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Gluten Related Disorders: People Shall not Live on Bread Alone
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Gluten Related Disorders: People Shall not Live on Bread Alone

A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (31 May 2015) | Viewed by 304418

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Carlo Catassi

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Guest Editor
1. Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy
2. Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP), Milan, Italy
Interests: celiac disease; gluten-related disorders; gluten sensitivity; pediatric gastroenterology; pediatric nutrition
Special Issues, Collections and Topics in MDPI journals
Professor Alessio Fasano

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Guest Editor
Mucosal Immunology and Biology Research Center, Massachusetts General Hospital East, Building 114, 16th Street (Mail Stop 114-3503), Charlestown, MA 02129-4404, USA.
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Once upon a time, gluten was not a part of the human diet, and therefore, there were no gluten-related disorders.  With the advent of agriculture 10,000 years ago, the introduction of gluten-containing grains in the human diet created conditions for human diseases related to gluten exposure. These diseases, including celiac disease, non-celiac gluten sensitivity, and wheat allergy, have distinct pathophysiological mechanisms, serological markers, and long-term treatments, but similar, often overlapping clinical presentations.  Though current research strives to clarify the boundaries between these entities, their differences can be difficult to distinguish.

For a very long time, awareness of these disorders has been limited and, therefore, the epidemiology of gluten-related disorders has been a “work in progress”. New epidemiological studies have revealed that gluten-related disorders are not limited to European regions; rather, they are present worldwide.

After centuries of neglected attention to celiac disease and other forms of gluten reaction, now we are observing another interesting phenomenon that is generating great confusion among health care professionals.  Nearly 25% of Americans (many more than the projected 3 million CD patients in the U.S.) are reducing or cutting gluten from their diets. This remarkable trend in the general population reflects the misconception that gluten can be harmful for everybody and, therefore, should be avoided to stay healthy, to lose weight, or even to prevent severe diseases.

This Special Issue of Nutrients will contain contributions from leading experts in the field of gluten-related disorders that will help dissipate this confusion by sharing their evidence-based science, which will help the reader to distinguish facts from fantasies.


Prof. Carlo Catassi
Prof. Alessio Fasano
Guest Editors

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Keywords

  • celiac disease
  • autoimmunity
  • food antigen trafficking
  • gut permeability
  • microbiome
  • food sensitivities

Published Papers (20 papers)

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Editorial

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152 KiB  
Editorial
Tempters and Gluten-Free Diet
by Carlo Catassi and Alessio Fasano
Nutrients 2016, 8(12), 786; https://doi.org/10.3390/nu8120786 - 03 Dec 2016
Cited by 3 | Viewed by 4846
Abstract
To the tempter that came to Him and said, “If You are the Son of God, tell these stones to become bread”.[...] Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)

