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NUTRITION AND THE GASTROINTESTINAL TRACT: Edited by M. Isabel T.D. Correia and Alastair Forbes

Noncoeliac gluten sensitivity

a diagnostic dilemma

Branchi, Federicaa,b,*; Aziz, Imrana,*; Conte, Dariob; Sanders, David S.a

Author Information
Current Opinion in Clinical Nutrition and Metabolic Care: September 2015 - Volume 18 - Issue 5 - p 508-514
doi: 10.1097/MCO.0000000000000207
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Dietary exposure to gluten has been expanding since the development of agriculture and cereal harvesting in the Neolithic age [1]. In Western countries, cereals are the major source of carbohydrates, but wheat is increasingly becoming part of the diet in Eastern countries as well, mirroring the expansion of the so-called occidental lifestyle. To date, wheat is among the most widely cultivated plant seeds in the world, alongside rice, with an annual production of more than 700 million tonnes [from].

Given that the human gastrointestinal and immune system developed around 2.5 million years ago, while consumption of gluten started between 9000 and 5000 BC, it is not surprising that over time a spectrum of disorders related to the ingestion of gluten have developed [1]. In fact, immune reactions to gluten may reflect a common response of the human body to external antigens/stimuli, perceived as potentially dangerous. The relatively recent introduction of dietary gluten may have clashed with an immune system still unprepared to develop an adaptive compensation to the exposure [1]. Moreover, the introduction of intensive agriculture, the selection of more resistant wheat varieties, and the adoption of gluten as an additive in the food industry for its viscoelastic and stabilizing properties have caused a dramatic increase in the average daily amount of gluten introduced into the Western diet. All these factors are probably contributing to the rise in incidence of gluten-related disorders and the emergence of new clinical manifestations [1,2].

In this review, we aim to describe the spectrum of gluten-related disorders with particular focus on noncoeliac gluten sensitivity (NCGS), an emerging clinical entity which has gained significant awareness within the scientific community and also the general public [3,4]. Attention will be devoted to the epidemiology, pathogenesis, intestinal symptoms, and suggested diagnostic approach towards this syndrome along with its ensuing uncertainties.

Box 1
Box 1:
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The term ‘gluten-related disorders’ encompasses different clinical entities in which the onset of symptoms is associated with exposure to gluten; Table 1[3,4]. The consumption of gluten-containing foods has classically been associated with coeliac disease, a chronic autoimmune enteropathy which develops as a consequence of dietary exposure to gluten in individuals with a genetic predisposition [human leukocyte antigen (HLA) class II DQ2 and/or DQ8 haplotypes] [5]. The pathogenic pathway that leads to coeliac disease has been extensively studied and consists of a T-cell-mediated adaptive immune reaction to gluten-derived peptides (gliadin) [6]. Gliadin deamidation by means of tissue transglutaminase, an enzyme of the extracellular matrix, and presentation of immunogenic epitopes by antigen presenting cells exposing DQ2-DQ8 HLA class II molecules are responsible for the inflammatory cascade that eventually leads to intestinal damage and villous atrophy [7]. Originally considered a rare disease typical of childhood, nowadays coeliac disease has been established as a common condition, which also affects adults, with an estimated worldwide prevalence of 1 : 100 individuals [6].

Table 1
Table 1:
Gluten-related disorders

An immunoglobulin E (IgE)-mediated inflammatory response to allergenic proteins contained in wheat and related cereals is the cause of wheat allergy [8]. Wheat allergy has an estimated prevalence between 0.1 and 1% and may present with different clinical manifestations depending on the route of exposure to gluten: direct contact may cause contact urticaria, inhalation causes occupational asthma and rhinitis, and ingestion leads to the traditional food allergy (with skin, gastrointestinal, or respiratory manifestations) along with wheat-dependent exercise-induced anaphylaxis [8,9].

NCGS is considered as the new frontier of gluten-related disorders. The condition is characterized by symptoms triggered by the ingestion of gluten-containing food, yet in the absence of diagnostic markers for either coeliac disease or wheat allergy [3,4]. The immunopathogenesis of NCGS is unclear but appears to show at least involvement of the innate immune system [10,11], with reports also suggesting the possibility of adaptive elements [12▪]. NCGS is characterized by a wide range of intestinal and extraintestinal symptoms; Table 2. The intestinal symptoms are akin to that of irritable bowel syndrome (IBS), presenting with abdominal discomfort, bloating, and altered bowel habit. For this reason, and considering that for both NCGS and IBS reliable serology is lacking, NCGS may be considered as belonging to the spectrum of IBS. Indeed, it has been shown that gluten may alter bowel-barrier function in patients with diarrhoea-predominant IBS [13▪▪].

