on their own
initiative for at least 6
months
Exclusion criteria: CD, WA, IBD, gastrointestinal
comorbidity, allergy to nuts and sesame, alcohol
abuse, pregnancy, breast feeding, women in fertile age
without using contraception, long travel distance,
considerable infection, patients on
immunosuppressive agents’ therapy
GFD for 6 months, next 7 days on one of three diets challenge
(gluten 5,7g, fructans 2,1g and placebo), 7 days washout, then
crossover to next diet.
The primary outcome: gastrointestinal symptoms measured by
GSRS-IBS.
The secondary outcome: daily GI symptoms measured by VAS, life
quality depends on symptoms by SF-36, depression and anxiety
symptoms measured by Hospital Anxiety and Depression Scale,
Fatigue measured by Giessen Subjective Complaint List and VAS
The primary outcome: overall GSRS-IBS
higher in the fructans group (38,6) than in
the gluten group (33,1) and placebo (34,3).
The secondary outcome: overall GI
symptoms measured by VAS higher in
FODMAPs diet, decreased vitality and
greater weakness in the group of patients
receiving fructans
Limitations: high nocebo response
Roncoroni et
al. 2019
Individuals with NCGS
criteria, complaining about
functional GI symptoms
CD, WA, IBD, adult age (<18 years old), positive anti-
tissue transglutaminase IgA, psychiatric disorders,
major abdominal surgery, diabetes, GFD for previous
six months, autoimmune diseases and systemic
disorders, pregnancy, breast feeding, experience of
anaphylaxis and patients during pharmacotherapy
GFD for 3 weeks, then exposure to diets with gradually increasing
the amount of gluten: low-gluten diet (3.5–4 g gluten/day, week 1, n
= 22 + 2 dropped out patients), mid-gluten diet (6.7–8 g gluten/day,
week 2, n = 14), and a high-gluten diet (10–13 g gluten/day, week 3,
n = 8). Patients without GI symptoms on a previous diet were
classified into more gluten- containing diet. Patients with GI
symptoms were shifted back to a well-tolerated diet. Daily GI
symptoms measured by VAS, life quality depends on symptoms by
SF-36
Different reactions of patients after the
introduction of gluten. Limitation: a small study group
Medicina 2019, 55, 222 9 of 18
In 2015, Zanini et al. published a prospective, randomized, double-blind, placebo-controlled
study on patients without CD or wheat allergy as seen in Table 2. Scientists observed 35 patients (31
females and 4 males) being on a GFD due to their own initiative because of gastrointestinal symptoms
they had had on a diet containing gluten. They were switched to a diet containing gluten.
Participants’ ability to distinguish between flours containing gluten and gluten-free was assessed, as
well as their score in the Gastrointestinal Symptoms Rating Scale (GSRS). In order to participate in
the study, patients had to be over 6 months a self-prescribed GFD and have a Gastrointestinal
Symptoms Rating Scale (GSRS) below 4. The CD had had to be excluded before the start of the GFD.
Before the beginning of the study t-TG antibody levels were measured and patients were instructed
how to keep a diet diary. After 3 months, t-TG antibody level was checked again and GSRS
questionnaire was performed. The participants received 10-g sachets containing gluten-free or
gluten- containing flour labeled A or B. Patients were ordered to add contents to the pasta or soup
for 10 days. Then for 2 weeks there was a washout period. Then, the patients received a second sachet
with the other label, which they were to consume for 10 days. The primary outcome was the ability
of the participants to correctly identify flour containing gluten. The study showed that only 34% (12
participants) correctly identified gluten- containing flour. Two thirds of the participants were not able
to properly identify flour containing gluten. Almost half of the participants 17 (49%) misidentified
gluten-free flour as gluten-containing flour, but those patients recorded symptoms and their GSRS
scores increased on the flour not containing gluten. The gluten-free flour used in this test contained
FODMAP [45].
Hollon et al. in their study (Table 2) disclosure ex-vivo gliadin effect on gut permeability in
patients with active celiac disease (ACD), remission celiac disease (RCD) and gluten sensitivity (GS).