Research

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1173 KiB  
Article
Recognising and Managing Refractory Coeliac Disease: A Tertiary Centre Experience
by Ikram Nasr, Iman Nasr, Carl Beyers, Fuju Chang, Suzanne Donnelly and Paul J. Ciclitira
Nutrients 2015, 7(12), 9896-9907; https://doi.org/10.3390/nu7125506 - 01 Dec 2015
Cited by 13 | Viewed by 8123
Abstract
Refractory coeliac disease (RCD) is a rare complication of coeliac disease (CD) and involves malabsorption and villous atrophy despite adherence to a strict gluten-free diet (GFD) for at least 12 months in the absence of another cause. RCD is classified based on the [...] Read more.
Refractory coeliac disease (RCD) is a rare complication of coeliac disease (CD) and involves malabsorption and villous atrophy despite adherence to a strict gluten-free diet (GFD) for at least 12 months in the absence of another cause. RCD is classified based on the T-cells in the intra-epithelial lymphocyte (IEL) morphology into type 1 with normal IEL and type 2 with aberrant IEL (clonal) by PCR (polymerase chain reaction) for T cell receptors (TCR) at the β/γ loci. RCD type 1 is managed with strict nutritional and pharmacological management. RCD type 2 can be complicated by ulcerative jejunitis or enteropathy associated lymphoma (EATL), the latter having a five-year mortality of 50%. Management options for RCD type 2 and response to treatment differs across centres and there have been debates over the best treatment option. Treatment options that have been used include azathioprine and steroids, methotrexate, cyclosporine, campath (an anti CD-52 monoclonal antibody), and cladribine or fluadribine with or without autologous stem cell transplantation. We present a tertiary centre’s experience in the treatment of RCD type 2 where treatment with prednisolone and azathioprine was used, and our results show good response with histological recovery in 56.6% of treated individuals. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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2244 KiB  
Article
Increased Intraepithelial Vα24 Invariant NKT Cells in the Celiac Duodenum
by Enrique Montalvillo, David Bernardo, Beatriz Martínez-Abad, Yessica Allegretti, Luis Fernández-Salazar, Carmen Calvo, Fernando G. Chirdo, José A. Garrote and Eduardo Arranz
Nutrients 2015, 7(11), 8960-8976; https://doi.org/10.3390/nu7115444 - 30 Oct 2015
Cited by 6 | Viewed by 6460
Abstract
Celiac Disease (CD) is an interferon (IFN)γ-mediated duodenal hypersensitivity to wheat gluten occurring in genetically predisposed individuals. Gluten-free diet (GFD) leads to a complete remission of the disease. Vα24-restricted invariant NKT (iNKT) cells are important to maintain immune homeostasis in the gut mucosa [...] Read more.
Celiac Disease (CD) is an interferon (IFN)γ-mediated duodenal hypersensitivity to wheat gluten occurring in genetically predisposed individuals. Gluten-free diet (GFD) leads to a complete remission of the disease. Vα24-restricted invariant NKT (iNKT) cells are important to maintain immune homeostasis in the gut mucosa because of their unique capacity to rapidly produce large quantities of both T-helper (Th)1 and Th2 cytokines upon stimulation. We studied the presence of these cells in the CD duodenum. Duodenal biopsies were obtained from 45 untreated-CD patients (uCD), 15 Gluten Free Diet-CD patients (GFD-CD), 44 non-inflamed non-CD controls (C-controls) and 15 inflamed non-CD controls (I-controls). Two populations from Spain and Argentina were recruited. Messenger RNA (mRNA) expression of Vα24-Jα18 (invariant TCRα chain of human iNKT cells), IFNγ and intracellular transcription factor Forkhead Box P3 (Foxp3), and flow cytometry intraepithelial lymphocyte (IEL) profile were determined. Both uCD and GFD-CD patients had higher Vα24-Jα18 mRNA levels than non-CD controls (I and C-controls). The expression of Vα24-Jα18 correlated with Marsh score for the severity of mucosal lesion and also with increased mRNA IFNγ levels. uCD and GFD-CD patients had decreased mRNA expression of FoxP3 but increased expression of Vα24-Jα18, which revealed a CD-like molecular profile. Increased numbers of iNKT cells were confirmed by flow cytometry within the intraepithelial lymphocyte compartment of uCD and GFD-CD patients and correlated with Vα24-Jα18 mRNA expression. In conclusion, we have found an increased number of iNKT cells in the duodenum from both uCD and GFD-CD patients, irrespective of the mucosal status. A CD-like molecular profile, defined by an increased mRNA expression of Vα24-Jα18 together with a decreased expression of FoxP3, may represent a pro-inflammatory signature of the CD duodenum. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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91 KiB  
Article
Cutaneous Manifestations of Non-Celiac Gluten Sensitivity: Clinical Histological and Immunopathological Features
by Veronica Bonciolini, Beatrice Bianchi, Elena Del Bianco, Alice Verdelli and Marzia Caproni
Nutrients 2015, 7(9), 7798-7805; https://doi.org/10.3390/nu7095368 - 15 Sep 2015
Cited by 38 | Viewed by 11390
Abstract
Background: The dermatological manifestations associated with intestinal diseases are becoming more frequent, especially now when new clinical entities, such as Non-Celiac Gluten Sensitivity (NCGS), are identified. The existence of this new entity is still debated. However, many patients with diagnosed NCGS that present [...] Read more.
