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Reizdarm, Zöliakie, Weizenallergie, Weizensensitivität – die Schwierigkeit, die Spreu vom Weizen zu trennen
Abstract
Zusammenfassung
Ernährungsfaktoren spielen eine wichtige Rolle bei Auslösung und Verschlimmerung von Bauchschmerzen, Blähungen und Durchfall bei Patienten mit Reizdarmsyndrom (RDS). Seit Abgrenzung eines neuen Krankheitsbildes zwischen RDS und Zöliakie, der non-celiac gluten sensitivity/Weizensensitivität, und seit Erscheinen eines in Laienkreisen viel beachteten Bestsellers zu negativen gesundheitlichen Effekten von Weizen, hat eine glutenfreie Ernährung seit einigen Jahren erheblich an Popularität zugenommen.
In einer Übersicht werden die Unterschiede zwischen RDS, Zöliakie, Weizenallergie und Weizensensitivität dargestellt und Studien, die den Weizenbestandteilen Gluten oder Fruktanen/FODMAPs (fermentierbaren Oligo-, Di-, Monosacchariden und Polyolen) eine auslösende Rolle zusprechen, erörtert. Vor- und Nachteile einer glutenfreien Diät und FODMAP-armen Ernährung werden diskutiert. Abschließend wird erläutert, bei welchem Patienten zu einer glutenfreien Ernährung und bei welchem Patienten zu einer FODMAP-armen Ernährung geraten werden sollte.
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Objective
IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase (SI) gene variants for their potential relevance in IBS.
Design
We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population.
Results
CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05).
Conclusions
SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
From January 1, 2009, through December 31, 2014, there were 22 278 persons 6 years or older who participated in NHANESs who underwent serologic testing for celiac disease for whom information about prior diagnosis of celiac disease and use of gluten-free diet was obtained by direct interview. Celiac disease was defined as having either double-positive serologic test results on IgA tissue transglutaminase and endomysial antibody or a reported diagnosis by a health care professional coupled with being on a gluten-free diet. People on a gluten-free diet without celiac disease were identified as those adherent to a gluten-free diet without serologic test results positive for celiac disease or a physician-given diagnosis. Trends in the prevalence of celiac disease and in adherence to a gluten-free diet among people without celiac disease were estimated in the total population, as well as by age, sex, and race. Appropriate published weights and a direct standardization method were used to estimate prevalence. All analyses were conducted using R software, version 3.2.2 (R Foundation for Statistical Computing). The NHANES study was approved by the National Center for Health Statistics Research Ethics Review Board, and all participants provided written informed consent. This analysis per se was deemed exempt by the Rutgers New Jersey Medical School Institutional Review Board because the data set used in the analysis was completely deidentified.
Objective:
Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy.
Design:
Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components.
Results:
Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals.
Conclusions:
These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease.
Non-celiac gluten sensitivity (NCGS) is characterized by the onset of symptoms after eating gluten-containing food. We aimed to single out NCGS subjects among subjects with functional gastrointestinal symptoms. Patients were enrolled in a multicenter double-blind placebo-controlled trial with crossover. Symptoms and quality of life were evaluated by means of 10-cm VAS and SF36. Iron parameters, transaminases and C reactive protein (CRP) were evaluated. After a three-week-long gluten-free diet (GFD), responsive patients were randomly assigned to gluten intake (5.6 g/day) or placebo for seven days, followed by crossover. The primary endpoint was the worsening of symptoms (VAS increase ≥3 cm) during gluten ingestion compared to placebo. One hundred and forty patients were enrolled and 134 (17 males, mean age 39.1 ± 11.7 years, BMI 22.4 ± 3.8) completed the first period. A total of 101 subjects (10 males, mean age 39.3 ± 11.0 years, BMI 22.3 ± 4.0) reported a symptomatic improvement (VAS score 2.3 ± 1.2 vs. 6.5 ± 2.2 before and after GFD, p = 0.001). 98 patients underwent the gluten challenge and 28 (all females, mean age 38.9 ± 12.7 years, BMI 22.0 ± 2.9) reported a symptomatic relapse and deterioration of quality of life. No parameters were found to be statistically associated with positivity to the challenge. However, 14 patients responded to the placebo ingestion. Taking into account this finding, about 14% of patients responding to gluten withdrawal showed a symptomatic relapse during the gluten challenge. This group is suspected to have NCGS.
Abstract: In the present paper, we discuss the change in celiac disease (CD) awareness and
perception through patients’ concerns and the most recent literature. Nowadays CD has
moved in the public awareness (both doctors and population) from a rare disease to
a common one and the gluten free diet (GFD) is no longer the exclusive therapy for CD
patients but is becoming a popular health choice for everybody. Gluten-free food, once hard
to find and requiring home preparation, is now available at restaurants and grocery stores.
However, the quality of life of those affected by CD seems to be still compromised and this
is particularly true for those who find it difficult to adhere to a GFD and those who were
asymptomatic at the time of diagnosis. Intervention at diagnosis and follow-up to improve
the patients’ adaptation to the condition and its limitations should be implemented.
The spectrum of gluten-related disorders has widened in recent times and includes celiac disease, non-celiac gluten sensitivity, and wheat allergy. The complex of symptoms associated with these diseases, such as diarrhea, constipation or abdominal pain may overlap for the gluten related diseases, and furthermore they can be similar to those caused by various other intestinal diseases, such as irritable bowel syndrome (IBS). The mechanisms underlying symptom generation are diverse for all these diseases. Some patients with celiac disease may remain asymptomatic or have only mild gastrointestinal symptoms and thus may qualify for the diagnosis of IBS in the general clinical practice. Similarly, the overlap of symptoms between IBS and non-celiac gluten sensitivity (NCGS) often creates a dilemma for clinicians. While the treatment of NCGS is exclusion of gluten from the diet, some, but not all, of the patients with IBS also improve on a gluten-free diet. Both IBS and NCGS are common in the general population and both can coexist with each other independently without necessarily sharing a common pathophysiological basis. Although the pathogenesis of NCGS is not well understood, it is likely to be heterogeneous with possible contributing factors such as low-grade intestinal inflammation, increased intestinal barrier function and changes in the intestinal microbiota. Innate immunity may also play a pivotal role. One possible inducer of innate immune response has recently been reported to be amylase-trypsin inhibitor, a protein present in wheat endosperm and the source of flour, along with the gluten proteins.
Celiac disease is a multisystem immune based disorder that is triggered by the ingestion of gluten in genetically susceptible individuals. The prevalence of celiac disease has risen in recent decades and is currently about 1% in most Western populations. The reason for this rise is unknown, although environmental factors related to the hygiene hypothesis are suspected. The pathophysiology of celiac disease involves both the innate and adaptive immune response to dietary gluten. Clinical features are diverse and include gastrointestinal symptoms, metabolic bone disease, infertility, and many other manifestations. Although a gluten-free diet is effective in most patients, this diet can be burdensome and can limit quality of life; consequently, non-dietary therapies are at various stages of development. This review also covers non-celiac gluten sensitivity. The pathophysiology of this clinical phenotype is poorly understood, but it is a cause of increasing interest in gluten-free diets in the general population.