The results of the research indicated that in all four groups, including control group (NG), there is
certain response to gluten administration [46]. Researchers reported increased permeability
particularly comparing ACD and GS groups to RCD, which is due to gluten induced alteration of
intestinal barrier. Furthermore, researchers by means of quantification method investigated changes
in following cytokines IL-6, IL-8, IFN-γ, TNF-α, which showed no significant difference, however, in
this case a short period of incubation could implicate results. It should be emphasized that lack of
blindness in GFD challenge while recruiting GS group along with lack of GFD challenge in the control
group are important limitation in discussed study and could impact final results [46].
Shahbazkhani et al. investigated the relationship between dietary habits in IBS patients and
consequent symptom fluctuations (Table 2). In particular researchers were interested in gluten impact
on wellbeing of IBS patients and weather it may induce IBS-like symptoms. After rigid inclusion and
exclusion criteria, strict six-week GFD 72 patients were recruited and divided into two groups: gluten
containing group (study group), gluten free group (placebo group). Symptoms were analyzed by
means of visual analogue scale (VAS). The results of the research revealed significant worsening of
symptoms in a study group after gluten powder challenge. Scientists reported increase of overall
symptoms such as satisfaction with stool consistency, tiredness, nausea, bloating in study group
comparing to the control one. The results occurred to be statistically significant [47]. Nevertheless,
there was limitation such as gluten form—a packet of 100 g powder, which is not recommended
anymore by Salerno criteria [29].
According to the study published in Gastroenterology, scientists discovered that FODMAPs are
another wheat antigen along with gluten triggering symptoms in patients with NCGS. Biesiekierski
et al. conducted a double-blind crossover trial in which participated 37 patients suffering from NCGS
and IBD. The following exclusion criteria were applied: age less than 16 years, CD confirmed by
genetic tests and duodenal biopsy, alcohol abuse, chronic non-steroidal anti-inflammatory drugs
(NSAIDs) and immunosuppressant treatment, uncontrolled psychiatric illness. Patients who had
confirmed symptoms of IBS by accomplished the Rome III criteria and symptoms well controlled on
a GFD were qualified for the study. Another requirement was to follow the GFD 6 weeks before this
clinical trial. The first stage of the study was identical for all participants and the task was consuming
for a one week a gluten-free and low FODMAPs diet. After a 2-week washout period, patients were
randomly assigned to the three groups: high-gluten, low-gluten and placebo, without introducing
Medicina 2019, 55, 222 10 of 18
FODMAP into the diet. The symptoms of the patients were measured by using 100-mm VAS scoring
and Daily-Fatigue Impact Scale (D-FIS). All participants were asked to return to the second stage of
this study—trial in which all patients received each diets for 3-days [48]. Gluten-specific responses
were found only in 8% of patients. Scientists found a high nocebo effect and reproducibility of
induction of symptoms in each arm was low [48].
Biesiekierski et al. noticed that patients with NCGS do not present a statistically significant
occurrence of symptoms after introducing gluten into the diet, if at the same time they limit products
rich in FODMAP (Table 2). These results may suggest that the symptoms in patients suffering from
NCGS may in many cases be associated with intolerance to the contained sugars, but not
hypersensitivity to gluten. Surprisingly, the patients involved into study evinced eminently high VAS
ratings for their symptoms, despite being on GFD. Furthermore, an anticipatory nocebo response
could influence the final results of this DBPC research. It is interesting that all participants eventually
returned to GFD at the end of the trail as they ‘subjectively describe feeling better’ [48].
Scientists from Oslo, Skodje et al., conducted a study in which took part 59 patients on a GFD,
in whom CD was excluded (Table 2). Participants were divided into three groups: receiving diet
including gluten (5.7 g), fructans (2.1 g) and placebo. The clinical trial lasted 7 days and was preceded
by a 1-week washout period. The following symptoms were recorded: pain, bloating, diarrhea,
constipation, nausea, dizziness, weakness, sleepiness and tiredness. Participants filled a
questionnaire containing 13 questions about their gastrointestinal symptoms and filled VAS. The
results were measured by GSRS, Irritable Bowel Syndrome scale (GSRS-IBS), VAS, Short Form-36
(SF-36) and Giessen Subjective Complaint List [49]. Scientists observed that daily symptoms
calculated using VAS score were significantly higher in fructans diet. Furthermore, they noticed that
overall GSRS-IBS was higher in the FODMAPs group (38.6 g) than in the gluten group (33.1 g) and
placebo (34.3 g). More ailments were recorded in the group receiving fructans, compered to two
another groups. In addition, it was demonstrated that a diet rich in FODMAPSs caused greater
weakness and decreased vitality compared to the placebo and gluten groups. The results of the study
indicate that FODMAPs are a trigger factor of gastrointestinal complaints in patients suffering from
NCGS [49]. Thus, scientists are leaning towards renaming NCGS to a more recent NCWS [27].
