Non-coeliac Wheat Sensitivity Research Articles

Two randomized crossover multicenter studies investigating gastrointestinal symptoms after bread consumption in individuals with noncoeliac wheat sensitivity: do wheat species and fermentation type matter?

BackgroundMany individuals reduce their bread intake because they believe wheat causes their gastrointestinal (GI) symptoms. Different wheat species and processing methods may affect these responses. ObjectivesWe investigated the effects of 6 different bread types (prepared from 3 wheat species and 2 fermentation conditions) on GI symptoms in individuals with self-reported noncoeliac wheat sensitivity (NCWS). MethodsTwo parallel, randomized, double-blind, crossover, multicenter studies were conducted. NCWS individuals, in whom coeliac disease and wheat allergy were ruled out, received 5 slices of yeast fermented (YF) (study A, n = 20) or sourdough fermented (SF) (study B, n = 20) bread made of bread wheat, spelt, or emmer in a randomized order on 3 separate test days. Each test day was preceded by a run-in period of 3 d of a symptom-free diet and separated by a wash-out period of ≥7 d. GI symptoms were evaluated by change in symptom score (test day minus average of the 3-d run-in period) on a 0–100 mm visual analogue scale (ΔVAS), comparing medians using the Friedman test. Responders were defined as an increase in ΔVAS of ≥15 mm for overall GI symptoms, abdominal discomfort, abdominal pain, bloating, and/or flatulence. ResultsGI symptoms did not differ significantly between breads of different grains [YF bread wheat median ΔVAS 10.4 mm (IQR 0.0–17.8 mm), spelt 4.9 mm (−7.6 to 9.4 mm), emmer 11.0 mm (0.0–21.3 mm), P = 0.267; SF bread wheat 10.5 mm (−3.1 to 31.5 mm), spelt 11.3 mm (0.0–15.3 mm), emmer 4.0 mm (−2.9 to 9.3 mm), P = 0.144]. The number of responders was also comparable for both YF (6 to wheat, 5 to spelt, and 7 to emmer, P = 0.761) and SF breads (9 to wheat, 7 to spelt, and 8 to emmer, P = 0.761). ConclusionsThe majority of NCWS individuals experienced some GI symptoms for ≥1 of the breads, but on a group level, no differences were found between different grains for either YF or SF breads. Clinical Trial Registryclinicaltrials.gov, NCT04084470 (https://classic.clinicaltrials.gov/ct2/show/NCT04084470).

Prevalence, symptoms and risk factor profile of rumination syndrome and functional dyspepsia: a population-based study.

Rumination syndrome is a functional gastroduodenal disorder characterised by effortless regurgitation of recently ingested food. Emerging evidence reports duodenal eosinophilic inflammation in a subset, suggesting a shared pathophysiology with functional dyspepsia (FD). To assess the clinical features of rumination syndrome and FD in a community-based study. We mailed a survey assessing gastrointestinal symptoms, diet and psychological symptoms to 9835 residents of Olmsted County, MN, USA in 2017-2018; diagnostic codes were obtained from linked clinical records. The two disorders were assessed as mutually exclusive in 'pure' forms with a separate overlap group, all compared to a control group not meeting criteria for either. Prevalence of associations, and univariate and independent associations with predictors were assessed by logistic regression. Prevalence of rumination syndrome and FD were 5.8% and 7.1%, respectively; the overlap was 3.83-times more likely than expected by chance. Independent predictors for rumination (odds ratio (OR), 95% confidence interval (CI)) were female gender (1.79, 1.21-2.63), smoking (1.89, 1.28-2.78), gluten-free diet (1.58, 1.14-2.19), allergic rhinitis (1.45, 1.01-2.08) and depression (1.10, 1.05-1.16). FD was independently associated with female gender, depression, non-coeliac wheat sensitivity, migraine, irritable bowel syndrome and somatic symptoms. A similar reported efficacy (≥54%) of low fat or dairy-free diets was found with both disorders (P=0.53 and P=1.00, respectively). The strongest independent associations with overlapping FD and rumination syndrome were a history of rheumatoid arthritis (3.93, 1.28-12.06) and asthma (3.02, 1.44-6.34). Rumination syndrome overlaps with FD with a shared risk factor profile, suggesting a common pathophysiology.

