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Gluten Related Disorders: Coeliac Disease and Beyond

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutritional Epidemiology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 42786

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Special Issue Editors

Dr. Isabel Comino

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Guest Editor

Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain
Interests: coeliac disease; gluten-related disorders; gluten immunogenic peptides and proteins; proteomics; gluten food analysis; immunology; food allergy and intolerance

Dr. Carolina Sousa

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Guest Editor

Facultad de Farmacia, Departamento de Microbiología y Parasitología, Universidad de Sevilla, 41012 Sevilla, Spain
Interests: coeliac disease; gluten-related disorders; gluten immunogenic peptides and proteins; proteomics; gluten food analysis; immunology; food allergy and intolerance.

Special Issue Information

Dear Colleagues,

Gluten-related disorders (GRDs) have emerged as an epidemiologically relevant phenomenon with an estimated global prevalence of close to 5%. Different mechanisms are involved in the pathogenesis of GRDs. Although they are characterized by peculiar pathogenetic pathways involved in their development, they share similar clinical manifestations making their differential diagnosis challenging.

Among the gluten-related disorders, coeliac disease (CD) is the best known to date. It is characterized by a heterogeneous clinical presentation, affecting any organ or tissue with gastrointestinal, extraintestinal manifestations, subclinical, seronegative, or non-responsive, among others. However, CD research is changing rapidly due to a steady increase in knowledge tackling its pathophysiology, diagnosis, follow-up, and therapeutic options. Indeed, novel findings provide a deeper insight not only of CD, but also of other GRDs: wheat allergy, non-coeliac gluten sensitivity, dermatitis herpetiformis, and gluten ataxia. In this Special Issue, we aim to broaden our knowledge of all essential aspects of GRDs. Potential topics include the following:

Novel findings providing a deeper insight into the pathogenic mechanisms underlying GRDs.
Effect of the gluten-free diet (GFD) on GRDs, including patient management after diet instauration, adherence to the diet, and/or ways to monitor it.
Potential therapeutic strategies based on the immunopathogenesis of these disorders.
Clinical and pathogenic follow-up of patients with GRDs.
New knowledge about GFD: technological and nutritional aspects.

Dr. Isabel Comino
Dr. Carolina Sousa
Guest Editors

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Keywords

Gluten-related disorders
Coeliac disease
Gluten-free diet
Immunopathogenesis
Allergy
Intolerance
Clinical manifestations

Published Papers (13 papers)

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Editorial

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3 pages, 192 KiB

Open AccessEditorial

Advances in Celiac Disease and Gluten-Free Diet

by Isabel Comino and Carolina Sousa

Nutrients 2022, 14(3), 570; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14030570 - 28 Jan 2022

Cited by 4 | Viewed by 2926

Abstract

Celiac disease (CD) is a systemic disease that causes chronic enteropathy of the small intestine and develops through an inadequate immune response to gluten in genetically predisposed individuals [...] Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

Research

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16 pages, 2881 KiB

Open AccessArticle

Dynamics and Considerations in the Determination of the Excretion of Gluten Immunogenic Peptides in Urine: Individual Variability at Low Gluten Intake

by Laura Coto, Carolina Sousa and Angel Cebolla

Nutrients 2021, 13(8), 2624; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13082624 - 29 Jul 2021

Cited by 17 | Viewed by 2984

Abstract

Background: A lifelong strict gluten-free diet is the only available treatment for celiac disease, but total exclusion of gluten is difficult to achieve. The aim of this study was to determine the range of time and the amount of gluten immunogenic peptides (GIP) excreted in urine after specific gluten ingestions. Methods: 20 healthy participants followed the same diet for 12 days in which 50 mg and 2 g of gluten were ingested and all the urinations were collected. GIP were analyzed by lateral flow immunoassay (LFIA) tests and quantified using an LFIA reader. Results: GIP were detected in 15% and 95% of participants after 50 mg and 2 g gluten intakes, respectively. The higher frequency and concentration of GIP was found between 6 and 9 h after both gluten ingestions. The ranges of detection were 3–12 h (50 mg) and 0–15 h (2 g). Conclusions: An increase in the frequency of urine tests may be a suitable approach to avoid false negative results. The use of the LFIA test in three urine samples collected at different times may show a sensitivity of 19.6% for a gluten ingestion like 50 mg, increasing to 93% after 2 g consumption. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