Di Sabatino et al. observed increased severity of intestinal symptoms (abdominal bloating,
abdominal pain) and extra intestinal symptoms (foggy mind, depression, and aphthous stomatitis)
among subjects with suspected NCGS (excluded CD and WA). Although, this study did not make a
significant contribution in development of knowledge about NCGS and had some weaknesses such
as lack of a control group, it indicates possible symptoms experienced by NCGS patients (Table 2)
[50].
In order to prove that gluten is a trigger factor in patients with NCGS, Rosinach et al. conducted
a study in which 18 participants were assigned to gluten or placebo groups. In 10 out of 11 patients,
symptoms worsened in response to a gluten-containing diet, 7 of which were withdrawn from the
study due to the severity of the symptoms [51]. There was no early termination in the placebo group
although in 2 participants symptoms were observed (Table 2) [51].
Carroccio et al. collected and analyzed data from 200 patients examined in previous study with
diagnosed NCWS. Their findings are interesting because about 90% of patients who maintained
wheat-free diet (WFD) were characterized by significant improvement of IBS symptoms [52]. The
authors came to the conclusion that NCWS is a persistent condition and patients with NCWS should
therefore be correctly identified and treated with WFD (Table 2) [52].
Roncoroni et al. conducted a study on dietary exposure to differe nt amoun ts of glu ten in pa tients
meeting the criteria of the NCGS [53]. Researchers observed different reactions of patients after the
introduction of gluten. Some of them had a worsening of well-being and increased symptoms after a
small dose of gluten, others observed this effect after the medium dose and others only after a high
dose of gluten (Table 2) [53].
Carrocio et al. in their study in 2011 emphasize the link between particular food ingestion and
deteriorating symptoms in a subgroup of IBS patients [54]. It clearly shows alleviation of the
symptoms in 22% of IBS patients—whose previous treatment was ineffective—after eliminating
Medicina 2019, 55, 222 11 of 18
gluten from the diet. Moreover, researchers excluded association of DQ2 and DQ8 haplotypes with
frequent gluten sensitivity, however, patients presenting food hypersensitivity (FH) to both wheat-
and cow’s milk-protein were reported to be often DQ2/DQ8 positive. Fecal eosinophil cationic protein
(ECP) may be useful while identifying FH in IBS-patients (Table 3) [54].
Carroccio et al. in their study published in 2012 examined individuals with non-celiac WS,
diagnosed by DBPC challenge with IBS-like symptoms, compared to CD patients and IBS patients
[55]. Authors described presence of two types of WS subjects: WS similar to CD and WS associated
with multiple food hypersensitivity. Besides, symptoms such as anemia, weight loss, self-reported
wheat intolerance, coexistent atopy, and food allergy in infancy were noticed more often in WS
compared to IBS controls. Furthermore, WS individuals were characterized by higher frequency of
presence IgG/IgA anti-gliadin in serum, basophil activation (assessed by flow cytometric method)
and histology specific eosinophil infiltration of the duodenal and colon mucosa. This study shows
the differences between non-celiac WS and other gluten-related disorders (Table 3) [55].
Volta et al. in their study, assessed the level of immunoglobulin distinctive for CD in patients
with GS comparing to CD [56]. They revealed that 50% of GS patients presented IgG AGA, whereas
IgA AGA was seen only in a few patients in study group. Besides, researchers observed absence of
IgA EmA, IgA tTGA, IgG DGP-AGA, which are typical for CD, within GS group (Table 3) [56].
Basing on a study group conducted by Volta et al., Caio et al. continued research on AGA IgG
[38]. Scientists aimed to explore GFD impact on AGA IgG titer in AGA IgG positive patients (44
individuals) with NCGS. After six months of GFD AGA IgG disappeared in all the patients (Table 3).