Background: The dermatological manifestations associated with intestinal diseases are becoming more frequent, especially now when new clinical entities, such as Non-Celiac Gluten Sensitivity (NCGS), are identified. The existence of this new entity is still debated. However, many patients with diagnosed NCGS that present intestinal manifestations have skin lesions that need appropriate characterization. Methods: We involved 17 patients affected by NCGS with non-specific cutaneous manifestations who got much better after a gluten free diet. For a histopathological and immunopathological evaluation, two skin samples from each patient and their clinical data were collected. Results: The median age of the 17 enrolled patients affected by NCGS was 36 years and 76% of them were females. On the extensor surfaces of upper and lower limbs in particular, they all presented very itchy dermatological manifestations morphologically similar to eczema, psoriasis or dermatitis herpetiformis. This similarity was also confirmed histologically, but the immunopathological analysis showed the prevalence of deposits of C3 along the dermo-epidermal junction with a microgranular/granular pattern (82%). Conclusions: The exact characterization of new clinical entities such as Cutaneous Gluten Sensitivity and NCGS is an important objective both for diagnostic and therapeutic purposes, since these are patients who actually benefit from a GFD (Gluten Free Diet) and who do not adopt it only for fashion. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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403 KiB  
Article
Self-Reported Prevalence of Symptomatic Adverse Reactions to Gluten and Adherence to Gluten-Free Diet in an Adult Mexican Population
by Noe Ontiveros, Jesús A. López-Gallardo, Marcela J. Vergara-Jiménez and Francisco Cabrera-Chávez
Nutrients 2015, 7(7), 6000-6015; https://doi.org/10.3390/nu7075267 - 21 Jul 2015
Cited by 40 | Viewed by 7779
Abstract
The prevalence of symptomatic adverse reactions to gluten and adherence to gluten-free diet in Latin American countries is unknown. These measurements are strongly linked to gluten-related disorders. This work aimed to estimate the prevalence of adverse reactions to oral gluten and the adherence [...] Read more.
The prevalence of symptomatic adverse reactions to gluten and adherence to gluten-free diet in Latin American countries is unknown. These measurements are strongly linked to gluten-related disorders. This work aimed to estimate the prevalence of adverse reactions to oral gluten and the adherence to gluten-free diet in the adult Mexican population. To reach this aim, a self-administered questionnaire was designed and tested for clarity/comprehension and reproducibility. Then, a self-administered questionnaire-based cross-sectional study was conducted in the Mexican population. The estimated prevalence rates were (95% CI): 11.9% (9.9–13.5) and 7.8 (6.4–9.4) for adverse and recurrent adverse reactions to gluten respectively; adherence to gluten-free diet 3.7% (2.7–4.8), wheat allergy 0.72% (0.38–1.37); celiac disease 0.08% (0.01–0.45), and NCGS 0.97% (0.55–1.68). Estimated pooled prevalence of self-reported physician-diagnosis of gluten-related disorders was 0.88% (0.49–1.5), and 93.3% respondents reported adherence to gluten-free diet without a physician-diagnosis of gluten-related disorders. Symptom comparisons between those who reported recurrent adverse reactions to gluten and other foods showed statistically significant differences for bloating, constipation, and tiredness (p < 0.05). Gluten-related disorders may be underdiagnosed in the Mexican population and most people adhering to a gluten-free diet are doing it without proper diagnostic work-up of these disorders, and probably without medical/dietician advice. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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297 KiB  
Article
Analysis of Body Composition and Food Habits of Spanish Celiac Women
by Itziar Churruca, Jonatan Miranda, Arrate Lasa, María Bustamante, Idoia Larretxi and Edurne Simon
Nutrients 2015, 7(7), 5515-5531; https://doi.org/10.3390/nu7075234 - 08 Jul 2015
Cited by 25 | Viewed by 7482
Abstract
The purpose of the present work was both to analyze composition of Spanish celiac women and to study the food habits and gluten-free diet of these celiac patients, in order to determine whether they achieve a balanced and healthy diet as well as [...] Read more.
The purpose of the present work was both to analyze composition of Spanish celiac women and to study the food habits and gluten-free diet of these celiac patients, in order to determine whether they achieve a balanced and healthy diet as well as to highlight nutritional qualitative and/or quantitative differences. 54 adult celiac women (34 ± 13 years) took part in the six-month study. Height, weight and body composition were measured. An analysis of energy consumption and of the macronutrient distribution of their diet was carried out. Their fulfillment of micronutrient intake recommendations was verified. Participants showed a Body Mass Index of 21.6 ± 2.4 kg/m2. Energy Intake was slightly lower than the Dietary Reference Intakes. Excessive protein apart from over-consumption of fat was observed. More than three quarters of participants consumed meat in excess. Carbohydrate consumption along with that of fiber was below recommended levels. Vitamin D, iron, and iodine had a low percentage of recommendation compliance. In general, participants followed the recommendations of dairy products and fruit intake whereas vegetable consumption was not enough for the vast majority. We conclude that although the diet of celiac women does not differ much from the diet of general population, some considerations, such as reducing fat and protein consumption and increasing fiber intake, must be taken into account. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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472 KiB  
Article
Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria
by Carlo Catassi, Luca Elli, Bruno Bonaz, Gerd Bouma, Antonio Carroccio, Gemma Castillejo, Christophe Cellier, Fernanda Cristofori, Laura De Magistris, Jernej Dolinsek, Walburga Dieterich, Ruggiero Francavilla, Marios Hadjivassiliou, Wolfgang Holtmeier, Ute Körner, Dan A. Leffler, Knut E. A. Lundin, Giuseppe Mazzarella, Chris J. Mulder, Nicoletta Pellegrini, Kamran Rostami, David Sanders, Gry Irene Skodje, Detlef Schuppan, Reiner Ullrich, Umberto Volta, Marianne Williams, Victor F. Zevallos, Yurdagül Zopf and Alessio Fasanoadd Show full author list remove Hide full author list
Nutrients 2015, 7(6), 4966-4977; https://doi.org/10.3390/nu7064966 - 18 Jun 2015
Cited by 416 | Viewed by 47267
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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453 KiB  
Article
DQ2, DQ7 and DQ8 Distribution and Clinical Manifestations in Celiac Cases and Their First-Degree Relatives
by Magdalena Araya, Amaya Oyarzun, Yalda Lucero, Nelly Espinosa and Francisco Pérez-Bravo
Nutrients 2015, 7(6), 4955-4965; https://doi.org/10.3390/nu7064955 - 18 Jun 2015
Cited by 16 | Viewed by 7393
Abstract
HLA-linked genes are relevant to celiac disease (CD); the potential genetic differences present worldwide are not fully understood. Previous results suggest that the distribution of HLA-DQ2/DQ7/DQ8 in Chile may differ from that in Europe and North America. In celiac patients and their first-degree [...] Read more.
HLA-linked genes are relevant to celiac disease (CD); the potential genetic differences present worldwide are not fully understood. Previous results suggest that the distribution of HLA-DQ2/DQ7/DQ8 in Chile may differ from that in Europe and North America. In celiac patients and their first-degree relatives (FDRS), we assessed their clinical, serological and histological characteristics, determined HLA-DQ2, HLA-DQ7 and HLA-DQ8 alleles and genotypes, and evaluated the relations between them. A total of 222 individuals were assessed (56 cases, 166 FDRs). 16.9% of FDRs were tTG positive; 53.6% of them showed overweight/obesity and 3% undernourishment; they spontaneously declared being asymptomatic, but detailed questioning revealed that 60.7% experienced symptoms, which had not been investigated. DQ2 was present in 53.9% and 43.9.0% of cases and FDRs (p < 0.05). The most frequent genotype distribution was DQ2/DQ7 (fr 0.392 (cases) and 0.248 (FDRs), respectively, p < 0.02). The next most common genotypes were HLA-DQ2/DQ8 (fr 0.236 in FDRs and 0.176 in cases, p < 0.05). 3.92% cases were not HLA-DQ2/DQ8 carriers. Among tTG positive FDRs, 57.4%, 22.3% and 20.2% carried DQ2, DQ7 and DQ8, respectively. In cases, 72.7% of the biopsies classified Marsh ≥3 carried at least one DQ2; 91.7% of DQ2/DQ2 and 88.3% of DQ2/DQ7 were Marsh ≥3. Thus, DQ2 frequency is lower than reported; the higher frequency found for DQ8 and DQ7 concur with recent publications from Argentine and Brazil. These results suggest that although CD may manifest clinically in ways similar to those described in other populations, some genetic peculiarities in this region deserve further study. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
503 KiB  
Article
Non-Celiac Gluten Sensitivity Has Narrowed the Spectrum of Irritable Bowel Syndrome: A Double-Blind Randomized Placebo-Controlled Trial
by Bijan Shahbazkhani, Amirsaeid Sadeghi, Reza Malekzadeh, Fatima Khatavi, Mehrnoosh Etemadi, Ebrahim Kalantri, Mohammad Rostami-Nejad and Kamran Rostami
Nutrients 2015, 7(6), 4542-4554; https://doi.org/10.3390/nu7064542 - 05 Jun 2015
Cited by 117 | Viewed by 13483
Abstract
Several studies have shown that a large number of patients who are fulfilling the criteria for irritable bowel syndrome (IBS) are sensitive to gluten. The aim of this study was to evaluate the effect of a gluten-free diet on gastrointestinal symptoms in patients [...] Read more.
Several studies have shown that a large number of patients who are fulfilling the criteria for irritable bowel syndrome (IBS) are sensitive to gluten. The aim of this study was to evaluate the effect of a gluten-free diet on gastrointestinal symptoms in patients with IBS. In this double-blind randomized, placebo-controlled trial, 148 IBS patients fulfilling the Rome III criteria were enrolled between 2011 and 2013. However, only 72 out of the 148 commenced on a gluten-free diet for up to six weeks and completed the study; clinical symptoms were recorded biweekly using a standard visual analogue scale (VAS). In the second stage after six weeks, patients whose symptoms improved to an acceptable level were randomly divided into two groups; patients either received packages containing powdered gluten (35 cases) or patients received placebo (gluten free powder) (37 cases). Overall, the symptomatic improvement was statistically different in the gluten-containing group compared with placebo group in 9 (25.7%), and 31 (83.8%) patients respectively (p < 0.001). A large number of patients labelled as irritable bowel syndrome are sensitive to gluten. Using the term of IBS can therefore be misleading and may deviate and postpone the application of an effective and well-targeted treatment strategy in gluten sensitive patients. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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128 KiB  
Article
Sourdough Fermentation of Wheat Flour does not Prevent the Interaction of Transglutaminase 2 with α2-Gliadin or Gluten
by Niklas Engström, Ann-Sofie Sandberg and Nathalie Scheers
Nutrients 2015, 7(4), 2134-2144; https://doi.org/10.3390/nu7042134 - 25 Mar 2015
Cited by 19 | Viewed by 8105
Abstract
The enzyme transglutaminase 2 (TG2) plays a crucial role in the initiation of celiac disease by catalyzing the deamidation of gluten peptides. In susceptible individuals, the deamidated peptides initiate an immune response leading to celiac disease. Several studies have addressed lactic fermentation plus [...] Read more.