A diet with reduced content of fermentable short chain carbohydrates (fermentable oligo-, di-, monosaccharides and polyols, FODMAPs) has been reported to be effective in the treatment of patients with irritable bowel syndrome (IBS). However, there is no evidence for its superiority to traditional dietary advice for these patients. We compared the effects a diet low in FODMAPs with traditional dietary advice in a randomized, controlled trial of patients with IBS.
We performed a multi-center, parallel, single-blind study of 75 patients who met the Rome III criteria for IBS, enrolled at gastroenterology outpatient clinics in Sweden. Subjects were randomly assigned to groups that ate specific diets for 4 weeks: a diet low in FODMAPs (n=38) or a diet frequently recommended for patients with IBS (a regular meal pattern; avoidance of large meals; and reduced intake of fat, insoluble fibers, caffeine and gas-producing foods such as beans, cabbage, and onions), with greater emphasis on how and when to eat rather than on what foods to ingest (n=37). Symptom severity was assessed using the IBS severity scoring system, and patients completed a 4 day food diary before and at the end of the intervention.
A total of 67 patients completed the dietary intervention (33 completed the diet low in FODMAPs, 34 completed the traditional IBS diet). The severity of IBS symptoms was reduced in both groups during the intervention (P<.0001 in both groups, before vs at the end of the 4 week diet), without a significant difference between the groups (P=.62). At the end of the 4 week diet period, 19 patients (50%) in the low FODMAP group had reductions in IBS severity scores ≥50, compared with baseline, vs 17 patients (46%) in the traditional IBS diet group (P=.72). Food diaries demonstrated good adherence to the dietary advice.
A diet low in FODMAPs reduces symptoms of IBS symptoms as well as traditional IBS dietary advice. Combining elements from these 2 strategies might further reduce symptoms of IBS.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts' recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally.
While the central role of an adaptive, T cell-mediated immune response to certain gluten peptides in celiac disease is well established, the innate immune response to wheat proteins remains less well defined. We identified wheat amylase trypsin inhibitors (ATIs), but not gluten, as major stimulators of innate immune cells (dendritic cells > macrophages > monocytes), while intestinal epithelial cells were nonresponsive. ATIs bind to and activate the CD14-MD2 toll-like receptor 4 (TLR4) complex. This activation occurs both in vitro and in vivo after oral ingestion of purified ATIs or gluten, which is usually enriched in ATIs. Wheat ATIs represent a family of up to 17 proteins with molecular weights of around 15 kDa and a variable primary but conserved secondary structure characterized by 5 intrachain disulfide bonds and alpha helices. They mostly form di- and tetramers that appear to equally activate TLR4. Relevant biological activity is confined to ATIs in gluten-containing cereals, while gluten-free cereals display no or minimal activities. ATIs represent up to 4% of total wheat protein and are highly resistant to intestinal proteases. In line with their dose-dependent function as co-stimulatory molecules in adaptive immunity of celiac disease, they appear to play a role in promoting other immune-mediated diseases within and outside the GI tract. Thus, ATIs may be prime candidates of severe forms of non-celiac gluten (wheat) sensitivity. © 2015 S. Karger AG, Basel.
The role of wheat, and particularly of gluten protein, in our diet has recently been scrutinized. This article provides a summary of the main pathologies related to wheat in the human body, including celiac disease, wheat allergy, nonceliac wheat sensitivity, fructose malabsorption, and irritable bowel syndrome. Differences in reactivity are discussed for ancient, heritage, and modern wheats. Due to large variability among species and genotypes, it might be feasible to select wheat varieties with lower amounts and fewer types of reactive prolamins and fructans. Einkorn is promising for producing fewer immunotoxic effects in a number of celiac research studies. Additionally, the impact of wheat processing methods on wheat sensitivity is reviewed. Research indicates that germination and fermentation technologies can effectively alter certain immunoreactive components. For individuals with wheat sensitivity, less-reactive wheat products can slow down disease development and improve quality of life. While research has not proven causation in the increase in wheat sensitivity over the last decades, modern wheat processing may have increased exposure to immunoreactive compounds. More research is necessary to understand the influence of modern wheat cultivars on epidemiological change.
Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms `intestinal barrier¿ and `intestinal permeability¿ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by `intestinal permeability¿. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and ¿ more recently recognized ¿ obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.
A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.
Objective A low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols) diet reduces symptoms of IBS, but reduction of potential prebiotic and fermentative effects might adversely affect the colonic microenvironment. The effects of a low FODMAP diet with a typical Australian diet on biomarkers of colonic health were compared in a single-blinded, randomised, cross-over trial.
Design Twenty-seven IBS and six healthy subjects were randomly allocated one of two 21-day provided diets, differing only in FODMAP content (mean (95% CI) low 3.05 (1.86 to 4.25) g/day vs Australian 23.7 (16.9 to 30.6) g/day), and then crossed over to the other diet with ≥21-day washout period. Faeces passed over a 5-day run-in on their habitual diet and from day 17 to day 21 of the interventional diets were pooled, and pH, short-chain fatty acid concentrations and bacterial abundance and diversity were assessed.
Results Faecal indices were similar in IBS and healthy subjects during habitual diets. The low FODMAP diet was associated with higher faecal pH (7.37 (7.23 to 7.51) vs 7.16 (7.02 to 7.30); p=0.001), similar short-chain fatty acid concentrations, greater microbial diversity and reduced total bacterial abundance (9.63 (9.53 to 9.73) vs 9.83 (9.72 to 9.93) log10 copies/g; p<0.001) compared with the Australian diet. To indicate direction of change, in comparison with the habitual diet the low FODMAP diet reduced total bacterial abundance and the typical Australian diet increased relative abundance for butyrate-producing Clostridium cluster XIVa (median ratio 6.62; p<0.001) and mucus-associated Akkermansia muciniphila (19.3; p<0.001), and reduced Ruminococcus torques.
Conclusions Diets differing in FODMAP content have marked effects on gut microbiota composition. The implications of long-term reduction of intake of FODMAPs require elucidation.
Trial registration number ACTRN12612001185853.
Background & Aims
An increase in CD3+TCRγδ+ and a decrease in CD3− intraepithelial lymphocytes (IEL) is a characteristic flow cytometric pattern of celiac disease (CD) with atrophy. The aim was to evaluate the usefulness of both CD IEL cytometric pattern and anti-TG2 IgA subepithelial deposit analysis (CD IF pattern) for diagnosing lymphocytic enteritis due to CD.