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14 pages, 284 KiB

Open AccessArticle

Patient Perspectives of Living with Coeliac Disease and Accessing Dietetic Services in Rural Australia: A Qualitative Study

by Rachelle Lee, Elesa T. Crowley, Surinder K. Baines, Susan Heaney and Leanne J. Brown

Nutrients 2021, 13(6), 2074; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13062074 - 17 Jun 2021

Cited by 5 | Viewed by 2286

Abstract

Adapting to living with coeliac disease requires individuals to learn about and follow a strict gluten-free diet. Utilising a qualitative inductive approach, this study aimed to explore the perspectives of adults diagnosed with coeliac disease who have accessed dietetic services in a rural outpatient setting. A purposive sample of adults with coeliac disease who had accessed dietetic services from two rural dietetic outpatient clinics were recruited. Semi-structured interviews were conducted by telephone. Data were thematically analysed. Six participants were recruited and interviewed. Three key themes emerged: (i) optimising individualised support and services, (ii) adapting to a gluten-free diet in a rural context, and (iii) managing a gluten-free diet within the context of interpersonal relationships. Key issues identified in the rural context were access to specialist services and the increased cost of gluten-free food in more remote areas. The findings of this study have highlighted the difficulties associated with coeliac disease management and how dietetic consultation has the potential to influence confidence in management and improve lifestyle outcomes. Further qualitative research is required to expand on the findings of this study and inform future dietetic practice that meets the expectations and individual needs of people with coeliac disease in rural settings. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

12 pages, 600 KiB

Open AccessArticle

Long-Term Effect of a Gluten-Free Diet on Diarrhoea- or Bloating-Predominant Functional Bowel Disease: Role of the ‘Low-Grade Coeliac Score’ and the ‘Coeliac Lymphogram’ in the Response Rate to the Diet

by Fernando Fernández-Bañares, Beatriz Arau, Agnès Raga, Montserrat Aceituno, Eva Tristán, Anna Carrasco, Laura Ruiz, Albert Martín-Cardona, Pablo Ruiz-Ramírez and Maria Esteve

Nutrients 2021, 13(6), 1812; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13061812 - 26 May 2021

Cited by 7 | Viewed by 2611

Abstract

1. Background: The long-term effect of a gluten-free diet (GFD) on functional bowel disorders (FBDs) has been scarcely studied. The aim was to assess the effect of a GFD on FBD patients, and to assess the role of both the low-grade coeliac score and coeliac lymphogram in the probability of response to a GFD. 2. Methods: 116 adult patients with either predominant diarrhoea or abdominal bloating, fulfilling Rome IV criteria of FBD, were treated with a GFD. Duodenum biopsies were performed for both pathology studies and intraepithelial lymphocyte subpopulation patterns. Coeliac lymphogram was defined as an increase in TCRγδ⁺ cells plus a decrease in CD3⁻ cells. A low-grade coeliac score >10 was considered positive. 3. Results: Sustained response to GFD was observed in 72 patients (62%) after a median of 21 months of follow-up, who presented more often with coeliac lymphogram (37.5 vs. 11.4%; p = 0.02) and a score >10 (32 vs. 11.4%; p = 0.027) compared to non-responders. The frequency of low-grade coeliac enteropathy was 19.8%. 4. Conclusion: A GFD is effective in the long-term treatment of patients with previously unexplained chronic watery diarrhoea- or bloating-predominant symptoms fulfilling the criteria of FBD. The response rate was much higher in the subgroup of patients defined by the presence of both a positive low-grade coeliac score and coeliac lymphogram. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

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11 pages, 1158 KiB

Open AccessArticle

Intraepithelial Lymphocyte Cytometric Pattern Is a Useful Diagnostic Tool for Coeliac Disease Diagnosis Irrespective of Degree of Mucosal Damage and Age—A Validation Cohort

by Pablo Ruiz-Ramírez, Gerard Carreras, Ingrid Fajardo, Eva Tristán, Anna Carrasco, Isabel Salvador, Yamile Zabana, Xavier Andújar, Carme Ferrer, Diana Horta, Carme Loras, Roger García-Puig, Fernando Fernández-Bañares and Maria Esteve

Nutrients 2021, 13(5), 1684; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13051684 - 15 May 2021