Table 2
Table 2:
Spectrum of symptoms in patients with self-reported noncoeliac gluten sensitivity

Observational studies have suggested that between 0.6 and 13% of the general population self-report NCGS, with such individuals referring themselves to primary care and gastroenterology specialists describing an improvement of symptoms after starting a gluten-free diet (GFD) [14,15,16▪,17▪,18▪,19▪,20]. In addition, apparently more and more people choose to adopt a GFD, based on vague beliefs of it being a ‘healthy lifestyle choice’ than on the existence of a clinical condition [18▪,21]. The market for gluten-free products has been constantly growing in the past decades with the latest European reports estimating a 10.4% compound annual growth rate between 2014 and 2019 [22]. In such circumstances, the consistency of NCGS as a clinical entity has been questioned and is in need of solid validation.


For coeliac disease, the diagnosis is based on the combination of clinical data, serologic tests with high sensitivity and specificity (tissue transglutaminase antibodies and anti-endomysial antibodies), and histological evidence of duodenal villous atrophy, crypt hyperplasia, and/or intraepithelial lymphocytosis. [5] For wheat allergy, the diagnosis is based upon positive IgE wheat serology or skin prick test.

In contrast, NCGS (while testing negative for coeliac disease and wheat allergy) does not currently have any reliable biomarker of its own. Studies report that IgG antigliadin antibodies may be present in around 25–50% of patients with NCGS [10,11,20,23,24,25▪], although they lack specificity being found in up to 12% of the general population, as well as in patients with IBS (6–17%), connective tissue disorders (9%), and autoimmune liver diseases (21.5%) [23]. Nevertheless, in the context of NCGS, antigliadin antibody levels can normalize on a GFD and could, therefore, be a valid support for the diagnosis [25▪]. As regards to histological data, individuals with NCGS show no signs of villous atrophy at duodenal biopsies but it has been observed that individuals may have raised duodenal intraepithelial lymphocytes [10,11]. Nevertheless, in the setting of NCGS, the number of intraepithelial lymphocytes appears to be lower than that classically observed in coeliac disease (25–40 vs. >40 per 100 enterocytes) [10,11]. Further, genetic predisposition in the setting of NCGS is not as clear when compared with coeliac disease. Whereas all patients with coeliac disease carry the HLA-DQ2 and/or DQ8 haplotypes, the prevalence in NCGS patients is reported to be around 50%, which is moderately elevated yet comparable with the general population (∼40%) [16▪,23]. Moreover, up to 24% of patients with NCGS will report a family history of coeliac disease [26], suggesting a link between these two entities.

These factors need to be borne in mind when attempting to distinguish coeliac disease from NCGS, particularly as individuals may have already started a GFD prior to presentation and understandably be reluctant to recommence gluten back into their diet. In these circumstances, a diagnostic algorithm has been proposed to help exclude coeliac disease [27▪▪]. The application of HLA-DQ2/8 typing (where available) can be useful in that a negative result effectively rules out coeliac disease. In the case of HLA DQ2-DQ8 positivity, or where HLA-DQ typing is unavailable, the reintroduction of gluten in the diet (‘gluten challenge’) followed by serology and duodenal biopsies is advised. In patients with suspected NCGS, a short-term, low-dose gluten challenge (3 g/day for 2 weeks) as recently proposed for the diagnosis of coeliac disease could be a more suitable and desirable approach than the traditional high-dose gluten challenge of 10 g/day for 6–8 weeks [28▪▪].


In those with suspected NCGS, additional investigations can be undertaken by means of dietary elimination followed by double-blind placebo-controlled (DBPC) gluten-based rechallenges. This diagnostic approach has been applied in various clinical settings with satisfactory results, but its applicability in routine daily practise seems difficult and time-consuming; Table 3[24,29,30▪▪,31▪▪].

Table 3
Table 3:
Studies evaluating double-blind placebo-controlled dietary interventions for self-reported noncoeliac gluten sensitivity

Furthermore, despite the efforts of the high-quality DBPC studies mentioned in Table 3, the diagnosis of NCGS can still remain questionable. Other nongluten components which have thus far eluded complete elimination when performing such dietary interventions may be in fact responsible for triggering symptoms. The most commonly recognized are carbohydrates in the form of fermentable oligo, di, monosaccharides, and polyols (FODMAPs). FODMAPs are able to exert an osmotic effect in the intestinal lumen and enhance bacterial fermentation [32,33▪]. Considering that wheat and related cereals contain a considerable amount of FODMAPs, in the form of fructans (oligosaccharides), the efficacy of a low-FODMAP diet in controlling symptoms in patients with IBS and NCGS has been evaluated [30▪▪,34▪▪]. In fact, in the study by Biesiekierski et al.[30▪▪], patients with self-reported NCGS already on a GFD showed further improvement with a low-FODMAP diet and no worsening of symptoms was observed with blinded low-dose or high-dose gluten reintroduction compared with placebo. These data have subsequently led to the existence of NCGS being questioned as a clinical entity. However, it has to be considered that these results might have been biased by the nocebo effect seen in all arms, possibly as a consequence of an anticipatory effect because of the crossover study design.

