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Special Issue "From Ptolemaus to Copernicus: The Evolving System of Gluten-Related Disorders"

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

Deadline for manuscript submissions: closed (31 October 2016)

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

Special Issue Editors

Guest Editor
Prof. Dr. Carlo Catassi

Head, Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy; Past President, Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP)
E-Mail
Phone: +39 071 596 23 64 / +39 349 22 35 447
Fax: +39 071 36281
Interests: celiac disease; gluten-related disorders; gluten sensitivity; pediatric gastroenterology; pediatric nutrition
Guest Editor
Prof. Dr. Alessio Fasano

Mucosal Immunology and Biology Research Center, Massachusetts General Hospital East, Building 114, 16th Street (Mail Stop 114-3503), Charlestown, MA 02129-4404, USA
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Special Issue Information

Dear Colleagues,

Gluten is the major protein of wheat and other cereals (rye and barley), which is responsible for triggering celiac disease (CD) in genetically predisposed individuals. Until a few years ago, CD was the major (if not the only) well-known gluten-related disorder. However, in recent years it has become clear that gluten proteins may activate different pathological mechanisms, leading to a wide spectrum of human diseases, including non-celiac gluten sensitivity (NCGS), gluten ataxia, neuro-psychiatric disorders, and may others. Conceptually, we have therefore moved from a Ptolemaic to a Copernican system, i.e., CD is no longer the “center of the universe”, but is just one of the possible worlds of gluten intolerance. Many other gluten planets do indeed exist and deserve the attention of researchers and clinicians alike.

Although different gluten-related disorders show specific epidemiological, pathophysiological, and clinical aspects, these conditions share a trigger and treatment, the gluten-free diet. For a very long time, awareness of these disorders has been limited and, therefore, the epidemiology of gluten-related disorders is still a “work in progress”. Current research strives to clarify the boundaries between these entities, their disease mechanisms, and how a proper diagnosis can be implemented.

Nearly 25% of Americans (many more than the projected three 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, which will help to dissipate this confusion by sharing their evidence-based science, which will help the reader to distinguish facts from fantasies.

Prof. Dr. Carlo Catass
Prof. Dr. Alessio Fasano
Guest Editors


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Keywords

  • gluten-related disorders
  • celiac disease
  • non celiac gluten sensitivity
  • gluten intolerance
  • gluten-free diet

Published Papers (18 papers)

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Editorial

Jump to: Research, Review

Open AccessEditorial
Gluten-Free Diet Indications, Safety, Quality, Labels, and Challenges
Nutrients 2017, 9(8), 846; https://doi.org/10.3390/nu9080846
Received: 23 July 2017 / Revised: 27 July 2017 / Accepted: 31 July 2017 / Published: 8 August 2017
Cited by 6 | PDF Full-text (335 KB) | HTML Full-text | XML Full-text
Abstract
A gluten-free diet (GFD) is the safest treatment modality in patient with coeliac disease (CD) and other gluten-related disorders. Contamination and diet compliance are important factors behind persistent symptoms in patients with gluten related-disorders, in particular CD. How much gluten can be tolerated, [...] Read more.
A gluten-free diet (GFD) is the safest treatment modality in patient with coeliac disease (CD) and other gluten-related disorders. Contamination and diet compliance are important factors behind persistent symptoms in patients with gluten related-disorders, in particular CD. How much gluten can be tolerated, how safe are the current gluten-free (GF) products, what are the benefits and side effects of GFD? Recent studies published in Nutrients on gluten-free products’ quality, availability, safety, as well as challenges related to a GFD are discussed. Full article
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Research