Carrocio et al., in another research conducted in 2015, evaluated and described frequent ANA
positivity within NCWS patients group [57]. The study demonstrated ANA positivity occurring
along with DQ2/DQ8 haplotypes. As it was previously discussed, DQ2/DQ8 positivity is a distinctive
feature of CD rather than NCWS. Thus, researchers highlight the need of intraepithelial intestinal
flow cytometric pattern, which is an accurate method identifying seronegative CD patients, in the
initial diagnostic biopsy. However, scientists found autoimmune diseases (AD) particularly frequent
in study group. Autoimmune thyroiditis was reported to be the most frequent AD and amounted for
22% and 24% in retrospective and prospective groups respectively Table 3) [57].
Infantino et al. similarly to Volta observed frequent IgG AGA occurrence in NCGS patients,
however, the author highlights that it is still lacking diagnostic accuracy. Nevertheless, in some cases,
it can be helpful in the diagnostic process of NCGS patients [58].
Papers included in Table 3. Indicate IgG AGA and ECP to be helpful diagnostic tool while
diagnosing NCGS. Still they have limited application in a large group of NCGS patients and cannot
be widely used in NCGS diagnostic protocol [54,58].
Medicina 2019, 55, 222 12 of 18
Table 3. Researches on potential NCGS biomarkers.
References Study Group Exclusion Criteria Methods Findings Comments
Carroccio
et al. 2011
Individuals who
fulfilled Rome II
criteria for IBS
Individuals with organic
diseases
Symptom severity questionnaire was analyzed,
fecal samples were assayed, and levels of specific
immunoglobulin E were measured. Patients were
observed for 4 weeks, placed on an elimination
diet (without cow’s milk and derivatives, wheat,
egg, tomato, and chocolate) for 4 weeks, and kept
a diet diary. Those who reported improvements
after the elimination diet period were then
diagnosed with food hypersensitivity (FH),
based on the results of a double-blind, placebo-
controlled, oral food challenge (with cow’s milk
proteins and then with wheat proteins).
40 of patients with IBS (25%) were found to
have FH. Levels of fecal ECP and tryptase
were significantly higher among patients
with IBS and FH than those without FH. The
ECP assay was the most accurate assay for
diagnosis of FH, showing 65% sensitivity
and 91% specificity.
Limitations:
recruitment of
patients not in line
with Salerno
criteria.
Carroccio
et al. 2012
Individuals with
non-celiac
wheat
sensitivity
(NCWS),
IgA deficiency, self-exclusion of
wheat from the diet, lack of
DBPC-challenge method in the
diagnosis
A review of the clinical charts of patients with
IBS-like presentation, diagnosed with WS
challenge in the years 2001-2011.
1/3 IBS patients who underwent DBPC
wheat challenge were really suffering from
WS. WS group: higher frequency of anemia,
weight loss, self-reported wheat intolerance,
coexistent atopy, and food allergy in infancy
than the IBS controls, higher frequency of
positive serum assays for IgG/IgA anti-
gliadin and cytometric basophil activation in
“in vitro” assay, eosinophil infiltration of the
duodenal and colon mucosa. Two groups
with distinct clinical characteristics were
identified: WS alone (with similar to CD
clinical features) and WS with multiple food
hypersensitivity (clinical features similar to
those found in allergic patients)
Limitations:
recruitment of
patients not in line
with Salerno
criteria.
Volta et al.
2012
Individuals with
GS (NCGS) CD, WA
Retrospective evaluation of collected samples
from GS (study group) and CD (control group)
individuals. Assessment of IgG/IgA AGA, IgA
EmA, IgA tTGA, IgG DGP-AGA. HLA
DQ2/DQ8 presence was assessed
GS is characterized by IgG AGA positivity
(50%), although is less common comparing
to CD. IgA AGA are rare. GS patients were
lacking EmA, tTGA, and DGP-AGA.
Limitations: not
thoroughly
described exclusion
criteria for study
group
Caio et al.
2014
Individuals with
NCGS with
simultaneous
AGA IgG
positivity
CD, WA
AGA of both IgG and IgA classes were assayed
by ELISA in 44 NCGS and 40 CD patients after 6
months of gluten-free diet.
AGA IgG in NCGS patients disappear after
introduction of GFD.