Wheat ATIs: Characteristics and Role in Human Disease.

Amylase/trypsin-inhibitors (ATIs) comprise about 2–4% of the total wheat grain proteins and may contribute to natural defense against pests and pathogens. However, they are currently among the most widely studied wheat components because of their proposed role in adverse reactions to wheat consumption in humans. ATIs have long been known to contribute to IgE-mediated allergy (notably Bakers' asthma), but interest has increased since 2012 when they were shown to be able to trigger the innate immune system, with attention focused on their role in coeliac disease which affects about 1% of the population and, more recently, in non-coeliac wheat sensitivity which may affect up to 10% of the population. This has led to studies of their structure, inhibitory properties, genetics, control of expression, behavior during processing, effects on human adverse reactions to wheat and, most recently, strategies to modify their expression in the plant using gene editing. We therefore present an integrated account of this range of research, identifying inconsistencies, and gaps in our knowledge and identifying future research needs.Note This paper is the outcome of an invited international ATI expert meeting held in Amsterdam, February 3-5 2020

CRISPR-Cas9 Multiplex Editing of the α-Amylase/Trypsin Inhibitor Genes to Reduce Allergen Proteins in Durum Wheat

Wheat and its derived foods are widespread, representing one of the main food sources globally. During the last decades, the incidence of disorders related to wheat has become a global issue for the human population, probably linked to the spread of wheat-derived foods. It has been ascertained that structural and metabolic proteins, like α-amylase/trypsin inhibitors (ATI), are involved in the onset of wheat allergies (bakers’ asthma) and probably Non-Coeliac Wheat Sensitivity (NCWS). The ATI are a group of exogenous protease inhibitors, which are encoded by a multigene family dispersed over several chromosomes in durum and bread wheat. WTAI-CM3 and WTAI-CM16 subunits are considered among the main proteins involved in the onset of bakers’ asthma and probably NCWS. A CRISPR-Cas9 multiplexing strategy was used to edit the ATI subunits WTAI-CM3 and WTAI-CM16 in the grain of the Italian durum wheat cultivar Svevo with the aim to produce wheat lines with reduced amount of potential allergens involved in adverse reactions. Using a marker gene-free approach, whereby plants are regenerated without selection agents, homozygous mutant plants without the presence of CRISPR vectors were obtained directly from T0 generation. This study demonstrates the capability of CRISPR technology to knock out immunogenic proteins in a reduced time compared to conventional breeding programmes. The editing of the two target genes was confirmed either at molecular (sequencing and gene expression study) or biochemical (immunologic test) level. Noteworthy, as a pleiotropic effect, is the activation of the ATI 0.28 pseudogene in the edited lines.

Coeliac disease and noncoeliac wheat or gluten sensitivity.

Coeliac disease (CD) and noncoeliac wheat or gluten sensitivity (NCWS/NCGS) are common gluten-related disorders. Both conditions can present with gastrointestinal and extraintestinal manifestations, which can be a challenge for physicians to discern between. Whilst coeliac serology and histological assessment are required for the diagnosis of CD, there are no clear biomarkers for the diagnosis of NCGS. The management of both conditions is with a gluten-free diet (GFD), although the duration, as well as strictness of adherence to a GFD in NCGS, is unclear. Adherence to a GFD in CD can also be challenging, with recent developments of noninvasive assessments, although histological assessment via duodenal biopsies remains the gold standard. The management of refractory coeliac disease remains particularly challenging, often requiring specialist input. Whilst wheat is noted to be a trigger for symptom generation in NCGS, it is unclear which components of wheat are responsible for symptom generation in this group, with further research required to elucidate the pathophysiology.

Incidence and prevalence of self-reported non-coeliac wheat sensitivity and gluten avoidance in Australia.