Jump to: Editorial, Review

Open AccessArticle
Gluten Contamination in Naturally or Labeled Gluten-Free Products Marketed in Italy
Nutrients 2017, 9(2), 115; https://doi.org/10.3390/nu9020115
Received: 14 December 2016 / Revised: 28 January 2017 / Accepted: 3 February 2017 / Published: 7 February 2017
Cited by 11 | PDF Full-text (931 KB) | HTML Full-text | XML Full-text
Abstract
Background: A strict and lifelong gluten-free diet is the only treatment of celiac disease. Gluten contamination has been frequently reported in nominally gluten-free products. The aim of this study was to test the level of gluten contamination in gluten-free products currently available in [...] Read more.
Background: A strict and lifelong gluten-free diet is the only treatment of celiac disease. Gluten contamination has been frequently reported in nominally gluten-free products. The aim of this study was to test the level of gluten contamination in gluten-free products currently available in the Italian market. Method: A total of 200 commercially available gluten-free products (including both naturally and certified gluten-free products) were randomly collected from different Italian supermarkets. The gluten content was determined by the R5 ELISA Kit approved by EU regulations. Results: Gluten level was lower than 10 part per million (ppm) in 173 products (86.5%), between 10 and 20 ppm in 9 (4.5%), and higher than 20 ppm in 18 (9%), respectively. In contaminated foodstuff (gluten > 20 ppm) the amount of gluten was almost exclusively in the range of a very low gluten content. Contaminated products most commonly belonged to oats-, buckwheat-, and lentils-based items. Certified and higher cost gluten-free products were less commonly contaminated by gluten. Conclusion: Gluten contamination in either naturally or labeled gluten-free products marketed in Italy is nowadays uncommon and usually mild on a quantitative basis. A program of systematic sampling of gluten-free food is needed to promptly disclose at-risk products. Full article
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Open AccessArticle
Contact Dermatitis Due to Nickel Allergy in Patients Suffering from Non‐Celiac Wheat Sensitivity
Nutrients 2017, 9(2), 103; https://doi.org/10.3390/nu9020103
Received: 17 December 2016 / Accepted: 23 January 2017 / Published: 2 February 2017
Cited by 3 | PDF Full-text (220 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Non‐celiac wheat sensitivity (NCWS) is a new clinical entity in the world of gluten‐related diseases. Nickel, the most frequent cause of contact allergy, can be found in wheat and results in systemic nickel allergy syndrome and mimics irritable bowel syndrome (IBS). Objective: [...] Read more.
Background: Non‐celiac wheat sensitivity (NCWS) is a new clinical entity in the world of gluten‐related diseases. Nickel, the most frequent cause of contact allergy, can be found in wheat and results in systemic nickel allergy syndrome and mimics irritable bowel syndrome (IBS). Objective: To evaluate the frequency of contact dermatitis due to nickel allergy in NCWS patients diagnosed by a double‐blind placebo‐controlled(DBPC)challenge,and to identify the characteristics of NCWS patients with nickel allergy. Methods: We performed a prospective study of 60 patients (54 females, 6 males; mean age 34.1 ± 8.1 years) diagnosed with NCWS from December 2014 to November 2016; 80 age‐ and sex‐matched subjects with functional gastrointestina l symptoms served as controls. Patients reporting contact dermatitis related to nickel‐containing objects underwent nickel patch test (Clinicaltrials.gov registration number: NCT02750735).Results: Six out of sixty patients (10%) with NCWS suffered from contact dermatitis and nickel allergy and this frequency was statistically higher (p = 0.04)than observed in the control group(5%. The main clinical characteristic of NCWS patients with nickel allergy was a higher frequency of cutaneous symptoms after wheat ingestion compared to NCWS patients who did not suffer from nickel allergy (p < 0.0001. Conclusions: Contact dermatitis and nickel allergy are more frequent in NCWS patients than in subjects with functional gastrointestinal disorders;furthermore, these patients had a very high frequency of cutaneous manifestations after wheat ingestion. Nickel allergy should be evaluated in NCWS patients who have cutaneous manifestations after wheat ingestion. Full article
Open AccessArticle
Normal Bone Mineral Density Associates with Duodenal Mucosa Healing in Adult Patients with Celiac Disease on a Gluten-Free Diet
Nutrients 2017, 9(2), 98; https://doi.org/10.3390/nu9020098
Received: 11 January 2017 / Accepted: 23 January 2017 / Published: 31 January 2017
Cited by 5 | PDF Full-text (223 KB) | HTML Full-text | XML Full-text
Abstract
Impairment of bone mineral density (BMD) is frequent in celiac disease (CD) patients on a gluten-free diet (GFD). The normalization of intestinal mucosa is still difficult to predict. We aim to investigate the relationship between BMD and duodenal mucosa healing (DMH) in CD [...] Read more.