Carroccio
et al. 2015
NCWS patients
of the
Incomplete clinical charts were
excluded from retrospective
NCWS patients—tTG IgG, EmA IgA and IgG
negative, absence of intestinal villous atrophy
Patients with NCWS were more likely to be
ANA positive than both patients with CD
Limitations:
selection bias of the
Medicina 2019, 55, 222 13 of 18
retrospective
cohort study
study; for both studies: EmA in
the culture medium of the
duodenal biopsies, self-
exclusion of wheat from the diet
and refusal to reintroduce it
before entering the study, other
organic gastrointestinal
diseases.
and WA. Patient medical records were reviewed
to identify those with autoimmune disease (AD).
CD or IBS served as controls. Serum samples
were collected from all subjects and ANA levels
were measured by immunofluorescence analysis.
Participants completed a questionnaire and their
medical records were reviewed to identify those
with ADs. Individuals were randomly assigned
to groups given gluten or placebo for 1 week,
each via gastro-soluble capsules. After a 1 week
of gluten-free diet, participants crossed over to
the other group.
and IBS, in both the retrospective and
prospective studies. Patients with NCWS
showed a frequency of AD similar to CD,
but significantly higher than IBS controls, in
both the retrospective and prospective
studies. NCWS or CD are more likely to be
ANA-positive, have DQ2/DQ8 haplotypes
and AD compared with patients with IBS.
tertiary centers
conducting
research; evaluation
of the duodenal
histology; not in line
with Salerno criteria
NCWS patients
of the
prospective
study
Infantino et
al. 2015
Induviduals
with suspected
NCGS
CD, WA
Evaluation of collected samples from GS (study
group), CD and healthy (control group)
individuals. Assessment of IgG/IgA AGA, IgA
EmA, IgA tTGA, IgG/IgA DGP-AGA. HLA
DQ2/DQ8 presence was assessed
Statistically significant correlation between
AGA IgG and NCGS were found. However,
AGA IgG still remains to be weak NCGS
marker.
Limitations:
recruitment of
patients not in line
with Salerno
criteria; small study
group
Medicina 2019, 55, 222 14 of 18
4. Discussion
Nowadays, a gluten-free diet is fashionable and is promoted by many celebrities. Many people
undergo this fashion and despite lack of symptoms, try to reject gluten because they believe it may
harm their health. In 2016, as much as USD 15.5 billion was spent on gluten-free food sales. This value
is more than twice as high as in 2011. Lack of gluten in food consumed by people who tolerate it well
may not bring favorable results.
In a study conducted by Norsa et al., children with CD were tested for at least one year on a GFD
diet. As many as 34.8% of children on GFD diet had high concentrations of triglycerides on fasting,
24.1% high concentration of LDL cholesterol and 29.4% increased blood pressure. In 52 out of 114
participants there were available cards with information on blood lipids concentration before GFD
introduction. 24% of children on GFD had had LDL cholesterol borderline values. That was much
more than before the introduction of the diet (10%). However, these data did not meet the value of
statistical significance (p = 0.09) [59].
Studies show that gluten may have a positive effect on triglyceride levels. In a clinical trial in
which 20 adults with hyperlipidemia took part, a group with a balanced diet and a group with a high
gluten content (78 g per day with an average human intake of 10–15 g) were studied. The high gluten
diet group had a decreased triglyceride concentration of 19.2% (p = 0.0003) compared to the control
group after one month of the study [60]. In another study, a group of patients consuming 60 g of
gluten per day had a 13% (p = 0.05) lower triglyceride concentration compared to the control group
[61]. In a study published in 2017, the estimated gluten consumption lead to the protective effect
against cardiovascular disease (HR 0.85, 95% CI 0.77-0.93, p = 0.002) [62].
Gluten-free products can also be more than twice as expensive as regular products [63]. There
are other disadvantages of GFD. The GFD turned out to be poor in trace elements and vitamins, such
as zinc, iron, magnesium, calcium, vitamin D, vitamin B12, folate, and fiber [64,65]. Furthermore,
Tovoli et. al. compared scores obtained by NCWS and CD individuals using quality of life
questionnaire (CDQ) before GFD introduction and after at least one year. NCWS patients still
reported intestinal and parenteral symptoms, although symptoms were significantly reduced in
comparison to period before GFD. Therefore, other factors influencing NCWS should be investigated
[66].
Finally, based on revised research results, it is clear that NCGS still remains to be the subject of
uncertainty, especially in terms of other wheat components contribution to its symptoms. There are
only a few published forms of research in the last six years. It should be stressed that it is hard to
compare the results of each study as obtained methods and criteria significantly vary. Moreover, the
timing of onset of each research was of a great importance as some of them were conducted before
Salerno criteria were introduced, which led to many interpretations and qualification protocols of
patients with NCGS-like symptoms. Further investigations and seeking for biomarkers would play
key role in improving of the diagnostic process and patients’ follow up.