The enzyme transglutaminase 2 (TG2) plays a crucial role in the initiation of celiac disease by catalyzing the deamidation of gluten peptides. In susceptible individuals, the deamidated peptides initiate an immune response leading to celiac disease. Several studies have addressed lactic fermentation plus addition of enzymes as a means to degrade gluten in order to prevent adverse response in celiacs. Processing for complete gluten degradation is often harsh and is not likely to yield products that are of comparable characteristics as their gluten-containing counterparts. We are concerned that incomplete degradation of gluten may have adverse effects because it leads to more available TG2-binding sites on gluten peptides. Therefore, we have investigated how lactic acid fermentation affects the potential binding of TG2 to gluten protein in wheat flour by means of estimating TG2-mediated transamidation in addition to measuring the available TG2-binding motif QLP, in α2-gliadin. We show that lactic fermentation of wheat flour, as slurry or as part of sourdough bread, did not decrease the TG2-mediated transamidation, in the presence of a primary amine, to an efficient level (73%–102% of unfermented flour). Nor did the lactic fermentation decrease the available TG2 binding motif QLP in α2-gliadin to a sufficient extent in sourdough bread (73%–122% of unfermented control) to be useful for celiac safe food. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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1082 KiB  
Article
The Effects of Reduced Gluten Barley Diet on Humoral and Cell-Mediated Systemic Immune Responses of Gluten-Sensitive Rhesus Macaques
by Karol Sestak, Hazel Thwin, Jason Dufour, Pyone P. Aye, David X. Liu and Charles P. Moehs
Nutrients 2015, 7(3), 1657-1671; https://doi.org/10.3390/nu7031657 - 06 Mar 2015
Cited by 8 | Viewed by 7540
Abstract
Celiac disease (CD) affects approximately 1% of the general population while an estimated additional 6% suffers from a recently characterized, rapidly emerging, similar disease, referred to as non-celiac gluten sensitivity (NCGS). The only effective treatment of CD and NCGS requires removal of gluten [...] Read more.
Celiac disease (CD) affects approximately 1% of the general population while an estimated additional 6% suffers from a recently characterized, rapidly emerging, similar disease, referred to as non-celiac gluten sensitivity (NCGS). The only effective treatment of CD and NCGS requires removal of gluten sources from the diet. Since required adherence to a gluten-free diet (GFD) is difficult to accomplish, efforts to develop alternative treatments have been intensifying in recent years. In this study, the non-human primate model of CD/NCGS, e.g., gluten-sensitive rhesus macaque, was utilized with the objective to evaluate the treatment potential of reduced gluten cereals using a reduced gluten (RG; 1% of normal gluten) barley mutant as a model. Conventional and RG barleys were used for the formulation of experimental chows and fed to gluten-sensitive (GS) and control macaques to determine if RG barley causes a remission of dietary gluten-induced clinical and immune responses in GS macaques. The impacts of the RG barley diet were compared with the impacts of the conventional barley-containing chow and the GFD. Although remission of the anti-gliadin antibody (AGA) serum responses and an improvement of clinical diarrhea were noted after switching the conventional to the RG barley diet, production of inflammatory cytokines, e.g., interferon-gamma (IFN-γ), tumor necrosis factor (TNF) and interleukin-8 (IL-8) by peripheral CD4+ T helper lymphocytes, persisted during the RG chow treatment and were partially abolished only upon re-administration of the GFD. It was concluded that the RG barley diet might be used for the partial improvement of gluten-induced disease but its therapeutic value still requires upgrading—by co-administration of additional treatments. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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556 KiB  
Article
Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non-Celiac Gluten Sensitivity
by Justin Hollon, Elaine Leonard Puppa, Bruce Greenwald, Eric Goldberg, Anthony Guerrerio and Alessio Fasano
Nutrients 2015, 7(3), 1565-1576; https://doi.org/10.3390/nu7031565 - 27 Feb 2015
Cited by 170 | Viewed by 54239
Abstract
Background: Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: [...] Read more.
Background: Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: celiac patients with active disease (ACD), celiac patients in remission (RCD), non-celiac patients with gluten sensitivity (GS) and non-celiac controls (NC). Methods: Ex-vivo human duodenal biopsies were mounted in microsnapwells and luminally incubated with either gliadin or media alone. Changes in transepithelial electrical resistance were monitored over 120 min. Media was subsequently collected and cytokines quantified. Results: Intestinal explants from all groups (ACD (n = 6), RCD (n = 6), GS (n = 6), and NC (n = 5)) demonstrated a greater increase in permeability when exposed to gliadin vs. media alone. The increase in permeability in the ACD group was greater than in the RCD and NC groups. There was a greater increase in permeability in the GS group compared to the RCD group. There was no difference in permeability between the ACD and GS groups, between the RCD and NC groups, or between the NC and GS groups. IL-10 was significantly greater in the media of the NC group compared to the RCD and GS groups. Conclusions: Increased intestinal permeability after gliadin exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission. A higher concentration of IL-10 was measured in the media exposed to control explants compared to celiac disease in remission or gluten sensitivity. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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Review