Impairment of bone mineral density (BMD) is frequent in celiac disease (CD) patients on a gluten-free diet (GFD). The normalization of intestinal mucosa is still difficult to predict. We aim to investigate the relationship between BMD and duodenal mucosa healing (DMH) in CD patients on a GFD. Sixty-four consecutive CD patients on a GFD were recruited. After a median period of a 6-year GFD (range 2–33 years), patients underwent repeat duodenal biopsy and dual-energy X-ray absorptiometry (DXA) scan. Twenty-four patients (38%) displayed normal and 40 (62%) low BMD, 47 (73%) DMH, and 17 (27%) duodenal mucosa lesions. All patients but one with normal BMD (23 of 24, 96%) showed DMH, while, among those with low BMD, 24 (60%) did and 16 (40%) did not. At multivariate analysis, being older (odds ratio (OR) 1.1, 95% confidence interval (CI) 1.03–1.18) and having diagnosis at an older age (OR 1.09, 95% CI 1.03–1.16) were associated with low BMD; in turn, having normal BMD was the only variable independently associated with DMH (OR 17.5, 95% CI 1.6–192). In older CD patients and with late onset disease, BMD recovery is not guaranteed, despite a GFD. A normal DXA scan identified CD patients with DMH; thus, it is a potential tool in planning endoscopic resampling. Full article
Open AccessArticle
Prevalence of Self-Reported Gluten Sensitivity and Adherence to a Gluten-Free Diet in Argentinian Adult Population
Nutrients 2017, 9(1), 81; https://doi.org/10.3390/nu9010081
Received: 26 November 2016 / Revised: 30 December 2016 / Accepted: 16 January 2017 / Published: 21 January 2017
Cited by 13 | PDF Full-text (1478 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Previous studies suggest that the prevalence of wheat/gluten sensitivity and adherence to a gluten-free diet (GFD) are high in Latin population despite a poor diagnosis of celiac disease. However, these prevalence rates still remain unknown in most Latin American countries. Methods: A [...] Read more.
Background: Previous studies suggest that the prevalence of wheat/gluten sensitivity and adherence to a gluten-free diet (GFD) are high in Latin population despite a poor diagnosis of celiac disease. However, these prevalence rates still remain unknown in most Latin American countries. Methods: A cross-sectional survey study was conducted in Santa Fe, Argentina. Results: The estimated self-reported prevalence rates were (95% Confidence Interval [CI]): self-reported gluten sensitivity (SR-GS) 7.61% (6.2–9.2), SR-GS currently following a GFD 1.82% (1.2–2.7), celiac disease 0.58% (0.3–1.2), wheat allergy 0.33% (0.12–0.84), self-reported non-celiac gluten sensitivity (SR-NCGS) 6.28% (5.1–7.8), SR-NCGS currently following a GFD 0.91% (0.5–1.6), and adherence to a GFD 6.37% (5.1–7.9). SR-GS was more common in women (6.0%; p < 0.001) and associated with irritable bowel syndrome (p < 0.001). Among the GFD followers, 71.4% were doing it for reasons other than health-related benefits and 50.6% without medical/dietitian advice. In the non-SR-GS group, the main motivations for following a GFD were weight control and the perception that a GFD is healthier. Conclusion: In Argentina, gluten sensitivity is commonly reported and it seems that physicians/gastroenterologists are aware of celiac disease diagnosis. Trustable information about the benefits and potential consequences of following a GFD should be given to the general population. Full article
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Open AccessArticle
Content Validation and Semantic Evaluation of a Check-List Elaborated for the Prevention of Gluten Cross-Contamination in Food Services
Nutrients 2017, 9(1), 36; https://doi.org/10.3390/nu9010036
Received: 15 November 2016 / Revised: 21 December 2016 / Accepted: 26 December 2016 / Published: 6 January 2017
Cited by 7 | PDF Full-text (501 KB) | HTML Full-text | XML Full-text
Abstract
Conditions associated to the consumption of gluten have emerged as a major health care concern and the treatment consists on a lifelong gluten-free diet. Providing safe food for these individuals includes adapting to safety procedures within the food chain and preventing gluten cross-contamination [...] Read more.
Conditions associated to the consumption of gluten have emerged as a major health care concern and the treatment consists on a lifelong gluten-free diet. Providing safe food for these individuals includes adapting to safety procedures within the food chain and preventing gluten cross-contamination in gluten-free food. However, a gluten cross-contamination prevention protocol or check-list has not yet been validated. Therefore, the aim of this study was to perform the content validation and semantic evaluation of a check-list elaborated for the prevention of gluten cross-contamination in food services. The preliminary version of the check-list was elaborated based on the Brazilian resolution for food safety Collegiate Board Resolution 216 (RDC 216) and Collegiate Board Resolution 275 (RDC 275), the standard 22000 from the International Organization for Standardization (ISO 22000) and the Canadian Celiac Association Gluten-Free Certification Program documents. Seven experts with experience in the area participated in the check-list validation and semantic evaluation. The criteria used for the approval of the items, as to their importance for the prevention of gluten cross-contamination and clarity of the wording, was the achievement of a minimal of 80% of agreement between the experts (W-values ≥ 0.8). Moreover, items should have a mean ≥4 in the evaluation of importance (Likert scale from 1 to 5) and clarity (Likert scale from 0 to 5) in order to be maintained in the instrument. The final version of the check-list was composed of 84 items, divided into 12 sections. After being redesigned and re-evaluated, the items were considered important and comprehensive by the experts (both with W-values ≥ 0.89). The check-list developed was validated with respect to content and approved in the semantic evaluation. Full article
