Dr. Schär Institute

 group of 23 experts met in December 2016 to provide consensus and promote collaborative research. A previous literature review occurred in October 2014 and for this reason the new MeSH-based literature review encompassed all articles since that time but also key historical papers. Emerging studies in abstract form were also provided by attending experts. Based on this current evidence, five areas were identified where significant progress in the literature had occurred and are summarised below.
 

Prevalence of NCGS: Emerging data & ascertainment pitfalls

Published literature shows a NCGS prevalence range of 0.6-10.6% with huge variability explained by lack of diagnostic biomarker(s). A double-blind placebo-controlled (DBPC) challenge using 8g gluten is recommended to clarify a diagnosis of NCGS but this is not always possible in daily clinical practice.

Limited data on the overlap between NCGS & IBS-type symptoms exists. A recent UK population survey in >1000 adults demonstrated individuals with self-reported NCGS had an increased prevalence of fulfilling ROME III criteria for IBS compared in those without NCGS. An emerging epidemiological issue is represented by self-diagnosed NCGS with literature showing a prevalence range of 6.2-13%. It is imperative to first exclude CD or other causes related to specific triggers. It is possible to advise these patients that by identifying gluten as the reason for their symptoms gives them a risk ranging from 2-42% of the having undiagnosed CD. The wide range reflects an ascertainment bias related to referral patterns of centres that have published their data.
 

Update on Non IgE-mediated Wheat Allergy in NCGS

The hypothesis that NCGS could be a non IgE-mediated wheat allergy is based on clinical aspects, laboratory & histological data and by new endoscopic findings. Recent evidence has shown immunological activation in the intestinal mucosa of NCGS patients and gastrointestinal food allergies is often mediated by IgE-independent mechanisms involving mast cells, eosinophils and other immune cells. An increase in mucosal lymphocytes has been reported in a consistent percentage of patients with NCGS diagnosed by DBPC challenges. An increased infiltration of innate lymphocytes in the rectal mucosa of NCGS patients has been reported with a decreased infiltration after resumption of a wheat-free diet (WFD). Further work is required to clarify if NCGS could have an association with either IgE or non IgE-mediated wheat allergy.

A lack of consensus exists about intestinal permeability in NCGS, however, more recent studies have shown an increased permeability in NCGS. In one study a state of systemic immune activation was demonstrated, possibly in conjunction with a compromised intestinal epithelium,  which significantly improved on a WFD. Further research is required to understand how wheat components can contribute to a compromised gut epithelial barrier. Using confocal endomicroscopy characteristic mucosal changes after the administration of a wheat suspension were observed in 13 of 36 patients, and in all of the dietary elimination of the identified trigger, including wheat as a prominent cause, resulted in long-term improvement. Furthermore, 36% of wheat-sensitive IBS patients is in line with the proportions found in other studies and suggests this method may offer remarkable sensitivity and specificity for NCGS despite the drawback of patient sedation required to undertake the procedure.
 

Potentially harmful wheat components

These include gluten proteins, lipopolysaccharides, amylase/trypsin inhibitors (ATIs), wheat germ alggutinins (WGA) and fermentable oligo-, di- and monosaccharides and polyols (FODMAPs). Gluten proteins account for 70-80% of the total grain protein. Specific sequences from gluten have been shown to induce an innate immune response in CD and could also play a role in NCGS. Care is advised when undertaking an oral gluten or wheat challenge because all wheat and gluten is not the same with composition of different components varying depending on various factors, for example, wheat species, cultivar, growing conditions and processing.

ATIs are a family of at least 11 structurally similar wheat proteins which have a protective function. ATIs are high in most modern bread wheats and low in spelt, durum & emmer and einkorn wheat species. ATIs are also present in other gluten-containing cereals – barley and rye. Nutritional ATIs have been shown to enhance intestinal inflammation in IBD models in mice. Wheat-germ agglutinins (WGA) serve as protective proteins and have been shown to induce the release of pro-inflammatory cytokines and impair the integrity of the intestinal epithelial layer. However, in contrast to ATIs, no immune stimulatory activity has been observed in vivo.

FODMAPs are resistant to digestion and absorption in the small intestine with complete or partial fermentation in the large intestine. Of the FODMAPs, wheat contains fructans with modern wheat breads containing 0.5-0.7% fructans (based on product as consumed), spelt bread 0.2% and gluten-free bread 0.2%. The fructan content of gluten-free products depends on the recipe.
 

Pathogenetic mechanisms of IBS in which wheat can be the trigger

Wheat is regarded as a culprit of symptom generation in some cases with endomicroscopic features and histopathological abnormalities providing a morphological basis to the existence of (inflammatory) wheat sensitivity in a substantial subset of patients.
Insufficient degradation of gluten and other wheat proteins in the small intestine leaves undigested peptides that can pass through a more permeable epithelial barrier (‘leaky gut’), reach the submucosa and activate an immune response.

Regardless of the causal agent, there is agreement that the withdrawal of wheat from the diet can significantly improve symptoms in a subset of IBS patients, who can sometimes be diagnosed as NCGS. The gluten-sensitive IBS patients includes the vast majority of wheat-sensitive patients since only a minority of NCGS cases do not display a coexistent IBS. The interplay between the various components of wheat may elicit a wide array of intestinal and extra-intestinal symptoms in a subgroup of IBS patients by modulating intestinal permeability, microbiota composition, immune activation which, alone or in combination, also affect the gut-brain axis activity leading to symptom perception. Future research is required in this area.
 

Overlap between IBS-type symptoms and NCGS

IBS dietary research has focused on the two main components of the Western diet, specifically FODMAPs and gluten in relation to symptoms in IBS. The efficacy and probable mechanisms of a low FODMAP diet (LFD) have previously been outlined. However, not all studies looking at the LFD have reported a beneficial outcome for IBS patients and first-line dietary advice has been shown to have a similar efficacy to FODMAP reduction. In addition, the LFD is a complex one requiring delivery by an experienced dietitian to help ensure success and overall nutritional adequacy. The potentially negative effect of reducing FODMAP intake on microbiota and nutritional adequacy requires further investigation.

Overlap exists between NCGS and IBS. The fundamental difference is that patients with NCGS self-report symptoms related to gluten. Conversely, IBS patients do not report gluten as a specific stimulus. However, in previous literature, wheat is a commonly reported ‘food intolerance’ in IBS patients. A body of evidence now exists supporting a gluten-free diet (GFD) as a specific dietary intervention in IBS, however, the mechanism by which wheat or specific components such as gluten or ATIs, causes IBS-type symptoms is debated.

Similar concerns exist with the GFD as with the LFD relating to microbiota composition and nutritional adequacy. There is clearly some overlap between the two interventions. One of the key components excluded on a LFD is wheat with patients on a long-term LFD appearing to view a reduced intake of wheat as essential to maintain a symptomatic response. Therefore, a GFD may be a more practical option for IBS patients which does not impair food-related QOL to the same level as a LFD.
 

Conclusions

There are two groups of patients who may benefit from a GFD- those who present with self-reported gluten-related symptoms and who may have NCGS and those who present with IBS-type symptoms and could have gluten- or wheat-sensitive IBS. A range of dietary interventions now exist that may benefit these patients.

Link to full article: http://www.mdpi.com/2072-6643/9/11/1268/htm