The most recent study by Di Sabatino et al.[31▪▪] has aimed to address these uncertainties by performing a DBPC study using purified wheat gluten. This revealed an overall worsening of symptoms with gluten capsules compared with placebo. However, novel insights have now revealed that other proteins coexist alongside gluten, which may not have been extracted from the purified wheat-gluten used. As shown in Table 4[32,33▪,34−38], wheat-germ agglutinins (lectins) and in particular, amylase-trypsin inhibitors are able to trigger innate immunity, and therefore may have a role in the development of symptoms after ingestion of cereals [35–38].

Table 4
Table 4:
Nongluten components of wheat that can elicit symptoms in patients with self-reported noncoeliac gluten sensitivity

Hence, for these reasons, some authors suggested that ‘noncoeliac wheat sensitivity’ or ‘patients who avoid wheat and/or gluten’ may be more appropriate definitions [39,40], while waiting for advances in the understanding of the pathogenic pathways that lead to the development of this clinical condition.


Recent research has focused on the development of potential biomarkers to help diagnose NCGS. In-vitro cytometric basophil activation tests, based on cell surface expression of CD63, have been evaluated in the setting of NCGS and compared with the performance of the DBPC challenge, with discordant results in terms of accuracy and reproducibility [41–43]. Faecal detection of the eosinophil cationic protein has shown a satisfactory performance in a study (with 91% specificity and 65% sensitivity) [44]. Another potential tool to help the differentiation of NCGS from coeliac disease would be the determination of chemokine secretion after in-vitro stimulation of peripheral blood mononucleated cells with wheat strains. In fact, data from a preliminary study have shown an increase in CXCL10 production in both coeliac disease and NCGS as compared with healthy controls, but five-fold higher in coeliac disease than in NCGS [45]. Finally, confocal endomicroscopy is a novel instrument that shows food-associated changes in the intestinal mucosa of patients with IBS [46▪▪]. However, none of these tools are routinely available in clinical practise and still pose the question as to whether it is gluten or nongluten proteins evoking symptoms.


To date, the only approach to patients with NCGS consists of prescribing a GFD, with data supporting the use of a low-FODMAP diet in those who are still symptomatic [30▪▪]. No data on long-term effects of the GFD are available in the setting of NCGS. As opposed to coeliac disease, where the adherence of GFD has to be strict and lifelong, no clear evidence indicates the correct threshold of gluten intake responsible for the onset of symptoms in NCGS. It has still to be established whether the reintroduction of gluten in the diet of patients with NCGS may be considered after a limited period of GFD.


The term ‘NCGS’ encompasses a wide range of symptoms related to dietary exposure to gluten. A diagnosis of NCGS is suspected after coeliac disease and wheat allergy have been ruled out. To date, no reliable serological markers are available to prove the diagnosis, which relies mainly on the results of DBPC gluten-based challenges, a cumbersome method which is difficult to apply in everyday clinical practice.

Future research on gluten-related disorders should focus on understanding the pathogenesis of NCGS and consequently identifying more sensitive and specific biomarkers to lead the clinician towards a correct diagnosis. The role of gluten vs. nongluten protein components of wheat in the development of NCGS should be further investigated, as well as the influence of FODMAPs, also contained in wheat and related cereals, in the development of gastrointestinal symptoms.



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Conflicts of interest

There are no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest


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This article shows adaptive components with increased expression of interferon-γ.

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This randomised controlled study shows gluten to alter bowel-barrier function in patients with IBS-diarrhoea.

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This study evaluates the prevalence of self-reported NCGS in the general population. It demonstrates the use of a gluten-free diet outside of coeliac disease.

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This study evaluates the prevalence of self-reported NCGS in the general population. It demonstrates the use of a gluten-free diet outside of coeliac disease.

18▪. Golley S, Corsini N, Topping D, et al. Motivations for avoiding wheat consumption in Australia: results from a population survey. Public Health Nutr 2015; 18:490–499.

This study evaluates the prevalence of self-reported NCGS in the general population. It demonstrates the use of a gluten-free diet outside of coeliac disease.