Cited by 10 | Viewed by 2158

Abstract

Introduction: The study of intraepithelial lymphocytes (IEL) by flow cytometry is a useful tool in the diagnosis of coeliac disease (CD). Previous data showed that an increase in %TCRγδ⁺ and decrease of %CD3⁻ IEL constitute a typical CD cytometric pattern with a specificity of 100%. However, there are no data regarding whether there are differences in the %TCRγδ⁺ related to sex, age, titers of serology, and degree of histological lesion. Study aims: To confirm the high diagnostic accuracy of the coeliac cytometric patterns. To determine if there are differences between sex, age, serology titers, and histological lesion grade. Results: We selected all patients who fulfilled “4 of 5” rule for CD diagnosis (n = 169). There were no differences in %TCRγδ⁺ between sexes (p = 0.909), age groups (p = 0.986), serology titers (p = 0.53) and histological lesion grades (p = 0.41). The diagnostic accuracy of complete CD cytometric pattern was: specificity 100%, sensitivity 82%, PPV 100%, NPV 47%. Conclusion: We confirmed, in a validation cohort, the high diagnostic accuracy of complete CD pattern irrespective of sex, age, serology titers, and grade of mucosal lesion. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

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8 pages, 1011 KiB

Open AccessArticle

Celiac Disease-Type Tissue Transglutaminase Autoantibody Deposits in Kidney Biopsies of Patients with IgA Nephropathy

by Rakel Nurmi, Ilma Korponay-Szabó, Kaija Laurila, Heini Huhtala, Onni Niemelä, Jukka Mustonen, Satu Mäkelä, Katri Kaukinen and Katri Lindfors

Nutrients 2021, 13(5), 1594; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13051594 - 11 May 2021

Cited by 4 | Viewed by 2233

Abstract

An association between celiac disease and IgA nephropathy (IgAN) has been suggested. In celiac disease, in addition to circulating in serum, IgA-class tissue transglutaminase (tTG) autoantibodies are deposited in the small bowel mucosa and extraintestinal organs. In this case series of IgAN patients with or without celiac disease, we studied whether celiac disease-type IgA-tTG deposits occur in kidney biopsies. The study included nine IgAN patients, four of them with celiac disease. At the time of the diagnostic kidney biopsy serum tTG autoantibodies were measured and colocalization of IgA and tTG was investigated in the frozen kidney biopsies. Three IgAN patients with celiac disease had IgA-tTG deposits in the kidney even though in two of these the celiac disease diagnosis had been set years later. These deposits were not found in a patient with already diagnosed celiac disease following a gluten-free diet. Of the five non-celiac IgAN patients, three had IgA-tTG deposits in the kidney. We conclude that tTG-targeted IgA deposits can be found in the kidney biopsies of gluten-consuming IgAN patients but their specificity to celiac disease seems limited. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

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8 pages, 251 KiB

Open AccessArticle

Iron Transporter Protein Expressions in Children with Celiac Disease

by Marleena Repo, Markus Hannula, Juha Taavela, Jari Hyttinen, Jorma Isola, Pauliina Hiltunen, Alina Popp, Katri Kaukinen, Kalle Kurppa and Katri Lindfors

Nutrients 2021, 13(3), 776; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13030776 - 27 Feb 2021

Cited by 7 | Viewed by 2207

Abstract

Anemia is a frequent finding in children with celiac disease but the detailed pathophysiological mechanisms in the intestine remain obscure. One possible explanation could be an abnormal expression of duodenal iron transport proteins. However, the results have so far been inconsistent. We investigated this issue by comparing immunohistochemical stainings of duodenal cytochrome B (DCYTB), divalent metal transporter 1 (DMT1), ferroportin, hephaestin and transferrin receptor 1 (TfR1) in duodenal biopsies between 27 children with celiac disease and duodenal atrophy, 10 celiac autoantibody-positive children with potential celiac disease and six autoantibody-negative control children. Twenty out of these 43 subjects had anemia. The expressions of the iron proteins were investigated with regard to saturation and the percentage of the stained area or stained membrane length of the enterocytes. The results showed the stained area of ferroportin to be increased and the saturation of hephaestin to be decreased in celiac disease patients compared with controls. There were no differences in the transporter protein expressions between anemic and non-anemic patients. The present results suggest an iron status-independent alteration of ferroportin and hephaestin proteins in children with histologically confirmed celiac disease. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

8 pages, 656 KiB

Open AccessArticle

Rationale for Timing of Follow-Up Visits to Assess Gluten-Free Diet in Celiac Disease Patients Based on Data Mining

by Alfonso Rodríguez-Herrera, Joaquín Reyes-Andrade and Cristina Rubio-Escudero

Nutrients 2021, 13(2), 357; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13020357 - 25 Jan 2021