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413 KiB  
Review
Gliadin-Specific T-Cells Mobilized in the Peripheral Blood of Coeliac Patients by Short Oral Gluten Challenge: Clinical Applications
by Stefania Picascia, Roberta Mandile, Renata Auricchio, Riccardo Troncone and Carmen Gianfrani
Nutrients 2015, 7(12), 10020-10031; https://doi.org/10.3390/nu7125515 - 02 Dec 2015
Cited by 17 | Viewed by 6681
Abstract
Celiac disease (CD) is a common lifelong food intolerance triggered by dietary gluten affecting 1% of the general population. Gliadin-specific T-cell lines and T-cell clones obtained from intestinal biopsies have provided great support in the investigation of immuno-pathogenesis of CD. In the early [...] Read more.
Celiac disease (CD) is a common lifelong food intolerance triggered by dietary gluten affecting 1% of the general population. Gliadin-specific T-cell lines and T-cell clones obtained from intestinal biopsies have provided great support in the investigation of immuno-pathogenesis of CD. In the early 2000 a new in vivo, less invasive, approach was established aimed to evaluate the adaptive gliadin-specific T-cell response in peripheral blood of celiac patients on a gluten free diet. In fact, it has been demonstrated that three days of ingestion of wheat-containing food induces the mobilization of memory T lymphocytes reactive against gliadin from gut-associated lymphoid tissue into peripheral blood of CD patients. Such antigen-specific T-cells releasing interferon-γ can be transiently detected by using the enzyme-linked immunospot (ELISPOT) assays or by flow cytometry tetramer technology. This paper discusses the suitability of this in vivo tool to investigate the repertoire of gluten pathogenic peptides, to support CD diagnosis, and to assess the efficacy of novel therapeutic strategies. A systematic review of all potential applications of short oral gluten challenge is provided. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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Review
The Spectrum of Differences between Childhood and Adulthood Celiac Disease
by Rachele Ciccocioppo, Peter Kruzliak, Giuseppina C. Cangemi, Miroslav Pohanka, Elena Betti, Eugenia Lauret and Luis Rodrigo
Nutrients 2015, 7(10), 8733-8751; https://doi.org/10.3390/nu7105426 - 22 Oct 2015
Cited by 44 | Viewed by 16059
Abstract
An old saying states that ‘’children are not little adults” and this certainly holds true for celiac disease, as there are many peculiar aspects regarding its epidemiology, diagnosis, clinical presentations, associated diseases, and response to treatment in pediatric compared to adult populations, to [...] Read more.
An old saying states that ‘’children are not little adults” and this certainly holds true for celiac disease, as there are many peculiar aspects regarding its epidemiology, diagnosis, clinical presentations, associated diseases, and response to treatment in pediatric compared to adult populations, to such an extent that it merits a description of its own. In fact, contrary to the past when it was thought that celiac disease was a disorder predominantly affecting childhood and characterized by a malabsorption syndrome, nowadays it is well recognized that it affects also adult and elderly people with an impressive variability of clinical presentation. In general, the clinical guidelines for diagnosis recommend starting with specific serologic testing in all suspected subjects, including those suffering from extraintestinal related conditions, and performing upper endoscopy with appropriate biopsy sampling of duodenal mucosa in case of positivity. The latter may be omitted in young patients showing high titers of anti-transglutaminase antibodies. The subsequent management of a celiac patient differs substantially depending on the age at diagnosis and should be based on the important consideration that this is a lifelong condition. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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Review
Seronegative Celiac Disease and Immunoglobulin Deficiency: Where to Look in the Submerged Iceberg?
by Floriana Giorgio, Mariabeatrice Principi, Giuseppe Losurdo, Domenico Piscitelli, Andrea Iannone, Michele Barone, Annacinzia Amoruso, Enzo Ierardi and Alfredo Di Leo
Nutrients 2015, 7(9), 7486-7504; https://doi.org/10.3390/nu7095350 - 08 Sep 2015
Cited by 25 | Viewed by 7716
Abstract
In the present narrative review, we analyzed the relationship between seronegative celiac disease (SNCD) and immunoglobulin deficiencies. For this purpose, we conducted a literature search on the main medical databases. SNCD poses a diagnostic dilemma. Villous blunting, intraepithelial lymphocytes (IELs) count and gluten [...] Read more.