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Open AccessArticle
Evolution of Gluten Content in Cereal-Based Gluten-Free Products: An Overview from 1998 to 2016
Nutrients 2017, 9(1), 21; https://doi.org/10.3390/nu9010021
Received: 28 October 2016 / Revised: 16 December 2016 / Accepted: 16 December 2016 / Published: 3 January 2017
Cited by 5 | PDF Full-text (648 KB) | HTML Full-text | XML Full-text
Abstract
The treatment of Celiac disease consists in a strict lifelong gluten-free (GF) diet. As the ingestion of small amounts can have damaging complications, there has been an ongoing discussion regarding the safe threshold for dietary residual gluten. The aim was to analyze the [...] Read more.
The treatment of Celiac disease consists in a strict lifelong gluten-free (GF) diet. As the ingestion of small amounts can have damaging complications, there has been an ongoing discussion regarding the safe threshold for dietary residual gluten. The aim was to analyze the evolution of gluten content in cereal-based GF foodstuffs (n = 3141) from 1998 to 2016 measured by the enzyme-linked immunosorbent assay (ELISA) technique. Eight categories were defined: flours, breakfast cereals/bars, bakery, pasta, breads, dough, snacks, and yeasts, and these were divided into GF labeled-foods (GF-L) or reportedly GF foodstuffs, but not certified (GF-NC). Gluten-detection was decreased over time in line with the evolving European regulations about food information and gluten content claims. This decline started sooner in GF-L products than in GF-NC. As a whole, gluten was detected in 371 samples, with breakfast cereals/bars being the most contaminated group. Snacks and yeasts changed from being high gluten-detected samples to being totally GF over the years. The downside is that, of contaminated samples, those in the low levels of gluten detection range have decreased while flour samples containing over 100 mg/kg gluten have risen in the 2013–2016 period. Obtained data confirm that GF cereal-based foods are becoming safer but gluten control must be maintained. Full article
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Open AccessArticle
Prevalence and Characterization of Self-Reported Gluten Sensitivity in The Netherlands
Nutrients 2016, 8(11), 714; https://doi.org/10.3390/nu8110714
Received: 20 September 2016 / Revised: 28 October 2016 / Accepted: 3 November 2016 / Published: 8 November 2016
Cited by 27 | PDF Full-text (1873 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: A growing number of individuals reports symptoms related to the ingestion of gluten-containing food in the absence of celiac disease. Yet the actual prevalence is not well established. Methods: Between April 2015 and March 2016, unselected adults visiting marketplaces, dental practices and [...] Read more.
Background: A growing number of individuals reports symptoms related to the ingestion of gluten-containing food in the absence of celiac disease. Yet the actual prevalence is not well established. Methods: Between April 2015 and March 2016, unselected adults visiting marketplaces, dental practices and a university in The Netherlands were asked to complete a modified validated questionnaire for self-reported gluten sensitivity (srGS). Results: Among the 785 adults enquired, two had celiac disease. Forty-nine (6.2%) reported symptoms related to the ingestion of gluten-containing food. These individuals were younger, predominantly female and lived more frequently in urban regions compared with the other respondents. Symptoms reported included bloating (74%), abdominal discomfort (49%) and flatulence (47%). A total of 23 (47%) srGS individuals reported having had tried a gluten-free or gluten-restricted diet. Abdominal discomfort related to fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP)-containing food was more often reported in srGS individuals compared with the other respondents (73.5% vs. 21.7%, p < 0.001). Conclusion: Self-reported GS is common in The Netherlands, especially in younger individuals, females and urban regions, although the prevalence was lower than in a comparable recent UK study. It cannot be excluded that FODMAPs are in part responsible for these symptoms. Full article
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Open AccessArticle
Dietary Gluten-Induced Gut Dysbiosis Is Accompanied by Selective Upregulation of microRNAs with Intestinal Tight Junction and Bacteria-Binding Motifs in Rhesus Macaque Model of Celiac Disease
Nutrients 2016, 8(11), 684; https://doi.org/10.3390/nu8110684
Received: 29 August 2016 / Revised: 12 October 2016 / Accepted: 18 October 2016 / Published: 28 October 2016
Cited by 13 | PDF Full-text (3361 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The composition of the gut microbiome reflects the overall health status of the host. In this study, stool samples representing the gut microbiomes from 6 gluten-sensitive (GS) captive juvenile rhesus macaques were compared with those from 6 healthy, age- and diet-matched peers. A [...] Read more.