5. Conclusions
1. Symptoms of non-celiac gluten sensitivity are similar to gluten-related disease, irritable bowel
syndrome and Crohn’s disease.
2. With Salerno Experts’ Criteria of non-celiac gluten sensitivity it is possible to diagnose patients
properly and give them advice about nutritional treatment.
Author Contributions: Conceptualization, A.R., M.P., B.N.-I.; Methodology and resources A.M., K.B., B.N.-I.;
Visualization A.M., M.P., A.R., K.B.; Writing—Review & Editing A.R., M.P., A.M., K.B., B.N.-I.; Software K.B.;
Supervision—B.N.-I.
Funding: This research received no external funding
Conflicts of interest: The authors declare no conflict of interest.
Medicina 2019, 55, 222 15 of 18
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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open
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Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
... Our goal is to perform a meta-analysis of the study of HLA class II human leukocyte antigens (HLA-DQ2/DQ8) in adult patients with CD to provide light on a possible viewpoint and method for broader screening. In contrast to several other reviews, we are only interested in material pertaining to CD and not gluten intolerance or sensitivity [18]. ...
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... Or it is combined to balance the excessive 9 . Gluten present in wheat is considered a major health problem 10 . But in the Samhitās, Godhūma is never considered toxic, on the contrary is indicated even in complicated diseases. ...
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... Elfstrom (35) monitored 14,000 individuals with CD and documented statistically significant associations with an increased risk of liver disease, Addison's disease, thyroid disease, autoimmune heart disease, leukaemia, and lymphoma. On the other hand, symptoms of NCGS are similar to other gluten-related diseases, irritable bowel syndrome and Crohn's disease (36). According to the Losurdo et al. (37), the most commonly autoimmune disorders associated with NCGS are Hashimoto thyroiditis, dermatitis herpetiformis, psoriasis, and also rheumatologic diseases. ...
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Celiac disease (CD) is a disorder that affects both children and adults. Over the few last decades, several new atypical cases have been identified through improved diagnostic tools. On the other hand, the onset of CD at a later age, including atypical CD forms whose clinical picture overlaps with other autoimmune diseases, shows that currently there are several unknown gene mutations, which could be responsible for the disease development. Non-celiac gluten sensitivity (NCGS) is entity included by the ingestion of gluten leading to intestinal, or extraintestinal symptoms that improve once the gluten is removed from the nutrition. In this article relationships between genetically modified rodent animals with previously unknown multiple organ changes and CD, respectively NCGS are reviewed. Relationships between the small bowel histological changes and other organs pathology are discussed. Results of research document that changes have similar genetic background and can develop to serious autoimmune systematic diseases, including small bowel inflammation resembling atypical CD or NCGS. These may have extra-intestinal symptomatology but without a clear explanation of causes and differences in their manifestations. Research on animal models helps to discover links between several disorders associated with gastrointestinal damage. New methods based on individual gene mutations can help in atypical adult CD and NCGS recognitions in the future.
... Elfstrom (35) monitored 14,000 individuals with CD and documented statistically significant associations with an increased risk of liver disease, Addison's disease, thyroid disease, autoimmune heart disease, leukaemia, and lymphoma. On the other hand, symptoms of NCGS are similar to other gluten-related diseases, irritable bowel syndrome and Crohn's disease (36). According to the Losurdo et al. (37), the most commonly autoimmune disorders associated with NCGS are Hashimoto thyroiditis, dermatitis herpetiformis, psoriasis, and also rheumatologic diseases. ...
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Celiac disease (CD) is a disorder that affects both children and adults. Over the few last decades, several new atypical cases have been identified through improved diagnostic tools. On the other hand, the onset of CD at a later age, including atypical CD forms whose clinical picture overlaps with other autoimmune diseases, shows that currently there are several unknown gene mutations, which could be responsible for the disease development. Non-celiac gluten sensitivity (NCGS) is entity included by the ingestion of gluten leading to intestinal, or extraintestinal symptoms that improve once the gluten is removed from the nutrition. In this article relationships between genetically modified rodent animals with previously unknown multiple organ changes and CD, respectively NCGS are reviewed. Relationships between the small bowel histological changes and other organs pathology are discussed. Results of research document that changes have similar genetic background and can develop to serious autoimmune systematic diseases, including small bowel inflammation resembling atypical CD or NCGS. These may have extra-intestinal symptomatology but without a clear explanation of causes and differences in their manifestations. Research on animal models helps to discover links between several disorders associated with gastrointestinal damage. New methods based on individual gene mutations can help in atypical adult CD and NCGS recognitions in the future.