To determine the incidence of self-reported non-coeliac wheat sensitivity (SR-NCWS) and factors associated with its onset and resolution; to describe the prevalence of factors associated with gluten avoidance. Longitudinal cohort study; analysis of responses to self-administered validated questionnaires (Digestive Health and Wellbeing surveys, 2015 and 2018). Subset of an adult population sample randomly selected in 2015 from the electoral rolls for the Newcastle and Gosford regions of New South Wales. Prevalence of SR-NCWS (2015, 2018) and incidence and resolution of SR-NCWS, each by demographic and medical factors; prevalence of gluten avoidance and reasons for gluten avoidance (2018). 1322 of 2185 eligible participants completed the 2018 survey (response rate, 60.5%). The prevalence of SR-NCWS was similar in 2015 (13.8%; 95% CI, 12.0-15.8%) and 2018 (13.9%; 95% CI, 12.1-15.9%); 69 of 1301 respondents (5.3%) reported developing new onset (incident) SR-NCWS between 2015 and 2018 (incidence, 1.8% per year). Incident SR-NCWS was significantly associated with a diagnosis of functional dyspepsia, and negatively associated with being male or older. Gluten avoidance was reported in 2018 by 24.2% of respondents (20.5% partial, 3.8% complete avoidance); general health was the most frequent reason for avoidance (168 of 316 avoiders, 53%). All 13 participants with coeliac disease, 56 of 138 with irritable bowel syndrome (41%), and 69 of 237 with functional dyspepsia (29%) avoided dietary gluten. The prevalence of SR-NCWS was similar in 2015 and 2018. Baseline (2015) and incident SR-NCWS (2018) were each associated with functional gastrointestinal disorders. The number of people avoiding dietary gluten exceeds that of people with coeliac disease or SR-NCWS, and general health considerations and abdominal symptoms are the most frequently reported reasons for avoidance.

Breaking bread!

Humankind has existed for 2·5 million years but only in the past 10 000 years have we been exposed to wheat. Therefore, it could be considered that wheat (gluten) is a novel introduction to humankind's diet! Prior to 1939, the rationing system had already been devised. This led to an imperative to try to increase agricultural production. Thus, it was agreed in 1941 that there was a need to establish a Nutrition Society. The very roots of the Society were geared towards necessarily increasing the production of wheat. This goal was achieved and by the end of the 20th century, global wheat output had expanded by 5-fold. Perhaps, as a result, the epidemiology of coeliac disease (CD) or gluten sensitive enteropathy has changed. CD now affects 1 % or more of all adults. Despite this, delays in diagnosis are common, for every adult patient diagnosed approximately three-four cases are undetected. This review explores humankind's relationship with gluten, wheat chemistry, the rising prevalence of modern CD and the new entity of non-coeliac gluten or wheat sensitivity. The nutritional interventions of a low fermentable oligo-, di- and mono-saccharides and polyols diet and gluten-free diet (GFD) for irritable bowel syndrome and the evidence to support this approach (including our own published work) are also reviewed. There appears to be a rising interest in the GFD as a 'lifestyler', 'free from' or 'clean eater' choice, causing concern. Restrictive diets may lead to potential nutritional implications, with long-term effects requiring further exploration.

What’s in a name? ‘Non-coeliac gluten or wheat sensitivity’: controversies and mechanisms related to wheat and gluten causing gastrointestinal symptoms or disease

The global population has more than doubled over the past 40 years, supported by the ‘green revolution’ in agriculture producing high-yield grain varieties, including wheat, that are central to the...

Non-coeliac gluten sensitivity and the spectrum of gluten-related disorders: an updated overview.

The spectrum of gluten-related disorders includes coeliac disease (CD), wheat allergy (WA) and the suggested entity of non-coeliac gluten sensitivity (NCGS). An increasing number of the world's population are avoiding gluten due to the assumption of health benefits and self-diagnosed gastrointestinal and/or extra-intestinal symptoms. Unlike CD and WA, NCGS is a relatively new entity with an unknown prevalence and mechanisms, complicated by recent literature suggesting that gluten is not the only food component that may trigger symptoms experienced by this group of patients. The term 'non-coeliac wheat sensitivity' has been proposed as a more accurate term, allowing inclusion of other non-gluten wheat components such as fructans and amylase-trypsin inhibitors. There is inconsistent evidence when evaluating the effects of a gluten challenge in patients with suspected NCGS and there is a need for a standardised procedure to confirm the diagnosis, ultimately enabling the optimisation of clinical care. The present review will give an overview of the different gluten-related disorders and discuss the most recent scientific evidence investigating NCGS.