The composition of the gut microbiome reflects the overall health status of the host. In this study, stool samples representing the gut microbiomes from 6 gluten-sensitive (GS) captive juvenile rhesus macaques were compared with those from 6 healthy, age- and diet-matched peers. A total of 48 samples representing both groups were studied using V4 16S rRNA gene DNA analysis. Samples from GS macaques were further characterized based on type of diet administered: conventional monkey chow, i.e., wheat gluten-containing diet (GD), gluten-free diet (GFD), barley gluten-derived diet (BOMI) and reduced gluten barley-derived diet (RGB). It was hypothesized that the GD diet would lower the gut microbial diversity in GS macaques. This is the first report illustrating the reduction of gut microbial alpha-diversity (p < 0.05) following the consumption of dietary gluten in GS macaques. Selected bacterial families (e.g., Streptococcaceae and Lactobacillaceae) were enriched in GS macaques while Coriobacteriaceae was enriched in healthy animals. Within several weeks after the replacement of the GD by the GFD diet, the composition (beta-diversity) of gut microbiome in GS macaques started to change (p = 0.011) towards that of a normal macaque. Significance for alpha-diversity however, was not reached by the day 70 when the feeding experiment ended. Several inflammation-associated microRNAs (miR-203, -204, -23a, -23b and -29b) were upregulated (p < 0.05) in jejunum of 4 biopsied GS macaques fed GD with predicted binding sites on 16S ribosomal RNA of Lactobacillus reuteri (accession number: NR_025911), Prevotella stercorea (NR_041364) and Streptococcus luteciae (AJ297218) that were overrepresented in feces. Additionally, claudin-1, a validated tight junction protein target of miR-29b was significantly downregulated in jejunal epithelium of GS macaques. Taken together, we predict that with the introduction of effective treatments in future studies the diversity of gut microbiomes in GS macaques will approach those of healthy individuals. Further studies are needed to elucidate the regulatory pathways of inflammatory miRNAs in intestinal mucosa of GS macaques and to correlate their expression with gut dysbiosis. Full article
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Open AccessArticle
Effect of Bifidobacterium breve on the Intestinal Microbiota of Coeliac Children on a Gluten Free Diet: A Pilot Study
Nutrients 2016, 8(10), 660; https://doi.org/10.3390/nu8100660
Received: 10 August 2016 / Revised: 13 October 2016 / Accepted: 13 October 2016 / Published: 22 October 2016
Cited by 15 | PDF Full-text (5313 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Coeliac disease (CD) is associated with alterations of the intestinal microbiota. Although several Bifidobacterium strains showed anti-inflammatory activity and prevention of toxic gliadin peptides generation in vitro, few data are available on their efficacy when administered to CD subjects. This study evaluated the [...] Read more.
Coeliac disease (CD) is associated with alterations of the intestinal microbiota. Although several Bifidobacterium strains showed anti-inflammatory activity and prevention of toxic gliadin peptides generation in vitro, few data are available on their efficacy when administered to CD subjects. This study evaluated the effect of administration for three months of a food supplement based on two Bifidobacterium breve strains (B632 and BR03) to restore the gut microbial balance in coeliac children on a gluten free diet (GFD). Microbial DNA was extracted from faeces of 40 coeliac children before and after probiotic or placebo administration and 16 healthy children (Control group). Sequencing of the amplified V3-V4 hypervariable region of 16S rRNA gene as well as qPCR of Bidobacterium spp., Lactobacillus spp., Bacteroides fragilis group Clostridium sensu stricto and enterobacteria were performed. The comparison between CD subjects and Control group revealed an alteration in the intestinal microbial composition of coeliacs mainly characterized by a reduction of the Firmicutes/Bacteroidetes ratio, of Actinobacteria and Euryarchaeota. Regarding the effects of the probiotic, an increase of Actinobacteria was found as well as a re-establishment of the physiological Firmicutes/Bacteroidetes ratio. Therefore, a three-month administration of B. breve strains helps in restoring the healthy percentage of main microbial components. Full article
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Open AccessArticle
Persistent Intraepithelial Lymphocytosis in Celiac Patients Adhering to Gluten-Free Diet Is Not Abolished Despite a Gluten Contamination Elimination Diet
Nutrients 2016, 8(9), 525; https://doi.org/10.3390/nu8090525
Received: 8 July 2016 / Revised: 4 August 2016 / Accepted: 16 August 2016 / Published: 26 August 2016
Cited by 3 | PDF Full-text (842 KB) | HTML Full-text | XML Full-text
Abstract
The gluten-free diet (GFD) is the only validated treatment for celiac disease (CD), but despite strict adherence, complete mucosal recovery is rarely obtained. The aim of our study was to assess whether complete restitutio ad integrum could be achieved by adopting a restrictive [...] Read more.
The gluten-free diet (GFD) is the only validated treatment for celiac disease (CD), but despite strict adherence, complete mucosal recovery is rarely obtained. The aim of our study was to assess whether complete restitutio ad integrum could be achieved by adopting a restrictive diet (Gluten Contamination Elimination Diet, GCED) or may depend on time of exposure to GFD. Two cohorts of CD patients, with persisting Marsh II/Grade A lesion at duodenal biopsy after 12–18 months of GFD (early control) were identified. Patients in Cohort A were re-biopsied after a three-month GCED (GCED control) and patients in Cohort B were re-biopsied after a minimum of two years on a standard GFD subsequent to early control (late control). Ten patients in Cohort A and 19 in Cohort B completed the study protocol. There was no change in the classification of duodenal biopsies in both cohorts. The number of intraepithelial lymphocytes, TCRγδ+ (T-Cell Receptor gamma delta) T cell and eosinophils significantly decreased at GCED control (Cohort A) and at late control (Cohort B), compared to early control. Duodenal intraepithelial lymphocytosis persisting in CD patients during GFD is not eliminated by a GCED and is independent of the length of GFD. [NCT 02711696] Full article