19▪. Mardini HE, Westgate P, Grigorian AY. Racial differences in the prevalence of celiac disease in the US population: National Health and Nutrition Examination Survey (NHANES). Dig Dis Sci 2015.

This study evaluates the prevalence of self-reported NCGS in the general population. It demonstrates the use of a gluten-free diet outside of coeliac disease.

20. Volta U, Bardella MT, Calabrò A, et al. An Italian prospective multicenter survey on patients suspected of having nonceliac gluten sensitivity. BMC Med 2014; 12:85.
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This study demonstrates that antigliadin antobodies can normalize on a GFD in patients with NCGS, thereby supporting its diagnosis.

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27▪▪. Kabbani TA, Vanga RR, Leffler DA, et al. Celiac disease or nonceliac gluten sensitivity? An approach to clinical differential diagnosis. Am J Gastroenterol 2014; 109:741–746.

A practical guide for clinicians when faced with individuals self-reporting gluten sensitivity.

28▪▪. Leffler D, Schuppan D, Pallav K, et al. Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut 2013; 62:996–1004.

This study demonstrates that serological and histological changes in coeliac disease can occur with a shorter and smaller gluten-dosage than that historically proposed. This may be of value when evaluating patients who self-report gluten sensitivity.

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In this DBPC challenge trial, patients with self-reported NCGS were treated with a low-FODMAP diet leading to a further global improvement in symptoms. Afterwards, reintroduction of gluten in the otherwise low-FODMAP diet did not lead to a specific or dose-dependent relapse.

31▪▪. Di Sabatino A, Volta U, Salvatore C, et al. Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: a randomized, double-blind, placebo-controlled, cross-over trial. Clin Gastroenterol Hepatol 2015; doi: 10.1016/j.cgh.2015.01.029..

The most recent DBPC study showing purified wheat gluten to induce symptoms in NCGS.

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33▪. Murray K, Wilkinson-Smith V, Hoad C, et al. Differential effects of FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols) on small and large intestinal contents in healthy subjects shown by MRI. Am J Gastroenterol 2014; 109:110–119.

The mechanistic effects of FODMAPS elegantly demonstrated by MRI.

34▪▪. Halmos EP, Power VA, Shepherd SJ, et al. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology 2014; 146:67–75.e5.

This study shows how a low FODMAP diet improves IBS symptoms compared with a standard moderate-FODMAP containing diet.

35. Junker Y, Zeissig S, Kim SJ, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med 2012; 209:2395–2408.
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37. Haas H, Falcone FH, Schramm G, et al. Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils. Eur J Immunol 1999; 29:918–927.
38. Dalla Pellegrina C, Perbellini O, Scupoli MT, et al. Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol Appl Pharmacol 2009; 237:146–153.
39. Carroccio A, Rini G, Mansueto P. Nonceliac wheat sensitivity is a more appropriate label than nonceliac gluten sensitivity. Gastroenterology 2014; 146:320–321.
40. Tavakkoli A, Lewis SK, Tennyson CA, et al. Characteristics of patients who avoid wheat and/or gluten in the absence of celiac disease. Dig Dis Sci 2014; 59:1255–1261.
41. Carroccio A, Brusca I, Mansueto P, et al. A cytologic assay for diagnosis of food hypersensitivity in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2010; 8:254–260.
42. Carroccio A, Brusca I, Mansueto P, et al. A comparison between two different in vitro basophil activation tests for gluten- and cow's milk protein sensitivity in irritable bowel syndrome (IBS)-like patients. Clin Chem Lab Med 2013; 51:1257–1263.
43. Bucci C, Zingone F, Russo I, et al. Gliadin does not induce mucosal inflammation or basophil activation in patients with nonceliac gluten sensitivity. Clin Gastroenterol Hepatol 2013; 11:1294–1990.
44. Carroccio A, Brusca I, Mansueto P, et al. Fecal assays detect hypersensitivity to cow's milk protein and gluten in adults with irritable bowel syndrome. Clin Gastroenterol Hepatol 2011; 9:965–971.
45. Valerii MC, Ricci C, Spisni E, et al. Responses of peripheral blood mononucleated cells from nonceliac gluten sensitive patients to various cereal sources. Food Chem 2015; 176:167–174.
46▪▪. Fritscher-Ravens A, Schuppan D, Ellrichmann M, et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 2014; 147:1012–1020.

A recent study demonstrating immediate altered small bowel intestinal permeability (measured through confocal microendoscopy) after exposure to candidate food antigens in IBS patients, including wheat.


amylase-trypsin inhibitors; coeliac disease; fermentable carbohydrates; noncoeliac gluten sensitivity; wheat allergy

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