Methods
Two-hundred and five patients (144 females) who underwent duodenal biopsy for clinical suspicion of CD and positive celiac genetics were prospectively included. Fifty had villous atrophy, 70 lymphocytic enteritis, and 85 normal histology. Eight patients with non-celiac atrophy and 15 with lymphocytic enteritis secondary to Helicobacter pylori acted as control group. Duodenal biopsies were obtained to assess both CD IEL flow cytometric (complete or incomplete) and IF patterns.
Results
Sensitivity of IF, and complete and incomplete cytometric patterns for CD diagnosis in patients with positive serology (Marsh 1+3) was 92%, 85 and 97% respectively, but only the complete cytometric pattern had 100% specificity. Twelve seropositive and 8 seronegative Marsh 1 patients had a CD diagnosis at inclusion or after gluten free-diet, respectively. CD cytometric pattern showed a better diagnostic performance than both IF pattern and serology for CD diagnosis in lymphocytic enteritis at baseline (95% vs 60% vs 60%, p = 0.039).
Conclusions
Analysis of the IEL flow cytometric pattern is a fast, accurate method for identifying CD in the initial diagnostic biopsy of patients presenting with lymphocytic enteritis, even in seronegative patients, and seems to be better than anti-TG2 intestinal deposits.
Adherence to a gluten-free diet (GFD) for non-coeliac athletes (NCA) has become increasingly popular despite a paucity of supportive medical or ergogenic evidence. This study aimed to quantify the demographics of NCA and determine associated experiences, perceptions and sources of information related a GFD. Athletes (n=910, female=528, no gender selected=5) completed a 17-question online survey. Forty-one percent of NCA respondents, including 18-world and/or Olympic medalists, follow a GFD 50%-100% of the time (GFD>50): only 13% for treatment of reported medical conditions with 57% self-diagnosing their gluten sensitivity. The GFD>50 group characteristics included predominantly endurance sport athletes (70.0%) at the recreationally competitive level (32.3%), between 31-40 years of age (29.1%). Those who follow a GFD>50 reported experiencing, abdominal/gastrointestinal (GI) symptoms alone (16.7%) or in conjunction with two (30.7%) or three (35.7%) additional symptoms (e.g. fatigue) believed to be triggered by gluten. Eighty-four percent of GFD>50 indicted symptom improvement with gluten-removal. Symptom-based and non-symptom-based self-diagnosed gluten-sensitivity (56.7%) was the primary reason for adopting a GFD. Leading sources of GFD information were: online (28.7%), trainer/coach (26.2%) and other athletes (17.4%). Although 5-10% of the general population is estimated to benefit clinically from a GFD a higher prevalence of GFD adherence was found in NCA (41.2%). Prescription of a GFD amongst many athletes does not result from evidence-based practice suggesting that adoption of a GFD in the majority of cases was not based on medical rationale and may be driven by perception that gluten removal provides health benefits and an ergogenic edge in NCA.
Background:
Non-celiac gluten sensitivity (NCGS) is still an undefined syndrome with several unsettled issues despite the increasing awareness of its existence. We carried out a prospective survey on NCGS in Italian centers for the diagnosis of gluten-related disorders, with the aim of defining the clinical picture of this new syndrome and to establish roughly its prevalence compared with celiac disease.
Methods:
From November 2012 to October 2013, 38 Italian centers (27 adult gastroenterology, 5 internal medicine, 4 pediatrics, and 2 allergy) participated in this prospective survey. A questionnaire was used in order to allow uniform and accurate collection of clinical, biochemical, and instrumental data.
Results:
In total, 486 patients with suspected NCGS were identified in this 1-year period. The female/male ratio was 5.4 to 1, and the mean age was 38 years (range 3-81). The clinical picture was characterized by combined gastrointestinal (abdominal pain, bloating, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and systemic manifestations (tiredness, headache, fibromyalgia-like joint/muscle pain, leg or arm numbness, 'foggy mind,' dermatitis or skin rash, depression, anxiety, and anemia). In the large majority of patients, the time lapse between gluten ingestion and the appearance of symptoms varied from a few hours to 1 day. The most frequent associated disorders were irritable bowel syndrome (47%), food intolerance (35%) and IgE-mediated allergy (22%). An associated autoimmune disease was detected in 14% of cases. Regarding family history, 18% of our patients had a relative with celiac disease, but no correlation was found between NCGS and positivity for HLA-DQ2/-DQ8. IgG anti-gliadin antibodies were detected in 25% of the patients tested. Only a proportion of patients underwent duodenal biopsy; for those that did, the biopsies showed normal intestinal mucosa (69%) or mild increase in intraepithelial lymphocytes (31%). The ratio between suspected NCGS and new CD diagnoses, assessed in 28 of the participating centers, was 1.15 to 1.
Conclusions:
This prospective survey shows that NCGS has a strong correlation with female gender and adult age. Based on our results, the prevalence of NCGS seems to be only slightly higher than that of celiac disease.
Background:
Maintaining a gluten-free diet (GFD) without an underlying diagnosis of celiac disease has enjoyed widespread acceptance in the Unites States.
Methods:
We performed a cross-sectional study using a GFD questionnaire in 1647 patients with inflammatory bowel diseases (IBD) participating in the CCFA Partners longitudinal Internet-based cohort.
Results:
A diagnosis of celiac disease and non-celiac gluten sensitivity were reported by 10 (0.6%) and 81 (4.9%) respondents, respectively. Three hundred fourteen (19.1%) participants reported having previously tried a GFD and 135 (8.2%) reported current use of GFD. Overall 65.6% of all patients, who attempted a GFD, described an improvement of their gastrointestinal symptoms and 38.3% reported fewer or less severe IBD flares. In patients currently attempting a GFD, excellent adherence was associated with significant improvement of fatigue (P < 0.03).
Conclusions:
In this large group of patients with IBD, a substantial number had attempted a GFD, of whom the majority had some form of improvement in gastrointestinal symptoms. Testing a GFD in clinical practice in patients with significant intestinal symptoms, which are not solely explained by the degree of intestinal inflammation, has the potential to be a safe and highly efficient therapeutic approach. Further prospective studies into mechanisms of gluten sensitivity in IBD are warranted.
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder that affects approximately 10% to 20% of the general adult population in Europe and the Americas and is characterized by abdominal pain and altered bowel habits in the absence of reliable biomarkers. The pathophysiology of IBS is poorly understood and is currently thought to represent a complex interplay among the gut microbiota, low-grade inflammation, impaired mucosal barrier function, visceral hypersensitivity, gut motility, and alterations in the gut-brain axis. In any individual patient, 1 or more of these factors may interact to generate symptoms. Although up to 50% of patients report postprandial exacerbation of symptoms, few studies have critically assessed the role of diet in IBS. Furthermore, although many patients with IBS adopt any one of a host of dietary changes in an attempt to alleviate their symptoms, there has been, up until recently little scientific basis for any dietary recommendation in IBS. This review discusses the contribution of diet to the pathophysiology and symptoms of IBS.