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Open AccessArticle
Gastrointestinal Symptoms in Celiac Disease Patients on a Long-Term Gluten-Free Diet
Nutrients 2016, 8(7), 429; https://doi.org/10.3390/nu8070429
Received: 17 May 2016 / Revised: 7 July 2016 / Accepted: 11 July 2016 / Published: 14 July 2016
Cited by 9 | PDF Full-text (936 KB) | HTML Full-text | XML Full-text
Abstract
Experience suggests that many celiac patients suffer from persistent symptoms despite a long-term gluten-free diet (GFD). We investigated the prevalence and severity of these symptoms in patients with variable duration of GFD. Altogether, 856 patients were classified into untreated (n = 128), [...] Read more.
Experience suggests that many celiac patients suffer from persistent symptoms despite a long-term gluten-free diet (GFD). We investigated the prevalence and severity of these symptoms in patients with variable duration of GFD. Altogether, 856 patients were classified into untreated (n = 128), short-term GFD (1–2 years, n = 93) and long-term GFD (≥3 years, n = 635) groups. Analyses were made of clinical and histological data and dietary adherence. Symptoms were evaluated by the validated GSRS questionnaire. One-hundred-sixty healthy subjects comprised the control group. Further, the severity of symptoms was compared with that in peptic ulcer, reflux disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Altogether, 93% of the short-term and 94% of the long-term treated patients had a strict GFD and recovered mucosa. Untreated patients had more diarrhea, indigestion and abdominal pain than those on GFD and controls. There were no differences in symptoms between the short- and long-term GFD groups, but both yielded poorer GSRS total score than controls (p = 0.03 and p = 0.05, respectively). Furthermore, patients treated 1–2 years had more diarrhea (p = 0.03) and those treated >10 years more reflux (p = 0.04) than controls. Long-term treated celiac patients showed relatively mild symptoms compared with other gastrointestinal diseases. Based on our results, good response to GFD sustained in long-term follow-up, but not all patients reach the level of healthy individuals. Full article
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Open AccessArticle
Supplementation of Reduced Gluten Barley Diet with Oral Prolyl Endopeptidase Effectively Abrogates Enteropathy-Associated Changes in Gluten-Sensitive Macaques
Nutrients 2016, 8(7), 401; https://doi.org/10.3390/nu8070401
Received: 17 May 2016 / Revised: 21 June 2016 / Accepted: 23 June 2016 / Published: 28 June 2016
Cited by 6 | PDF Full-text (4065 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Celiac disease (CD) is an autoimmune disorder that affects approximately three million people in the United States. Furthermore, non-celiac gluten sensitivity (NCGS) affects an estimated additional 6% of the population, e.g., 20 million in the U.S. The only effective treatment of CD and [...] Read more.
Celiac disease (CD) is an autoimmune disorder that affects approximately three million people in the United States. Furthermore, non-celiac gluten sensitivity (NCGS) affects an estimated additional 6% of the population, e.g., 20 million in the U.S. The only effective treatment of CD and NCGS requires complete removal of gluten sources from the diet. While required adherence to a gluten-free diet (GFD) is extremely difficult to accomplish, efforts to develop additional supportive treatments are needed. To facilitate these efforts, we developed a gluten-sensitive (GS) rhesus macaque model to study the effects of novel therapies. Recently reported results from phase one of this project suggest that partial improvement—but not remission—of gluten-induced disease can be accomplished by 100-fold reduction of dietary gluten, i.e., 200 ppm—by replacement of conventional dietary sources of gluten with a mutant, reduced gluten (RG) barley (lys3a)-derived source. The main focus of this (phase two) study was to determine if the inflammatory effects of the residual gluten in lys3a mutant barley grain could be further reduced by oral supplementation with a prolylendopeptidase (PE). Results reveal that PE supplementation of RG barley diet induces more complete immunological, histopathological and clinical remission than RG barley diet alone. The combined effects of RG barley diet and PE supplementation resulted in a further decrease of inflammatory mediators IFN-γ and TNF secretion by peripheral lymphocytes, as well as decreased plasma anti-gliadin and anti-intestinal tissue transglutaminase (TG2) antibodies, diminished active caspase production in small intestinal mucosa, and eliminated clinical diarrhea—all comparable with a gluten-free diet induced remission. In summary, the beneficial results of a combined RG barley and PE administration in GS macaques may warrant the investigation of similar synergistic approaches. Full article
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Review