In the present narrative review, we analyzed the relationship between seronegative celiac disease (SNCD) and immunoglobulin deficiencies. For this purpose, we conducted a literature search on the main medical databases. SNCD poses a diagnostic dilemma. Villous blunting, intraepithelial lymphocytes (IELs) count and gluten “challenge” are the most reliable markers. Immunohistochemistry/immunofluorescence tissue transglutaminase (tTG)-targeted mucosal immunoglobulin A (IgA) immune complexes in the intestinal mucosa of SNCD patients may be useful. In our experience, tTG-mRNA was similarly increased in seropositive celiac disease (CD) and suspected SNCD, and strongly correlated with the IELs count. This increase is found even in the IELs’ range of 15–25/100 enterocytes, suggesting that there may be a “grey zone” of gluten-related disorders. An immune deregulation (severely lacking B-cell differentiation) underlies the association of SNCD with immunoglobulin deficiencies. Therefore, CD may be linked to autoimmune disorders and immune deficits (common variable immunodeficiency (CVID)/IgA selective deficiency). CVID is a heterogeneous group of antibodies dysfunction, whose association with CD is demonstrated only by the response to a gluten-free diet (GFD). We hypothesized a familial inheritance between CD and CVID. Selective IgA deficiency, commonly associated with CD, accounts for IgA-tTG seronegativity. Selective IgM deficiency (sIgMD) is rare (<300 cases) and associated to CD in 5% of cases. We diagnosed SNCD in a patient affected by sIgMD using the tTG-mRNA assay. One-year GFD induced IgM restoration. This evidence, supporting a link between SNCD and immunoglobulin deficiencies, suggests that we should take a closer look at this association. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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Review
Central America in Transition: From Maize to Wheat Challenges and Opportunities
by Amado Salvador Peña and Jakob Bart Arie Crusius
Nutrients 2015, 7(9), 7163-7171; https://doi.org/10.3390/nu7095330 - 26 Aug 2015
Cited by 7 | Viewed by 6006
Abstract
The Central American countries: Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, and Panama are in transition from a dietary culture based mainly on maize to a wheat-containing diet. Several other changes are occurring, such as a decrease of parasitic and infectious diseases. The [...] Read more.
The Central American countries: Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, and Panama are in transition from a dietary culture based mainly on maize to a wheat-containing diet. Several other changes are occurring, such as a decrease of parasitic and infectious diseases. The environmental changes permit a prediction of an increase of celiac disease and other autoimmune diseases such as type I diabetes and thyroid disease in these genetically heterogeneous countries. At present, celiac disease and gluten-related disorders are considered to be of no relevance at the level of public health in these nations. This review documents the presence of celiac disease in Central America. It draws attention to some of the challenges in planning systematic studies in the region since up until recently celiac disease was unknown. The aim of this review is to disseminate knowledge obtained with preliminary data, to stimulate clinical and basic scientists to study these diseases in Central America and to alert authorities responsible for the planning of education and health, to find possibilities to avoid a rise in these disorders before the epidemics start, as has occurred in the Mediterranean countries. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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Review
The Role of Gluten in Celiac Disease and Type 1 Diabetes
by Gloria Serena, Stephanie Camhi, Craig Sturgeon, Shu Yan and Alessio Fasano
Nutrients 2015, 7(9), 7143-7162; https://doi.org/10.3390/nu7095329 - 26 Aug 2015
Cited by 61 | Viewed by 23842
Abstract
Celiac disease (CD) and type 1 diabetes (T1D) are autoimmune conditions in which dietary gluten has been proven or suggested to play a pathogenic role. In CD; gluten is established as the instigator of autoimmunity; the autoimmune process is halted by removing gluten [...] Read more.
Celiac disease (CD) and type 1 diabetes (T1D) are autoimmune conditions in which dietary gluten has been proven or suggested to play a pathogenic role. In CD; gluten is established as the instigator of autoimmunity; the autoimmune process is halted by removing gluten from the diet; which allows for resolution of celiac autoimmune enteropathy and subsequent normalization of serological markers of the disease. However; an analogous causative agent has not yet been identified for T1D. Nevertheless; the role of dietary gluten in development of T1D and the potentially beneficial effect of removing gluten from the diet of patients with T1D are still debated. In this review; we discuss the comorbid occurrence of CD and T1D and explore current evidences for the specific role of gluten in both conditions; specifically focusing on current evidence on the effect of gluten on the immune system and the gut microbiota. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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Review
Intestinal Microbiota and Celiac Disease: Cause, Consequence or Co-Evolution?
by María Carmen Cenit, Marta Olivares, Pilar Codoñer-Franch and Yolanda Sanz
Nutrients 2015, 7(8), 6900-6923; https://doi.org/10.3390/nu7085314 - 17 Aug 2015
Cited by 128 | Viewed by 20815
Abstract
It is widely recognized that the intestinal microbiota plays a role in the initiation and perpetuation of intestinal inflammation in numerous chronic conditions. Most studies report intestinal dysbiosis in celiac disease (CD) patients, untreated and treated with a gluten-free diet (GFD), compared to [...] Read more.