To assess the prevalence of and explanations for wheat avoidance, including reported symptoms, diagnoses and information sources influencing the decision to avoid wheat, and to investigate potential psychological predictors of this behaviour.
Cross-sectional population survey.
The study was conducted in Australia, using a nationwide postal omnibus survey.
Adults aged 18 years and over (n 1184; 52·9 % female) selected at random from the Australian Electoral Roll.
With cases of stated and suspected coeliac disease (1·2 %) excluded, 7·3 % of the sample reported adverse physiological effects, predominantly gastrointestinal, that they associated with wheat consumption. Few among this group (5·7 %) claimed a formally diagnosed intolerance or allergy requiring avoidance of wheat-based foods. Symptomatic wheat avoidance was highly correlated with dairy avoidance and predicted by gender (female), lesser receptiveness to conventional medicine and greater receptiveness to complementary medicine, but not by neuroticism, reasoning style or tendency to worry about illness.
The data indicate that many adult Australians are consciously avoiding consumption of wheat foods, predominantly without any formal diagnosis. Reported symptoms suggest a physiological but not allergenic basis to this behaviour. Questions to be answered concern whether symptoms are attributed correctly to wheat, the agents (wheat components, dietary factors or additives) and physiological mechanism(s) involved, the nutritional adequacy of avoiders' diets, and the clinical and psychosocial processes that lead a substantial number of adults to avoid consuming wheat (or any other dietary factor) apparently independently of a medical diagnosis.
Objectives:
Differentiating between celiac disease (CD) and non-celiac gluten sensitivity (NCGS) is important for appropriate management but is often challenging.
Methods:
We retrospectively reviewed records from 238 patients who presented for the evaluation of symptoms responsive to gluten restriction without prior diagnosis or exclusion of CD. Demographics, presenting symptoms, serologic, genetic, and histologic data, nutrient deficiencies, personal history of autoimmune diseases, and family history of CD were recorded. NCGS was defined as symptoms responsive to a gluten-free diet (GFD) in the setting of negative celiac serology and duodenal biopsies while on a gluten-containing diet or negative human leukocyte antigen (HLA) DQ2/DQ8 testing.
Results:
Of the 238 study subjects, 101 had CD, 125 had NCGS, 9 had non-celiac enteropathy, and 3 had indeterminate diagnosis. CD subjects presented with symptoms of malabsorption 67.3% of the time compared with 24.8% of the NCGS subjects (P<0.0001). In addition, CD subjects were significantly more likely to have a family history of CD (P=0.004), personal history of autoimmune diseases (P=0.002), or nutrient deficiencies (P<0.0001). The positive likelihood ratio for diagnosis of CD of a >2× upper limit of normal IgA trans-glutaminase antibody (tTG) or IgA/IgG deaminated gliadan peptide antibody (DGP) with clinical response to GFD was 130 (confidence interval (CI): 18.5-918.3). The positive likelihood ratio of the combination of gluten-responsive symptoms and negative IgA tTG or IgA/IgG DGP on a regular diet for NCGS was 9.6 (CI: 5.5-16.9). When individuals with negative IgA tTG or IgA/IgG DGP also lacked symptoms of malabsorption (weight loss, diarrhea, and nutrient deficiencies) and CD risk factors (personal history of autoimmune diseases and family history of CD), the positive likelihood ratio for NCGS increased to 80.9.
Conclusions:
On the basis of our findings, we have developed a diagnostic algorithm to differentiate CD from NCGS. Subjects with negative celiac serologies (IgA tTG or IgA/IgG DGP) on a regular diet are unlikely to have CD. Those with negative serology who also lack clinical evidence of malabsorption and CD risk factors are highly likely to have NCGS and may not require further testing. Those with equivocal serology should undergo HLA typing to determine the need for biopsy.
Irritable bowel syndrome (IBS) is a functional condition of the bowel that is diagnosed using clinical criteria. This paper discusses the nature of the diagnostic process for IBS and how this impacts epidemiological measurements. Depending on the diagnostic criteria employed, IBS affects around 11% of the population globally. Around 30% of people who experience the symptoms of IBS will consult physicians for their IBS symptoms. These people do not have significantly different abdominal symptoms to those who do not consult, but they do have greater levels of anxiety and lower quality of life. Internationally, there is a female predominance in the prevalence of IBS. There is 25% less IBS diagnosed in those over 50 years and there is no association with socioeconomic status. IBS aggregates within families and the genetic and sociological factors potentially underlying this are reviewed. Patients diagnosed with IBS are highly likely to have other functional disease and have more surgery than the general population. There is no evidence that IBS is associated with an increased mortality risk. The epidemiological evidence surrounding these aspects of the natural history is discussed.
Zusammenfassung
Eine glutenfreie Ernährung ist seit 60 Jahren die einzige Therapieoption für Patienten mit Zöliakie oder Dermatitis herpetiformis zur Normalisierung der Beschwerden und Verhinderung von Komplikationen. Eine glutenfreie Ernährung erfreut sich jedoch in jüngster Zeit zunehmender Beliebtheit wegen vermuteter Effekte auf Wohlbefinden und Leistungsfähigkeit sowie zur Kontrolle des Körpergewichts.
In der vorliegenden Übersicht wird auf gesicherte Indikationen für eine glutenfreie Ernährung, auf die Notwendigkeit einer eingehenden Beratung und Schulung des Patienten, auf Probleme und Schwierigkeiten bei der Umsetzung einer glutenfreien Ernährung in den täglichen Alltag und auf mögliche Nebenwirkungen unter Langzeittherapie eingegangen. Neue Methoden zur Überprüfung der Adhärenz zu einer glutenfreien Ernährung werden erörtert, die ernährungsmedizinische Qualität etlicher lebensmitteltechnologisch hergestellter glutenfreier Nahrungsmittel wird kritisch diskutiert.
Dietary intake of fermentable oligo-, di- and monosaccharides, and polyols (FODMAP) has previously been shown to aggravate the symptoms of the irritable bowel syndrome (IBS), furthermore being associated with wheat sensitivity and a bread wheat-specific intolerance. FODMAP in whole grain flours and breads made of different varieties of bread wheat, spelt, durum, emmer, and einkorn were determined by high-performance anion exchange chromatography with pulsed amperometric detection. Fructans and raffinose were the only FODMAP detected in wheat flour. Total FODMAP contents ranged from 1.24±0.38 to 2.01±0.42g/100g DM in emmer and einkorn flours, respectively. During bread making, prolonging dough proofing times (>4 hours) allowed to effectively diminish FODMAP levels of the final product by up to 90%. Therefore, the applied processing method was substantially more important than the selection of the used variety in order to obtain low-FODMAP wheat bakery products, suitable for consumption by IBS patients.