Cited by 11 | Viewed by 1837

Abstract

The assessment of compliance of gluten-free diet (GFD) is a keystone in the supervision of celiac disease (CD) patients. Few data are available documenting evidence-based follow-up frequency for CD patients. In this work we aim at creating a criterion for timing of clinical follow-up for CD patients using data mining. We have applied data mining to a dataset with 188 CD patients on GFD (75% of them are children below 14 years old), evaluating the presence of gluten immunogenic peptides (GIP) in stools as an adherence to diet marker. The variables considered are gender, age, years following GFD and adherence to the GFD by fecal GIP. The results identify patients on GFD for more than two years (41.5% of the patients) as more prone to poor compliance and so needing more frequent follow-up than patients with less than 2 years on GFD. This is against the usual clinical practice of following less patients on long term GFD, as they are supposed to perform better. Our results support different timing follow-up frequency taking into consideration the number of years on GFD, age and gender. Patients on long term GFD should have a more frequent monitoring as they show a higher level of gluten exposure. A gender perspective should also be considered as non-compliance is partially linked to gender in our results: Males tend to get more gluten exposure, at least in the cultural context where our study was carried out. Children tend to perform better than teenagers or adults. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

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10 pages, 246 KiB

Open AccessArticle

General Health, Systemic Diseases and Oral Status in Adult Patients with Coeliac Disease

by Alessandro Nota, Silvio Abati, Floriana Bosco, Isabella Rota, Elisabetta Polizzi and Simona Tecco

Nutrients 2020, 12(12), 3836; https://0-doi-org.brum.beds.ac.uk/10.3390/nu12123836 - 15 Dec 2020

Cited by 9 | Viewed by 1967

Abstract

The prevalence of coeliac disease in the general population is 0.5–1%; however, most patients remain undiagnosed until adult age. In some cases, the onset is represented by sub-clinical signs, some of which can be found in the mouth. The aim of this research was to identify any associations between the clinical characteristics of coeliac disease and oral manifestations. A structured questionnaire was administered to a group of 237 individuals with coeliac disease. 100% of the subjects fully completed the questionnaire. Among them, 182 (76.7%) were female, 64 patients (27%) were aged 15 to 24 years, 159 (67%) were aged 25 to 55 and 14 (6%) were aged 56 and over. Significant associations were observed in caries prevalence and dentin sensitivity; in addition, an inappropriate diet was related to oral manifestations; following a gluten-free diet could be important to control the gingival bleeding levels and to manage oral symptoms associated to coeliac disease. In general, the presence of inflammatory symptoms in the mouth seems to be associated with general symptoms of inflammation related to coeliac disease. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

10 pages, 692 KiB

Open AccessArticle

First-degree Relatives of Celiac Disease Patients Have Increased Seroreactivity to Serum Microbial Markers

by Liisa Viitasalo, Sari Iltanen, Heini Huhtala, Päivi Saavalainen, Katri Kaukinen, Katri Lindfors and Kalle Kurppa

Nutrients 2020, 12(4), 1073; https://0-doi-org.brum.beds.ac.uk/10.3390/nu12041073 - 13 Apr 2020

Cited by 4 | Viewed by 2436

Abstract

Risk of celiac disease (CD) is increased in relatives of CD patients due to genetic and possible environmental factors. We recently reported increased seropositivity to anti-Saccharomyces cerevisiae (ASCA), Pseudomonas fluorescens-associated sequence (anti-I2) and Bacteroides caccae TonB-linked outer membrane protein (anti-OmpW) antibodies in CD. We hypothesized these markers also to be overrepresented in relatives. Seropositivity and levels of ASCA, anti-I2 and anti-OmpW were compared between 463 first-degree relatives, 58 untreated and 55 treated CD patients, and 80 controls. CD-associated human leukocyte antigen (HLA)-haplotypes and transglutaminase (tTGab) and endomysium (EmA) antibodies were determined. One or more of the microbial antibodies was present in 75% of relatives, 97% of untreated and 87% of treated CD patients and 44% of the controls. The relatives had higher median ASCA IgA (9.13 vs. 4.50 U/mL, p < 0.001), ASCA IgG (8.91 vs. 5.75 U/mL, p < 0.001) and anti-I2 (absorbance 0.74 vs. 0.32, p < 0.001) levels than controls. There was a weak, positive correlation between tTGab and ASCA (r = 0.31, p < 0.001). Seropositivity was not significantly associated with HLA. To conclude, seropositivity to microbial markers was more common and ASCA and anti-I2 levels higher in relatives of CD patients than controls. These findings were not associated with HLA, suggesting the role of other genetic and environmental factors. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