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Open AccessReview
The Low FODMAP Diet: Many Question Marks for a Catchy Acronym
Nutrients 2017, 9(3), 292; https://doi.org/10.3390/nu9030292
Received: 29 December 2016 / Revised: 6 March 2017 / Accepted: 13 March 2017 / Published: 16 March 2017
Cited by 23 | PDF Full-text (227 KB) | HTML Full-text | XML Full-text
Abstract
FODMAP, “Fermentable Oligo-, Di- and Mono-saccharides And Polyols”, is a heterogeneous group of highly fermentable but poorly absorbed short-chain carbohydrates and polyols. Dietary FODMAPs might exacerbate intestinal symptoms by increasing small intestinal water volume, colonic gas production, and intestinal motility. In recent years [...] Read more.
FODMAP, “Fermentable Oligo-, Di- and Mono-saccharides And Polyols”, is a heterogeneous group of highly fermentable but poorly absorbed short-chain carbohydrates and polyols. Dietary FODMAPs might exacerbate intestinal symptoms by increasing small intestinal water volume, colonic gas production, and intestinal motility. In recent years the low-FODMAP diet for treatment of irritable bowel syndrome (IBS) has gained increasing popularity. In the present review we aim to summarize the physiological, clinical, and nutritional issues, suggesting caution in the prolonged use of this dietary treatment on the basis of the existing literature. The criteria for inclusion in the FODMAPs list are not fully defined. Although the low-FODMAP diet can have a positive impact on the symptoms of IBS, particularly bloating and diarrhea, the quality of the evidence is lower than optimal, due to frequent methodological flaws, particularly lack of a proper control group and/or lack of blinding. In particular, it remains to be proven whether this regimen is superior to conventional IBS diets. The drastic reduction of FODMAP intake has physiological consequences, e.g., on the intestinal microbiome and colonocyte metabolism, which are still poorly understood. A low-FODMAP diet imposes an important restriction of dietary choices due to the elimination of some staple foods, such as wheat derivatives, lactose-containing dairy products, many vegetables and pulses, and several types of fruits. For this reason, patients may be at risk of reduced intake of fiber, calcium, iron, zinc, folate, B and D vitamins, and natural antioxidants. The nutritional risk of the low-FODMAP diet may be higher in persons with limited access to the expensive, alternative dietary items included in the low-FODMAP diet. Full article
Open AccessReview
Evolutionary Developments in Interpreting the  Gluten‐Induced Mucosal Celiac Lesion: An  Archimedian Heuristic
Nutrients 2017, 9(3), 213; https://doi.org/10.3390/nu9030213
Received: 19 December 2016 / Accepted: 22 February 2017 / Published: 28 February 2017
Cited by 5 | PDF Full-text (3459 KB) | HTML Full-text | XML Full-text
Abstract
The evolving history of the small intestinal biopsy and its interpretation—and misinterpretations—are described in this paper. Certain interpretative errors in the technical approaches to histological assessment are highlighted—even though we may never be rid of them. For example, mucosal “flattening” does not reduce [...] Read more.
The evolving history of the small intestinal biopsy and its interpretation—and misinterpretations—are described in this paper. Certain interpretative errors in the technical approaches to histological assessment are highlighted—even though we may never be rid of them. For example, mucosal “flattening” does not reduce individual villi to their cores, as still seems to be widely believed. Neither is the mucosa undergoing an atrophic process—since it can recover structurally. Rather, the intestinal mucosa manifests a vast hypertrophic response resulting in the formation of large plateaus formed from partially reduced villi and their amalgamation with the now increased height and width of the inter‐villous ridges: this is associated with considerable increases in crypt volumes. Sections through mosaic plateaus gives an erroneous impression of the presence of stunted, flat‐topped villi which continues to encourage both the continued use of irrelevant “atrophy” terminologies and a marked failure to perceive what random sections through mosaic plateaus actually look like. While reviewing the extensive 40+ year literature on mucosal analysis, we extracted data on intraepithelial lymphocytes (IEL) counts from 607 biopsies, and applied receiver‐operating characteristic (ROC)‐curve analysis. From that perspective, it appears that counting IEL/100 enterocyte nuclei in routine haematoxylin and eosin (H&E) sections provides the most useful discriminator of celiac mucosae at histological level, with an effective cut‐off of 27 IEL, and offering a very high sensitivity with few false negatives. ROC‐curve analysis also revealed the somewhat lesser accuracies of either CD3+ or γδ+ IEL counts. Current official guidelines seem to be somewhat inadequate in clearly defining the spectrum of gluten‐induced mucosal pathologies and how they could be optimally interpreted, as well as in promoting the ideal manner for physicians and pathologists to interact in interpreting intestinal mucosae submitted for analysis. Future trends should incorporate 3‐D printing and computerised modelling in order to exemplify the subtle micro‐anatomical features associated with the crypt‐villus interzone. The latter needs precise delineation with use of mRNA in‐section assays for brush border enzymes such as alkaline phosphate and esterase. Other additional approaches are needed to facilitate recognition and interpretation of the features of this important inter‐zone, such as wells, basins and hypertrophic alterations in the size of inter‐villous ridges. The 3‐D computerised models could considerably expand our understandings of the microvasculature and its changes—in relation both to crypt hypertrophy, in addition to the partial attrition and subsequent regrowth of villi from the inter‐villous ridges during the flattening and recovery processes, respectively. Full article