Objectives:
Response to gluten challenge (GC) is a key feature in diagnostic algorithms and research trials in celiac disease (CD). Currently, autoantibody titers, late responders to GC, and invasive duodenal biopsies are used to evaluate gluten responsiveness. This study investigated the accuracy of serum intestinal-fatty acid binding protein (I-FABP), a marker for intestinal epithelial damage, to predict intestinal damage during GC in patients with CD.
Methods:
Twenty adult CD patients in remission underwent a two-week GC with 3 or 7.5 g of gluten daily. Study visits occurred at day -14, 0, 3, 7, 14, and 28. Serum I-FABP, antibodies to tissue transglutaminase (tTG-IgA), deamidated gliadin peptides (IgA-DGP), and anti-actin (AAA-IgA) were assessed at each visit. Villous-height to crypt-depth ratio (Vh:Cd) and intraepithelial lymphocyte (IEL) count were evaluated at day -14, 3, and 14. Forty-three CD-serology negative individuals were included to compare serum I-FABP levels in CD patients on a gluten-free diet (GFD) with those in healthy subjects.
Results:
Serum I-FABP levels increased significantly during a two-week GC. In contrast, the most pronounced autoantibody increase was found at day 28, when patients had already returned to a GFD for two weeks. IgA-AAA titers were only significantly elevated at day 28. I-FABP levels and IEL count correlated at baseline (r=0.458, P=0.042) and at day 14 (r=0.654, P=0.002) of GC. Neither gluten dose nor time on a GFD influenced I-FABP change during GC.
Conclusions:
Serum I-FABP levels increased significantly during a two-week GC in adult CD patients and correlated with IEL count. The data suggest that serum I-FABP is an early marker of gluten-induced enteropathy in celiac patients and may be of use in both clinical and research settings.Am J Gastroenterol advance online publication, 17 May 2016; doi:10.1038/ajg.2016.162.
Background & aims:
The only available treatment for celiac disease (CD) is lifelong adherence to gluten free (GF)-diet. However, GF-diet may lead to possible nutrient unbalance resulting in improper nutritional quality of diet. The aim of this study is to evaluate the nutritional quality of GF-diet.
Methods:
MEDLINE(®)/PubMed and Cochrane Library were electronically searched for articles published between 1990/01/01 and 2015/09/01.
Results:
GF-diet was found to be poor in alimentary fiber due in particular to the necessary avoidance of several kinds of foods naturally rich in fiber (i.e. grain) and the low content of fiber of GF product that are usually made with starches and/or refined flours. Micronutrients are also found to be poor, in particular Vit. D, Vit. B12 and folate, in addition to some minerals such as iron, zinc, magnesium and calcium. Moreover, an inadequate macronutrient intake was reported related above all to the focus on the avoidance of gluten that often leaving back the importance of nutritional quality of the choice. In particular, it was found a higher content of both saturated and hydrogenated fatty acids and an increase in the glycemic index and glycemic load of the meal.
Conclusions:
Despite the GF-diet is necessary in celiac disease treatment and the attention is on gluten avoidance, the evaluation of nutritional quality of the diet must be considered. Moreover, educational strategies based on the relationship between nutrients and food and human health could be developed to optimize the therapeutic approach in celiac patients.
Celiac disease (CD) is a model for common complex disorders with a high degree of heritability. The human leukocyte antigen (HLA) DQ genotype, specifically HLA-DQ2 and HLA-DQ8, is the strongest genetic risk factor. Genome-wide association studies (GWAS) have identified 57 single nucleotide polymorphisms (SNPs) located in the associated 39 non-HLA regions with mainly immunological functions. Together with HLA, these regions explain approximately 54 % of the disease’s heritability. Molecular functional analyses are necessary to delineate the true causal genetic variants and the pathways involved. Since CD shares many of its genetic susceptibility regions and implicated pathways with other immune-related diseases, a combined analysis may discover more common genetic variants with smaller effect sizes. HLA-DQ genotyping can already be used to exclude a diagnosis of CD, for example, as a test in the screening of individuals from high-risk groups, such as patients with type 1 diabetes or autoimmune thyroiditis, and first-degree relatives of CD patients. Discovering more genetic susceptibility variants and the pathways involved may ultimately contribute to risk stratification for follow-up and treatment, and lead to new therapeutic targets.
Over the last 25 years, with the concerted effort of many researchers, we have learned a lot about the pathophysiology of celiac disease (CD). Now, CD is the best understood autoimmune/immune-mediated illness. This chapter will discuss current understanding of gluten as an antigen, antigen-presentation, and the role of HLA-DQ2/DQ8, how gluten peptides cross the intestinal epithelial cell barrier, the importance of tissue transglutaminase for modifying gluten peptides for presentation, the role of intestinal T cells in coordinating inflammation, how intraepithelial lymphocytes are triggered to attack intestinal epithelial cells, and the role of antibody response.
Purpose of review:
This article evaluates the current status of the gut barrier in gastrointestinal disorders.
Recent findings:
The gut barrier is a complex, multicomponent, interactive, and bidirectional entity that includes, but is not restricted to, the epithelial cell layer. Intestinal permeability, the phenomenon most readily and commonly studied, reflects just one (albeit an important one) function of the barrier that is intimately related to and interacts with luminal contents, including the microbiota. The mucosal immune response also influences barrier integrity; effects of inflammation per se must be accounted for in the interpretation of permeability studies in disease states.
Summary:
Although several aspects of barrier function can be assessed in man, one must be aware of exactly what a given test measures, as well as of its limitations. The temptation to employ results from a test of paracellular flux to imply a role for barrier dysfunction in disorders thought to be based on bacterial or macromolecular translocation must be resisted. Although changes in barrier function have been described in several gastrointestinal disorders, their primacy remains to be defined. At present, few studies support efficacy for an intervention that improves barrier function in altering the natural history of a disease process.
Celiac Disease and Gluten: Multidisciplinary Challenges and Opportunities is a unique reference work-the first to integrate the insights of the causes and effects of celiac disease from the chemistry of reaction-causing foods to the diagnosis, pathogenesis, and symptoms that lead to proper diagnoses and treatment. With an estimated three million people in the United States alone affected by celiac disease, an autoimmune digestive disease, only five percent are properly diagnosed. Drawing on the connection between foods containing gluten and the resulting symptoms, this resource offers distinctive information that directly explores and links food science, medical diagnostics, and treatment information. A helpful tool for researchers and medical practitioners alike, Celiac Disease and Gluten: Multidisciplinary Challenges and Opportunities helps refine research targets, and provides a comprehensive overview on the multidisciplinary approaches to all crucial aspects related to celiac disease. • Presents key information from medical and food science research, as well as provides clinical insights • Provides direct corollary insights between source and symptom • Written by experts whose detailed experiments and results have shaped our understanding of celiac disease.