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Review

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22 pages, 423 KiB

Open AccessReview

Challenges of Monitoring the Gluten-Free Diet Adherence in the Management and Follow-Up of Patients with Celiac Disease

by Herbert Wieser, Ángela Ruiz-Carnicer, Verónica Segura, Isabel Comino and Carolina Sousa

Nutrients 2021, 13(7), 2274; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13072274 - 30 Jun 2021

Cited by 30 | Viewed by 4438

Abstract

Celiac disease (CD) is a chronic gluten-responsive immune mediated enteropathy and is treated with a gluten-free diet (GFD). However, a strict diet for life is not easy due to the ubiquitous nature of gluten. This review aims at examining available evidence on the degree of adherence to a GFD, the methods to assess it, and the barriers to its implementation. The methods for monitoring the adherence to a GFD are comprised of a dietary questionnaire, celiac serology, or clinical symptoms; however, none of these methods generate either a direct or an accurate measure of dietary adherence. A promising advancement is the development of tests that measure gluten immunogenic peptides in stools and urine. Causes of adherence/non-adherence to a GFD are numerous and multifactorial. Inadvertent dietary non-adherence is more frequent than intentional non-adherence. Cross-contamination of gluten-free products with gluten is a major cause of inadvertent non-adherence, while the limited availability, high costs, and poor quality of certified gluten-free products are responsible for intentionally breaking a GFD. Therefore, several studies in the last decade have indicated that many patients with CD who follow a GFD still have difficulty controlling their diet and, therefore, regularly consume enough gluten to trigger symptoms and damage the small intestine. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

14 pages, 331 KiB

Open AccessFeature PaperReview

Food Safety and Cross-Contamination of Gluten-Free Products: A Narrative Review

by Herbert Wieser, Verónica Segura, Ángela Ruiz-Carnicer, Carolina Sousa and Isabel Comino

Nutrients 2021, 13(7), 2244; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13072244 - 29 Jun 2021

Cited by 28 | Viewed by 7575

Abstract

A gluten-free diet (GFD) is currently the only effective treatment for celiac disease (CD); an individual’s daily intake of gluten should not exceed 10 mg. However, it is difficult to maintain a strict oral diet for life and at least one-third of patients with CD are exposed to gluten, despite their best efforts at dietary modifications. It has been demonstrated that both natural and certified gluten-free foods can be heavily contaminated with gluten well above the commonly accepted threshold of 20 mg/kg. Moreover, meals from food services such as restaurants, workplaces, and schools remain a significant risk for inadvertent gluten exposure. Other possible sources of gluten are non-certified oat products, numerous composite foods, medications, and cosmetics that unexpectedly contain “hidden” vital gluten, a proteinaceous by-product of wheat starch production. A number of immunochemical assays are commercially available worldwide to detect gluten. Each method has specific features, such as format, sample extraction buffers, extraction time and temperature, characteristics of the antibodies, recognition epitope, and the reference material used for calibration. Due to these differences and a lack of official reference material, the results of gluten quantitation may deviate systematically. In conclusion, incorrect gluten quantitation, improper product labeling, and poor consumer awareness, which results in the inadvertent intake of relatively high amounts of gluten, can be factors that compromise the health of patients with CD. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

18 pages, 1376 KiB

Open AccessReview

New Insights into Non-Dietary Treatment in Celiac Disease: Emerging Therapeutic Options

by Verónica Segura, Ángela Ruiz-Carnicer, Carolina Sousa and María de Lourdes Moreno

Nutrients 2021, 13(7), 2146; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13072146 - 23 Jun 2021

Cited by 12 | Viewed by 5983

Abstract

To date, the only treatment for celiac disease (CD) consists of a strict lifelong gluten-free diet (GFD), which has numerous limitations in patients with CD. For this reason, dietary transgressions are frequent, implying intestinal damage and possible long-term complications. There is an unquestionable need for non-dietary alternatives to avoid damage by involuntary contamination or voluntary dietary transgressions. In recent years, different therapies and treatments for CD have been developed and studied based on the degradation of gluten in the intestinal lumen, regulation of the immune response, modulation of intestinal permeability, and induction of immunological tolerance. In this review, therapeutic lines for CD are evaluated with special emphasis on phase III and II clinical trials, some of which have promising results. Full article

(This article belongs to the Special Issue Gluten Related Disorders: Coeliac Disease and Beyond)

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