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Научные труды, представленные в сборнике, посвящены различным аспектам состояния здоровья в разрезе актуальных вопросов медицины, социальной работы, психологии и педагогики. Ряд проблем рассматривается с позиции мультидисциплинарного подхода ввиду нахождения на стыке специальностей, что способствует их расширенному пониманию и поиску новых решений. В рамках работы конференции специалисты в сфере науки и практики имеют возможность обмениваться опытом, приходить к единому решению по формированию специальных компетенций, находить новые идеи для совместной деятельности по реализации научных, образовательных и иных проектов. В сборнике размещены материалы авторов из различных регионов России, Украины, Монголии, Белоруссии, Кыргызстана, Казахстана, Болгарии, Китая, Польши, Японии. Сборник предназначен для медицинских и социальных работников, педагогов образовательных учреждений
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Non-celiac gluten sensitivity (NCGS) is a condition characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing foods in the absence of celiac disease and wheat allergy. The diagnosis is cumbersome and currently confirmed only by gluten withdrawal and double-blind placebo challenge protocols. There is great overlap in symptoms between NCGS and other functional gastrointestinal disorders, making a differential diagnosis difficult. The pathophysiology of NCGS is largely unclear, and there are contrasting data on the trigger of this condition. This review will highlight the state-of-the-art knowledge on NCGS and the key open questions.
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Background Nonceliac gluten sensitivity (NCGS) is a recently defined clinical entity characterized by intestinal and extraintestinal symptoms associated with gluten ingestion in individuals in whom celiac disease (CD) or wheat allergy (WA) has been excluded. Despite its name and definition, gluten has been shown to precipitate symptoms in only 16–30% of these patients. In addition to gluten, other components of wheat, including fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), alpha-amylase trypsin inhibitors (ATIs) and wheat germ agglutinin have been implicated in the causation of the symptoms of NCGS, with FODMAPs garnering the most attention. We present a review of the existing literature evaluating the role of FODMAPs in NCGS symptomatology. Methods A systematic review of PubMed, Cochrane, EMBASE, and Google Scholar for keywords fructans, non-celiac gluten sensitivity, NCGS, FODMAPs, and gluten-free diet (GFD) was conducted through a series of advanced searches. Articles related to the use of fructans or FODMAPs were analyzed. Results FODMAPs were found to be associated with gastrointestinal and extraintestinal symptoms in NCGS. Conclusions A low FODMAP diet has potential for improvement of clinical symptoms in NCGS. In addition, some evidence suggests an additional benefit to simultaneous adherence to both low FODMAP diet and GFD.
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Gluten-related disorders are characterized by both intestinal and extraintestinal manifestations. Previous studies have suggested an association between gluten-related disorder and psychiatric comorbidities. The objective of our current review is to provide a comprehensive review of this association in children and adults. A systematic literature search using MEDLINE, Embase and PsycINFO from inception to 2018 using terms of ‘celiac disease’ or ‘gluten-sensitivity-related disorders’ combined with terms of ‘mental disorders’ was conducted. A total of 47 articles were included in our review, of which 28 studies were conducted in adults, 11 studies in children and eight studies included both children and adults. The majority of studies were conducted in celiac disease, two studies in non-celiac gluten sensitivity and none in wheat allergy. Enough evidence is currently available supporting the association of celiac disease with depression and, to a lesser extent, with eating disorders. Further investigation is warranted to evaluate the association suggested with other psychiatric disorders. In conclusion, routine surveillance of potential psychiatric manifestations in children and adults with gluten-related disorders should be carried out by the attending physician.