Background/objectives:
Adherence to gluten-free diet in self reported non-coeliac gluten sensitive subjects is scarcely researched. Objectives of the study were to compare dietary adherence in coeliac disease (CD) subjects and in non-coeliac gluten sensitive (NCGS) subjects, and to estimate gluten exposure based on weighed food records and analysis of gluten content in selected food items.
Subjects/methods:
Twenty-three subjects with biopsy verified CD on a gluten-free diet and 34 HLA-DQ2(+) NCGS subjects on a self-instituted gluten-free diet were enrolled. The latter group was under investigation of CD. Dietary adherence was assessed by frequency questionnaire and structured forms supplied by weighed food records. For the analyses of food samples, the sandwich R5-ELISA, Ridascreen(®) Gliadin competitive method was used.
Results:
There was no difference in dietary adherence between CD and NCGS subjects (83% vs 68%, p = 0.21). NCGS subjects were mainly self-educated in gluten-free diet compared to CD subjects (91% and 39%, respectively, p < 0.001). In non-adherent subjects, there was no difference in gluten exposure between CD and NCGS (10 vs 138 mg/day, p = 0.83). There was no difference in BMR-factor between CD and NCGS subjects, or between adherent and non-adherent subjects.
Conclusions:
Both CD and NCGS subjects were largely adherent, and adherence did not differ between the groups. Gluten exposure varied greatly, and some CD and NCGS subjects reached gluten intake above 500 mg/day, which might have considerable health effects on the individual, especially in case of coeliac disease.
It is unknown whether symptoms in non-coeliac patients (non-CD) meeting clinical diagnostic criteria for noncoeliac gluten sensitivity (NCGS) are specifically triggered by gluten.
To assess gluten sensitivity in patients diagnosed with NCGS.
We studied 35 non-CD subjects (31 females) that were on a gluten-free diet (GFD), in a double-blind challenge study. Participants were randomised to receive either gluten-containing flour or gluten-free flour for 10 days, followed by a 2-week washout period and were then crossed over. The main outcome measure was their ability to identify which flour contained gluten. Secondary outcome measures were based upon Gastrointestinal Symptoms Rating Scale (GSRS) scores.
The gluten-containing flour was correctly identified by 12 participants (34%), who were classified as having NCGS. Their mean GSRS dimension scores were significantly higher following gluten challenge compared to baseline. The scores were: pain, 1.7 ± 0.8 vs. 2.6 ± 1.0; reflux, 1.6 ± 0.5 vs. 2.2 ± 0.9; indigestion, 1.9 ± 0.7 vs. 3.2 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 2.9 ± 1.5 and constipation, 1.9 ± 0.9 vs. 2.9 ± 1.3. Seventeen participants (49%) erroneously considered the gluten-free flour to contain gluten. Their mean GSRS dimension scores were significantly higher following gluten-free flour challenge compared to baseline. The scores were: pain, 1.6 ± 0.9 vs. 3.0 ± 0.9; reflux, 1.4 ± 0.5 vs. 2.3 ± 1.1; indigestion, 2.0 ± 1.1 vs. 3.7 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 3.0 ± 1.2 and constipation, 1.6 ± 0.9 vs. 2.6 ± 1.3. The other six participants (17%) were unable to distinguish between the flours.
Double-blind gluten challenge induces symptom recurrence in just one-third of patients fulfilling the clinical diagnostic criteria for non-coeliac gluten sensitivity.
© 2015 John Wiley & Sons Ltd.
IBS is one of the most common types of functional bowel disorder. Increasing attention has been paid to the causative role of food in IBS. Food ingestion precipitates or exacerbates symptoms, such as abdominal pain and bloating in patients with IBS through different hypothesised mechanisms including immune and mast cell activation, mechanoreceptor stimulation and chemosensory activation. Wheat is regarded as one of the most relevant IBS triggers, although which component(s) of this cereal is/are involved remain(s) unknown. Gluten, other wheat proteins, for example, amylase-trypsin inhibitors, and fructans (the latter belonging to fermentable oligo-di-mono-saccharides and polyols (FODMAPs)), have been identified as possible factors for symptom generation/exacerbation. This uncertainty on the true culprit(s) opened a scenario of semantic definitions favoured by the discordant results of double-blind placebo-controlled trials, which have generated various terms ranging from non-coeliac gluten sensitivity to the broader one of non-coeliac wheat or wheat protein sensitivity or, even, FODMAP sensitivity. The role of FODMAPs in eliciting the clinical picture of IBS goes further since these short-chain carbohydrates are found in many other dietary components, including vegetables and fruits. In this review, we assessed current literature in order to unravel whether gluten/wheat/FODMAP sensitivity represent 'facts' and not 'fiction' in IBS symptoms. This knowledge is expected to promote standardisation in dietary strategies (gluten/wheat-free and low FODMAP) as effective measures for the management of IBS symptoms.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
There is much interest in wheat sensitivity among people without celiac disease (NCWS), but little is known about any risks associated with the condition. We evaluated the prevalence of autoimmune diseases among patients with NCWS, and investigated whether they carry anti-nuclear antibodies (ANA).
We performed a retrospective study of 131 patients diagnosed with NCWS (121 female; mean age, 29.1 y) at 2 hospitals in Italy from January 2001 through June 2011. Data were also collected from 151 patients with celiac disease or irritable bowel syndrome (IBS) (controls). Patients' medical records were reviewed to identify those with autoimmune diseases. We also performed a prospective study of 42 patients (38 female; mean age, 34 y) diagnosed with NCWS from July 2011 through March 2014 at 3 hospitals in Italy. One hundred age- and sex-matched subjects with celiac disease 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 autoimmune diseases.
In the retrospective analysis, similar portions of subjects with NCWS (29%) and celiac disease (29%) developed autoimmune diseases (mainly Hashimoto's thyroiditis, 29 cases), compared with a smaller proportion of subjects with IBS (4%) (P<.001). In the prospective study, 24% of subjects with NCWS, 20% if subjects with celiac disease, and 2% subjects with IBS developed autoimmune diseases (P<.001). In the retrospective study, serum samples tested positive for ANA in 46% of subjects with NCWS (median titer 1:80), 24% of subjects with celiac disease (P<.001), and 2% of subjects IBS (P<.001); in the prospective study, serum samples were positive for ANA in 28% of subjects with NCWS, 7.5% of subjects with celiac disease (P=.02), and 6% of subjects with IBS (P=.005 vs patients with NCWS). ANA positivity was associated with the presence of the HLA DQ2/DQ8 haplotypes (P<.001).