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Open AccessReview
Biomarkers to Monitor Gluten-Free Diet Compliance in Celiac Patients
Nutrients 2017, 9(1), 46; https://doi.org/10.3390/nu9010046
Received: 31 October 2016 / Revised: 29 November 2016 / Accepted: 27 December 2016 / Published: 6 January 2017
Cited by 17 | PDF Full-text (637 KB) | HTML Full-text | XML Full-text
Abstract
Gluten-free diet (GFD) is the only treatment for celiac disease (CD). There is a general consensus that strict GFD adherence in CD patients leads to full clinical and histological remission accompanied by improvement in quality of life and reduced long-term complications. Despite the [...] Read more.
Gluten-free diet (GFD) is the only treatment for celiac disease (CD). There is a general consensus that strict GFD adherence in CD patients leads to full clinical and histological remission accompanied by improvement in quality of life and reduced long-term complications. Despite the importance of monitoring the GFD, there are no clear guidelines for assessing the outcome or for exploring its adherence. Available methods are insufficiently accurate to identify occasional gluten exposure that may cause intestinal mucosal damage. Serological tests are highly sensitive and specific for diagnosis, but do not predict recovery and are not useful for follow-up. The use of serial endoscopies, it is invasive and impractical for frequent monitoring, and dietary interview can be subjective. Therefore, the detection of gluten immunogenic peptides (GIP) in feces and urine have been proposed as new non-invasive biomarkers to detect gluten intake and verify GFD compliance in CD patients. These simple immunoassays in human samples could overcome some key unresolved scientific and clinical problems in CD management. It is a significant advance that opens up new possibilities for the clinicians to evaluate the CD treatment, GFD compliance, and improvement in the quality of life of CD patients. Full article
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Open AccessReview
What Do We Know Now about IgE-Mediated Wheat Allergy in Children?
Nutrients 2017, 9(1), 35; https://doi.org/10.3390/nu9010035
Received: 30 October 2016 / Revised: 19 December 2016 / Accepted: 27 December 2016 / Published: 4 January 2017
Cited by 9 | PDF Full-text (657 KB) | HTML Full-text | XML Full-text
Abstract
IgE-mediated wheat allergy is a gluten-related disorder. Wheat is one of the five most common food allergens in children. However, the natural history of IgE-mediated wheat allergy has seldom been described in the research literature. This study presents the current state of knowledge [...] Read more.
IgE-mediated wheat allergy is a gluten-related disorder. Wheat is one of the five most common food allergens in children. However, the natural history of IgE-mediated wheat allergy has seldom been described in the research literature. This study presents the current state of knowledge about the IgE-mediated wheat allergy in children. Full article
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Open AccessReview
Properties of Gluten Intolerance: Gluten Structure, Evolution, Pathogenicity and Detoxification Capabilities
Nutrients 2016, 8(10), 644; https://doi.org/10.3390/nu8100644
Received: 28 August 2016 / Revised: 30 September 2016 / Accepted: 11 October 2016 / Published: 18 October 2016
Cited by 29 | PDF Full-text (2531 KB) | HTML Full-text | XML Full-text
Abstract
Theterm gluten intolerance may refer to three types of human disorders: autoimmune celiac disease (CD), allergy to wheat and non-celiac gluten sensitivity (NCGS). Gluten is a mixture of prolamin proteins present mostly in wheat, but also in barley, rye and oat. Gluten can [...] Read more.
Theterm gluten intolerance may refer to three types of human disorders: autoimmune celiac disease (CD), allergy to wheat and non-celiac gluten sensitivity (NCGS). Gluten is a mixture of prolamin proteins present mostly in wheat, but also in barley, rye and oat. Gluten can be subdivided into three major groups: S-rich, S-poor and high molecular weight proteins. Prolamins within the groups possess similar structures and properties. All gluten proteins are evolutionarily connected and share the same ancestral origin. Gluten proteins are highly resistant to hydrolysis mediated by proteases of the human gastrointestinal tract. It results in emergence of pathogenic peptides, which cause CD and allergy in genetically predisposed people. There is a hierarchy of peptide toxicity and peptide recognition by T cells. Nowadays, there are several ways to detoxify gluten peptides: the most common is gluten-free diet (GFD), which has proved its effectiveness; prevention programs, enzymatic therapy, correction of gluten pathogenicity pathways and genetically modified grains with reduced immunotoxicity. A deep understanding of gluten intolerance underlying mechanisms and detailed knowledge of gluten properties may lead to the emergence of novel effective approaches for treatment of gluten-related disorders. Full article
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