Nutrition: Searching for the immunological basis of wheat sensitivity.

A new study has advanced our knowledge on the pathogenesis of noncoeliac wheat sensitivity (NCWS), implicating the activation of innate immunity markers and immunological mechanisms at the basis of NCWS. However, limitations in the design of studies performed in this field will need addressing to help identify the root cause of NCWS.

From coeliac disease to noncoeliac gluten sensitivity; should everyone be gluten free?

Gluten-free diets (GFDs) have seen a disproportional rise in use and popularity relative to the prevalence of established gluten-related disorders such as coeliac disease or immunoglobulin E wheat allergy. This entity has been termed noncoeliac gluten sensitivity (NCGS). This review aims to provide a current perspective on the emerging evidence for and against NCGS, along with the associated need for a GFD. NCGS and the benefits of a GFD are reported amongst patients with irritable bowel syndrome, inflammatory bowel disease, and nonintestinal disorders such as neuropsychiatric diseases and fibromyalgia. However, no reliable biomarkers currently exist to diagnose NCGS and hence confirmatory testing can only be performed using double-blind placebo-controlled gluten-based challenges. Unfortunately, such tests are not available in routine clinical practice. Furthermore, recent novel studies have highlighted the role of other gluten-based components in contributing to the symptoms of self-reported NCGS. These include fermentable oligo, di, mono-saccharides and polyols, amylase trypsin inhibitors, and wheat germ agglutinins. Therefore, NCGS is now seen as a spectrum encompassing several biological responses and terms such as 'noncoeliac wheat sensitivity' have been suggested as a wider label to define the condition. Despite the rising use of a GFD further studies are required to clearly establish the extent and exclusivity of gluten in NCGS.

Bloating, Autonomic Nervous Dysfunction and Non-coeliac Wheat Sensitivity (WS): A Connection?

Purpose: Abdominal symptoms, particularly bloating and altered bowel habit, precipitated by cereals in patients with no evidence of coeliac disease has been termed “non coeliac wheat sensitivity.” These symptoms also occur in up to 30% of patients with IBS. It is currently uncertain if symptoms in (WS) are precipitated by gluten, other components of wheat flour or both. In the absence of defining changes in histology, coeliac antibodies and (faecal lactoferrin highly sensitive c-reactive protein) intestinal permeability the cause of WS remains speculative. Up to 80% of IBS sufferers are women. Symptoms of autonomic dysfunction are common in IBS including cold hands and feet and even overt Raynaud's phenomena. Little attention has been paid to autonomic dysfunction as a causative factor in WS. Methods: The Gut Foundation carried out an on-line survey of 1,295 female patients who had not been diagnosed with IBS to determine the prevalence of bloating, its site and precipitating factors. A key part of this questionnaire was whether or not individuals complained of cold hands and feet which were thought to represent the physical features of autonomic dysfunction. Results: Two-thirds of the 1,295 women experienced bloating and in 17% (31% with cold hands and feet) this was severe enough to compromise their quality of life. 725 (56%) of the women claimed to suffer from cold hands and feet some even having classical Raynaud's phenomena. Bloating was located in the upper abdomen (25%), mid abdomen (26%), low abdomen (27%), and all over (22%). There was a correlation with constipation, especially in those with upper and mid abdominal bloating. 0.8% had had a speculative diagnosis of coeliac disease. There was no weight difference in any of the age groups 18-29, 30-39 and 40-49 and no symptom correlation with weight, level of education or affluence. Symptoms were worse during menstruation, though not pregnancy. Conclusion: As bloating is such a common problem in the female population who comprise 70-80% of those with IBS, and there may be a link with cold hands and feet, which represents a disturbance of autonomic function, it is reasonable to ascribe this as a possible cause of non-coeliac wheat sensitivity. Diet produces little change in symptoms, except with the FODMAP diet which largely excludes all the high fibre, potentially gas-producing nutrients. These results suggest that autonomic dysfunction could play a significant role in the aetiology of WS. More detailed studies of autonomic dysfunction are warranted in WS. This research was supported by an industry grant from Kellogg's.