Higher proportions of patients with NCWS or celiac disease develop autoimmune disorders, are ANA positive, and showed DQ2/DQ8 haplotypes compared to patients with IBS.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Implementation of gluten-free diets amongst non-celiac athletes has rapidly increased in recent years due to perceived ergogenic and health benefits. The aim of this study was to investigate the effects of a gluten-free diet (GFD) on exercise performance, gastrointestinal (GI) symptoms, perceived well-being, intestinal injury, and inflammatory responses in non-celiac athletes.
Thirteen competitive endurance cyclists (8 males, 5 females) with no positive clinical screening for celiac disease or history of irritable bowel syndrome (mean±SD; age: 32±7 years; weight: 71.1±13.4kg; height 177.0±11.8cm, VO2max 59.1±8.0ml.kgmin) were allocated to a seven day gluten-containing diet (GCD) or GFD separated by a 10-day washout in a controlled randomized double-blind, cross-over study. Cyclists ate a GFD alongside either gluten-containing or gluten-free food bars (16g wheat gluten per day) while habitual training and nutrition behaviors were controlled. During each diet, cyclists completed the Daily Analysis of Life Demand for Athletes (DALDA) and GI questionnaires (post-exercise and daily). On day seven cyclists completed a submaximal steady-state (SS) 45 minute ride at 70% peak power followed by a 15 minute time-trial (TT). Blood samples were taken pre-exercise, post SS and post TT to determine intestinal fatty acid binding protein (IFABP) and inflammatory markers (cytokine responses: IL-1β, IL-6, IL-8, IL-10, IL-15, TNF-α). Mixed effect logistic regression was used to analyze data.
TT performance was not significantly different (p=0.37) between the GCD (245.4±53.4kJ) and GFD (245.0±54.6kJ). GI symptoms during exercise, daily, and DALDA responses were similar for each diet (p>0.11). There were no significant differences in IFABP (p=0.69) or cytokine (P>0.13) responses.
A short-term GFD had no overall effect on performance, GI symptoms, well-being, and a select indicator of intestinal injury or inflammatory markers in non-celiac endurance athletes.
The immune response causing celiac disease (CD) depends on the activation of intestinal CD4+ T cells by gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 molecules, the main genetic risk factor. However, additional factors are necessary to impair immune tolerance to dietary gluten, to stimulate intraepithelial lymphocytes (IEL) and to induce intestinal damage. Key Messages: Current data point to a central role of interleukin-15 (IL-15). In situ and ex vivo studies indicate that IL-15 stimulates the accumulation and cytotoxic activation of CD8+ T IEL in active CD, and that of the malignant innate-like IEL in type II refractory CD (RCDII). Other studies show that IL-15 impairs the immunoregulatory control of effector T cells, notably CD8+. Recently, animal models have been designed to investigate the respective role of CD4+ T cells and IL-15 in CD. We discuss more particularly our results in such a model, which shows that IL-15 produced in excess in the intestine can cooperate with CD4+ T cells specific for a dietary antigen to trigger a celiac-like enteropathy. In this mouse model, CD4+ T cells activated by dietary ovalbumin secreted IL-2 which, along with IL-15, stimulated the expansion of noncognate intestinal cytotoxic CD8+ T cells containing large amounts of granzyme B. In the presence of IL-15, the latter cells did not respond to regulatory T cells, and accumulated in the intestine close to epithelial damage.
On the basis of these data, we propose that, in CD, gluten-specific CD4+ T cells synthesize cytokines that synergize with IL-15 to license the expansion and activation of cytotoxic IEL, which drive tissue damage. We suggest that IL-15 is a meaningful therapeutic target, notably in patients with RCDII in which malignant IEL can respond to IL-15 independently of signals provided by CD4+ T cells. © 2015 S. Karger AG, Basel.
Celiac disease is a multifactorial and polygenic disease with autoimmune features. The disease is caused by an inappropriate immune response to gluten. Elimination of gluten from the diet leads to disease remission, which is the basis for today's treatment of the disease. There is an unmet need for new alternative treatments. Key Messages: Genetic findings point to adaptive immunity playing a key role in the pathogenesis of celiac disease. MHC is by far the single most important genetic factor in the disease. In addition, a number of non-MHC genes, the majority of which have functions related to T cells and B cells, also contribute to the genetic predisposition, but each of them has modest effect. The primary MHC association is with HLA-DQ2 and HLA-DQ8. These HLA molecules present gluten epitopes to CD4+ T cells which can be considered to be the master regulators of the immune reactions that lead to the disease. The epitopes which the T cells recognize are usually deamidated, and this deamidation is mediated by the enzyme transglutaminase 2 (TG2). Celiac disease patients have disease-specific antibodies. In addition to antibodies to gluten, these include autoantibodies to TG2. Antibodies to deamidated gluten are nearly as specific for celiac disease as the anti-TG2 antibodies. Both types of antibodies appear only to be produced in subjects who are HLA-DQ2 or HLA-DQ8 when they are consuming gluten.
It is hardly coincidental that TG2 is implicated in T-cell epitope formation and at the same time a target for autoantibodies. Understanding this connection is one of the major challenges for obtaining a complete understanding of how gluten causes tissue destruction and remodeling of the mucosa in the small bowel. © 2015 S. Karger AG, Basel.
While it is well documented and widely appreciated that ingestion of wheat (and less so rye and barley) is associated with gastrointestinal symptoms such as bloating or abdominal pain, the component of wheat to which such an effect is attributed is less well established. Key Messages: Wheat is a complex of proteins (80% gluten, 20% metabolic proteins), carbohydrates (starch, non-starch polysaccharides, fructans), lipids and other components. The majority of attention has focused on gluten as the culprit in triggering symptoms, but re-challenge studies have nearly all used wheat flour-related products (such as bread) as the stimulus. When carbohydrate-deplete gluten was used as the challenge agent, gluten-specific feelings of depression and not gut symptoms were observed in those who fulfilled strict criteria of 'non-coeliac gluten sensitivity', thereby underlining the complexity of cereals and of undertaking research in this area. Candidate components other than gluten include poorly absorbed oligosaccharides (mainly fructans), non-gluten wheat proteins such as amylase-trypsin inhibitors or wheat germ agglutinin, and exorphins released during the digestion of gluten. Specific biological and/or clinical effects associated with gluten-free diets or wheat ingestion need to be carefully dissected before attribution to gluten can be claimed.
Currently, coeliac disease is the only common condition that has been unequivocally linked to gluten. Inaccurate attribution will be associated with suboptimal therapeutic advice and at least partly underlies the current gluten-free epidemic gripping the Western world. © 2015 S. Karger AG, Basel.
