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Non-coeliac gluten sensitivity: are we closer to separating the wheat from the chaff?
  1. Maria Ines Pinto-Sánchez,
  2. Elena F Verdú
  1. Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
  1. Correspondence to Dr Elena F Verdu, McMaster University, 1280 Main Street West, HSc 3N8, Hamilton, Ontario, Canada L8S 4K1; verdue{at}

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There is growing interest in the role of food as a trigger of functional bowel disorders such as IBS. Indeed, more than 60% of patients with IBS relate the occurrence of bloating and abdominal pain after the ingestion of certain foods.1 Despite intense research in the area, the identification of specific food triggers has remained elusive and this has hampered our understanding of the underlying pathophysiology of these conditions.

One clinical entity that embodies the complex relationship between food and gut functional symptoms is non-coeliac gluten sensitivity or non-coeliac wheat sensitivity (NCGS/NCWS) (figure 1). The two names reveal the existing ambiguity regarding the exact component/s in wheat responsible for the worsening or onset of the associated functional symptoms. NCGS/NCWS is thus a clinical descriptor of patients, in whom coeliac disease and wheat allergy have been ruled out, that present with intestinal and/or extra-intestinal symptoms after ingestion of gluten-containing foods.2 One of the dilemmas related to this condition is that this broad definition potentially includes patients with different underlying pathogenesis, leading to confusion in clinical practice and in research studies. Although gluten has been recognised as a trigger of functional symptoms in mice3 and in a subgroup of patients with IBS,4 it is unclear whether non-gluten protein fractions in wheat could also be responsible for symptom generation. While gluten proteins are dominant in terms of amount and impact, proteomic analysis of the mature wheat grain has revealed the presence of about 1125 individual components. Wheat grains contain 10%–12% protein of which 80% is gluten and the remainder is composed of starch granules that are trapped in the protein matrix. The wheat grain protein fraction includes gluten proteins such as gliadins and glutenins, which upon modification by digestive enzymes release peptides that can induce a CD4+ T-cell response in individuals with coeliac human leukocyte antigen (HLA)-haplotypes (HLA-DQ2 or DQ8) and cause coeliac disease. However, non-antigenic gluten peptides, such as the 31–43, can stimulate innate immune responses that are independent of HLA genotype and thus could contribute to non-coeliac reactions to gluten.5 To complicate matters, non-gluten proteins are also present in wheat and include serine proteinase inhibitors (serpins), thioredoxin, agglutinin and α-amylase/trypsin inhibitors (ATIs).6 The latter have been shown to induce innate immune activation through a toll-like receptor (TLR)-4 pathway.7 Thus, ATIs constitute an interesting protein fraction in wheat that could independently, or in combination with gluten proteins, trigger low-grade inflammation and gut dysfunction in non-coeliac people. There is therefore the potential for a variety of wheat proteins to induce immune activation and gut dysfunction and to contribute to the clinical entity of NCGS/NCWS.

Figure 1

Schematic representation of food sensitivity and intolerance as one of many potential causes of functional symptoms. Wheat allergy and coeliac disease represent food-triggered conditions with defined pathogenesis.

In the current issue, Uhde et al8 investigate whether sensitivity to wheat in non-coeliac people is associated with systemic immune activation that may be linked to an enteropathy. The study included 80 individuals with diagnosis of NCWS who were identified by a questionnaire developed by the group, and further diagnosed by the criteria proposed by the Salerno consensus.2 They recorded GI and extra-intestinal symptoms and collected blood samples from 100 patients at baseline and in 20 patients after 6 months of gluten-free diet. Multiple markers for coeliac disease, including IgA antibodies to TG2, IgG and IgA antibodies to deamidated gliadin and IgG, IgA and IgM antibodies to native gliadin (AGAs) and HLA markers, as well as antibodies to bacterial flagellin, endotoxin-core antibodies (EndoCAb), lipopolysaccharide-binding protein (LBP), soluble CD14 and intestinal fatty acid binding protein (FABP2) were also measured. Forty samples from patients with biopsy-proven active coeliac disease and 40 samples from healthy subjects served as controls. Compared with healthy controls, the coeliac disease and NCWS cohorts had similar levels of IgG AGA, while IgA AGA was greater in patients with coeliac disease than in NCWS, and IgM AGA was only found to be elevated in the NCWS cohort. AGAs, in the absence of coeliac-specific serology such as TG2 Ab, have been previously suggested as a potential diagnostic marker for NCGS/NCWS. Although AGAs are not specific, their positivity, especially at high titres, in patients with a clinical picture suggestive of NCGS/NCWS may be regarded as a diagnostic adjunct.9 Uhde et al8 show that in parallel to symptom resolution, AGAs normalised in almost all patients with NCWS within 6 months of gluten-free diet. The authors then raise the provocative hypothesis that the increased antibody response to wheat gluten proteins in NCWS may be the consequence of an intestinal barrier defect that results in the inadequate regulation of the interaction between the gut luminal antigens and systemic circulation, thus leading to peripheral immune activation. Their data turn out to support this, showing elevated levels of serum soluble CD14 (sCD14) and LBP, as well as antibody reactivity to bacterial lipopolysaccharide and flagellin in individuals with NCWS compared with healthy controls and patients with coeliac disease. Similarly to patients with coeliac disease, the NCWS patients in this study also had elevated levels of FABP2, a marker of gut epithelial cell damage, suggesting compromised intestinal barrier integrity. Although not all studies have consistently reported altered intestinal permeability in patients with NCGS/NCWS,9 this may relate to the heterogeneity of patients included as well as the fact that clinical measurements of intestinal permeability in the clinical setting are problematic.10 Uhde et al show that in parallel to symptom resolution, there is a significant change towards normalisation in the levels of AGAs and antibodies to bacterial antigens, as well as sCD14, LBP and FAB2 in patients with NCWS after 6 months of gluten-free diet.

Finally, it is important to raise caution and prudence in the interpretation of dietary intervention trials in IBS or patients with potential NCGS/NCWS. A symptomatic response to gluten-containing food or improvement after its withdrawal may be a result of a combination of mechanisms. Patients may respond to more than one trigger, and thus symptomatic food reactions are likely to be individual, rather than universal. For this reason, studies that combine symptomatic responses to dietary intervention and investigation of defined pathophysiological mechanisms and biological markers should be encouraged. The challenge lies in increasing our understanding of the complexity of the relationship between food and functional symptoms, and in identifying subgroups of patients that will mostly benefit from tailored dietary interventions.


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  • Contributors EFV designed the outline of the commentary and figure. MIP-S and EFV discussed the content and wrote the commentary.

  • Funding EFV holds a Canada Research Chair and is funded by CIHR grant MOP 142773. MIPS holds a CIHR-CGA fellowship award.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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