It is widely recognized that the intestinal microbiota plays a role in the initiation and perpetuation of intestinal inflammation in numerous chronic conditions. Most studies report intestinal dysbiosis in celiac disease (CD) patients, untreated and treated with a gluten-free diet (GFD), compared to healthy controls. CD patients with gastrointestinal symptoms are also known to have a different microbiota compared to patients with dermatitis herpetiformis and controls, suggesting that the microbiota is involved in disease manifestation. Furthermore, a dysbiotic microbiota seems to be associated with persistent gastrointestinal symptoms in treated CD patients, suggesting its pathogenic implication in these particular cases. GFD per se influences gut microbiota composition, and thus constitutes an inevitable confounding factor in studies conducted in CD patients. To improve our understanding of whether intestinal dysbiosis is the cause or consequence of disease, prospective studies in healthy infants at family risk of CD are underway. These studies have revealed that the CD host genotype selects for the early colonizers of the infant’s gut, which together with environmental factors (e.g., breast-feeding, antibiotics, etc.) could influence the development of oral tolerance to gluten. Indeed, some CD genes and/or their altered expression play a role in bacterial colonization and sensing. In turn, intestinal dysbiosis could promote an abnormal response to gluten or other environmental CD-promoting factors (e.g., infections) in predisposed individuals. Here, we review the current knowledge of host-microbe interactions and how host genetics/epigenetics and environmental factors shape gut microbiota and may influence disease risk. We also summarize the current knowledge about the potential mechanisms of action of the intestinal microbiota and specific components that affect CD pathogenesis. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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Review
Bones of Contention: Bone Mineral Density Recovery in Celiac Disease—A Systematic Review
by Patricia Grace-Farfaglia
Nutrients 2015, 7(5), 3347-3369; https://doi.org/10.3390/nu7053347 - 07 May 2015
Cited by 63 | Viewed by 15732
Abstract
Metabolic bone disease is a frequent co-morbidity in newly diagnosed adults with celiac disease (CD), an autoimmune disorder triggered by the ingestion of dietary gluten. This systematic review of studies looked at the efficacy of the gluten-free diet, physical activity, nutrient supplementation, and [...] Read more.
Metabolic bone disease is a frequent co-morbidity in newly diagnosed adults with celiac disease (CD), an autoimmune disorder triggered by the ingestion of dietary gluten. This systematic review of studies looked at the efficacy of the gluten-free diet, physical activity, nutrient supplementation, and bisphosphonates for low bone density treatment. Case control and cohort designs were identified from PubMed and other academic databases (from 1996 to 2015) that observed newly diagnosed adults with CD for at least one year after diet treatment using the dual-energy x-ray absorptiometry (DXA) scan. Only 20 out of 207 studies met the inclusion criteria. Methodological quality was assessed using the Strengthening of the Reporting of Observational Studies in Epidemiology (STROBE) statement checklist. Gluten-free diet adherence resulted in partial recovery of bone density by one year in all studies, and full recovery by the fifth year. No treatment differences were observed between the gluten-free diet alone and diet plus bisphosphonates in one study. For malnourished patients, supplementation with vitamin D and calcium resulted in significant improvement. Evidence for the impact of physical activity on bone density was limited. Therapeutic strategies aimed at modifying lifestyle factors throughout the lifespan should be studied. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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Case Report
Gluten Psychosis: Confirmation of a New Clinical Entity
by Elena Lionetti, Salvatore Leonardi, Chiara Franzonello, Margherita Mancardi, Martino Ruggieri and Carlo Catassi
Nutrients 2015, 7(7), 5532-5539; https://doi.org/10.3390/nu7075235 - 08 Jul 2015
Cited by 66 | Viewed by 21820
Abstract
Non-celiac gluten sensitivity (NCGS) is a syndrome diagnosed in patients with symptoms that respond to removal of gluten from the diet, after celiac disease and wheat allergy have been excluded. NCGS has been related to neuro-psychiatric disorders, such as autism, schizophrenia and depression. [...] Read more.
Non-celiac gluten sensitivity (NCGS) is a syndrome diagnosed in patients with symptoms that respond to removal of gluten from the diet, after celiac disease and wheat allergy have been excluded. NCGS has been related to neuro-psychiatric disorders, such as autism, schizophrenia and depression. A singular report of NCGS presenting with hallucinations has been described in an adult patient. We report a pediatric case of a psychotic disorder clearly related to NCGS and investigate the causes by a review of literature. The pathogenesis of neuro-psychiatric manifestations of NCGS is unclear. It has been hypothesized that: (a) a “leaky gut” allows some gluten peptides to cross the intestinal membrane and the blood brain barrier, affecting the endogenous opiate system and neurotransmission; or (b) gluten peptides may set up an innate immune response in the brain similar to that described in the gut mucosa, causing exposure from neuronal cells of a transglutaminase primarily expressed in the brain. The present case-report confirms that psychosis may be a manifestation of NCGS, and may also involve children; the diagnosis is difficult with many cases remaining undiagnosed. Well-designed prospective studies are needed to establish the real role of gluten as a triggering factor in neuro-psychiatric disorders. Full article
(This article belongs to the Special Issue Gluten Related Disorders: People Shall not Live on Bread Alone)
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