Background
Noncoeliac gluten sensitivity (NCGS) is a controversial emerging disorder. Despite reported symptoms related to the ingestion of gluten, NCGS remains a diagnosis based on the exclusion of coeliac disease, given the absence of reliable biomarkers.AimTo evaluate the prevalence, diagnostic exclusion of coeliac disease and the efficacy of a gluten-free diet (GFD) for NCGS patients.MethodsA PubMed search was performed up to December 2014. According to consensus diagnostic criteria, NCGS was defined as self-reported gluten intolerance, negative coeliac serology and absence of villous atrophy. Studies evaluating the impact of a GFD on patients with irritable bowel syndrome (IBS) were also included.ResultsPrevalence rates of NCGS (0.5–13%) differed widely. Seventeen studies, including 1561 patients (26 children), met the inclusion criteria for NCGS. HLA haplotypes could not be linked to histology [normal or lymphocytic enteritis (LE)] in 1123 NCGS patients. HLADQ2/DQ8 haplotypes were present in 44% of NCGS patients. After advanced diagnostic techniques in 189 NCGS patients combining LE and HLADQ2/DQ8 haplotypes, 39 (20%) were reclassified as coeliac disease. There was a higher than expected family history of coeliac disease and autoimmune disorders in NCGS patients. A GFD resulted in variable results for variable, but significantly improved stool frequency in HLADQ2 positive diarrhoea-predominant IBS patients.Conclusions
Prevalence rates for NCGS are extremely variable. A subset of NCGS patients might belong in the so-called ‘coeliac-lite’ disease. The benefit of a GFD for NCGS patients is currently controversial. HLADQ2 positive diarrhoea-type IBS patients might gain symptom improvement from a GFD.
There is debate over the existence of nonceliac gluten sensitivity (NCGS) -intestinal and extra-intestinal symptoms in response to ingestion of gluten-containing foods by people without celiac disease or wheat allergy. We performed a randomized, double-blind, placebo-controlled, cross-over trial to determine the effects of administration of low doses of gluten to subjects with suspected NCGS.
We enrolled 61 adults without celiac disease or wheat allergy who believe ingestion of gluten-containing food to be the cause of their intestinal and extra-intestinal symptoms. Participants were randomly assigned to groups given either 4.375 g/day gluten or rice starch (placebo) for 1 week, each via gastro-soluble capsules. After a 1 week of gluten-free diet, participants crossed over to the other group. The primary outcome was the change in overall (intestinal and extra-intestinal) symptoms, determined by established scoring systems, between gluten and placebo intake. A secondary outcome was the change in individual symptom scores between gluten vs placebo.
According to the per-protocol analysis of data from the 59 patients who completed the trial, intake of gluten significantly increased overall symptoms compared with placebo (P=.034). Abdominal bloating (P=.040) and pain (P=.047), among the intestinal symptoms, and foggy mind (P=.019), depression (P=.020), and aphthous stomatitis (P=.025), among the extra-intestinal symptoms, were significantly more severe when subjects received gluten than placebo.
In a cross-over trial of subjects with suspected NCGS, the severity of overall symptoms increased significantly during 1 week of intake of small amounts of gluten, compared with placebo. Clinical trial no: ISRCTN72857280.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Background & aims:
We investigated suspected food intolerances in patients with irritable bowel syndrome (IBS) using confocal laser endomicroscopy (CLE) for real-time visualization of structural/functional changes in the intestinal mucosa after food challenge. Patients with functional changes after food challenge (CLE+) were placed on personalized exclusion diets and followed up for long-term symptom relief.
Methods:
Thirty-six IBS patients with suspected food intolerance and 10 patients with Barrett's esophagus (controls) without IBS symptoms were examined by CLE at University Hospital Schleswig-Holstein (Kiel, Germany). Diluted food antigens were administered directly to the duodenal mucosa through the working channel of the endoscope. Epithelial breaks, intervillous spaces, and the number of intraepithelial lymphocytes (IEL) were measured before and after the food challenge. CLE+ patients were placed on exclusion diets, given symptom score questionnaires, and followed up for 1 year; controls resumed their previous diet.
Results:
CLE showed a real-time response to food antigens in 22 of 36 patients; no responses were observed in 14 of 36 patients (CLE-) or any of the controls. Baseline IELs were significantly higher in CLE+ than CLE- subjects (P = .004); numbers increased significantly after food challenge (P = .0008). Within 5 minutes of exposure of CLE+ patients to food antigens, IELs increased, epithelial leaks/gaps formed, and intervillous spaces widened. Epithelial leaks and intervillous spaces also increased significantly in CLE+ vs baseline (both P < .001). The concordance of IELs measured by CLE and conventional histology was 70.6%; they did not correlate (P = .89; r(2) = 0.027). Symptom scores improved more than 50% in CLE+ patients after a 4-week exclusion diet and increased to 74% at 12 months; symptoms continued in CLE- patients.
Conclusions:
Based on CLE analysis of IBS patients with a suspected food intolerance, exposure to candidate food antigens caused immediate breaks, increased intervillous spaces, and increased IELs in the intestinal mucosa. These changes are associated with patient responses to exclusion diets. Registered at clinicaltrials.gov (registration number: NCT01692613).
Reports suggest that gluten sensitivity (GS) exists in the absence of coeliac disease (CD). This clinical entity has been termed noncoeliac gluten sensitivity (NCGS).
To determine the population prevalence of self-reported GS and referral characteristics to secondary care.
A UK population-based questionnaire screened for GS and related symptoms. Diagnostic outcomes were also analyzed in patients referred to secondary care with GS. CD diagnosis entailed a positive coeliac serology (endomysial and/or tissue transglutaminase antibodies) plus Marsh 1-3 on duodenal biopsies. NCGS diagnosis was based on exclusion of CD. Clinical comparisons were made between NCGS and CD.
A total of 1002 adults in the population (female 55%, mean age 39 years). The self-reported prevalence for GS was 13% (female 79%, mean age 39.5 years, P<0.0001), with 3.7% consuming a gluten-free diet and 0.8% known to have a doctor diagnosis of CD. Individuals with GS had an increased prevalence of fulfilling the Rome III criteria for irritable bowel syndrome, in comparison with those without GS (20 vs. 3.89%, odds ratio 6.23, P<0.0001).In secondary care 200 GS patients (female 84%, mean age 39.6 years) were investigated, in whom 7% were found to have CD and 93% to have NCGS. All CD patients were human leucocyte antigen DQ2 or DQ8 positive compared with 53% of NCGS cases (P=0.0003). Nutritional deficiencies (P≤0.003), autoimmune disorders (23.1 vs. 9.7%, P=0.0001) and a lower mean BMI (23.7 vs. 25.8, P=0.001) were significantly associated with CD compared with NCGS.
GS is commonly self-reported with symptoms suggesting an association with irritable bowel syndrome. The majority of patients have NCGS, an entity which demonstrates clinical and immunologic difference to CD.