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Non Celiac Gluten Sensitivity (NCGS) is characterized by immunological, morphological or symptomatic manifestations precipitated by gluten ingestion in individuals without celiac disease (CD). The most important challenge in NCGS is the diagnosis, currently based only on clinical observation. The "Salerno criteria" have been pointed out to achieve a reliable diagnosis even if they lack immediacy and practicality, thus making questionable patient's adherence. Therefore, biological indicators supporting the clinical diagnosis of NCGS are advisable. For these reasons, many attempts have been performed in order to identify possible serological, immunological, histopathological, immunohistochemical and pathophysiological aspects characterizing this condition with the aim of using them for diagnostic purposes. In the present narrative review, we carried out an update of the current scenario of potential markers of NCGS. The main fault of available studies is that, in most cases investigations have been pointed out towards molecules, which cannot be searched in the current laboratories of clinical analysis. Therefore, the matter has been confined within basic research. Additionally, in these studies, sensitivity and specificity of biological markers were not computable. This is a relevant limit, since an ideal test for NCGS should have a good discriminative power against both CD and other causes of microscopic enteritis. Until now, serological tests have failed, while the search for a soluble marker indicative of activation of innate immune system as well as immunohistochemistry could be the promising bases for the development of appropriate investigations in the future. © 2018 RIGLD, Research Institute for Gastroenterology and Liver Diseases.
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Within the last decade, non-celiac gluten/wheat sensitivity (NCGS) has been increasingly discussed not only in the media but also among medical specialties. The existence and the possible triggers of NCGS are controversial. Three international expert meetings which proposed recommendations for NCGS were not independently organized and only partially transparent regarding potential conflicts of interest of the participants. The present position statement reflects the following aspects about NCGS from an allergist’s and nutritionist’s point of view: (A) Validated diagnostic criteria and/or reliable biomarkers are still required. Currently, this condition is frequently self-diagnosed, of unknown prevalence and non-validated etiology. (B) Gluten has not been reliably identified as an elicitor of NCGS because of high nocebo and placebo effects. Double-blind, placebo-controlled provocation tests are of limited value for the diagnosis of NCGS and should be performed in a modified manner (changed relation of placebo and active substance). (C) Several confounders hamper the assessment of subjective symptoms during gluten-reduced or gluten-free diets. Depending on the selection of food items, e.g., an increased vegetable intake with soluble fibers, diets may induce physiological digestive effects and can modify gastrointestinal transit times independent from the avoidance of gluten. (D) A gluten-free diet is mandatory in celiac disease based on scientific evidence. However, a medically unjustified avoidance of gluten may bear potential disadvantages and risks. (E) Due to a lack of diagnostic criteria, a thorough differential diagnostic work-up is recommended when NCGS is suspected. This includes a careful patient history together with a food-intake and symptom diary, if necessary an allergy diagnostic workup and a reliable exclusion of celiac disease. We recommend such a structured procedure since a medically proven diagnosis is required before considering the avoidance of gluten.
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Background & aims: Non-celiac gluten sensitivity (NCGS) is characterized by intestinal and extra-intestinal symptoms triggered by ingestion of gluten. However, non-gluten triggers have recently been implicated, and a FODMAP (fermentable oligo-, di-, monosaccharides and polyols)-reduced diet can partially improve symptoms in NCGS. Our aim was to analyze the effect of a low FODMAP versus a gluten-free diet (GFD) on clinical symptoms, psychological well-being, intestinal inflammation and integrity, and stool microbiota. Methods: Nineteen patients with NCGS and ten healthy controls consumed a gluten-containing standard diet before starting a two-week low FODMAP diet; after a five day transition period, participants ingested a GFD for another two weeks. The primary outcome measure was the improvement of clinical symptoms in NCGS patients under the different diets. Secondary outcomes were the determination of dietary effects on intestinal inflammation, psychological well-being, and differences in stool microbiota between NCGS patients and controls. Results: The low FODMAP diet and especially the GFD led to a significant improvement of clinical and psychological symptoms in NCGS. A clear reduction in duodenal intraepithelial lymphocytes and mucin-producing Goblet cells was found after the GFD in these patients. Significant microbial differences between NCGS patients and controls were noticed in stool samples at every time point. Both diets caused microbial shifts in all participants, with a greater variability on genus level and metabolisms groups in NCGS patients. Conclusions: Our findings suggest a multifactorial etiology of NCGS, due to a functional effect caused by FODMAPs, combined with a mild gluten-triggered immune reaction, and a microbiota dysbalance. CLINICALTRIAL. Gov id: NCT03268720.