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Guidelines for best practices in monitoring established coeliac disease in adult patients.
Elli, L, Leffler, D, Cellier, C, Lebwohl, B, Ciacci, C, Schumann, M, Lundin, KEA, Chetcuti Zammit, S, Sidhu, R, Roncoroni, L, et al
Nature reviews. Gastroenterology & hepatology. 2024;(3):198-215
Abstract
Coeliac disease (CeD) is an immunological disease triggered by the consumption of gluten contained in food in individuals with a genetic predisposition. Diagnosis is based on the presence of small bowel mucosal atrophy and circulating autoantibodies (anti-type 2 transglutaminase antibodies). After diagnosis, patients follow a strict, life-long gluten-free diet. Although the criteria for diagnosis of this disease are well defined, the monitoring phase has been studied less and there is a lack of specific guidelines for this phase. To develop a set of clinical guidelines for CeD monitoring, we followed the Grading of Recommendations Assessment, Development and Evaluation methodology. Statements and recommendations with the level of evidence were developed and approved by the working group, which comprised gastroenterologists, pathologists, dieticians and biostatisticians. The proposed guidelines, endorsed by the North American and European coeliac disease scientific societies, make recommendations for best practices in monitoring patients with CeD based on the available evidence. The evidence level is low for many topics, suggesting that further research in specific aspects of CeD would be valuable. In conclusion, the present guidelines support clinicians in improving CeD treatment and follow-up and highlight novel issues that should be considered in future studies.
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Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.
Lebwohl, B, Ma, C, Lagana, SM, Pai, RK, Baker, KA, Zayadi, A, Hogan, M, Bouma, G, Cellier, C, Goldsmith, JD, et al
Gastroenterology. 2024;(1):88-102
Abstract
BACKGROUND & AIMS There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.
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Accuracy of the No-Biopsy Approach for the Diagnosis of Celiac Disease in Adults: A Systematic Review and Meta-Analysis.
Shiha, MG, Nandi, N, Raju, SA, Wild, G, Cross, SS, Singh, P, Elli, L, Makharia, GK, Sanders, DS, Penny, HA
Gastroenterology. 2024;(4):620-630
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Abstract
BACKGROUND & AIMS Current international guidelines recommend duodenal biopsies to confirm the diagnosis of celiac disease in adult patients. However, growing evidence suggests that immunoglobulin A (IgA) anti-tissue transglutaminase (tTg) antibody levels ≥10 times the upper limit of normal (ULN) can accurately predict celiac disease, eliminating the need for biopsy. We performed a systematic review and meta-analysis to evaluate the accuracy of the no-biopsy approach to confirm the diagnosis of celiac disease in adults. METHODS We systematically searched MEDLINE, EMBASE, Cochrane Library, and Web of Science from January 1998 to October 2023 for studies reporting the sensitivity and specificity of IgA-tTG ≥10×ULN against duodenal biopsies (Marsh grade ≥2) in adults with suspected celiac disease. We used a bivariate random effects model to calculate the summary estimates of sensitivity, specificity, and positive and negative likelihood ratios. The positive and negative likelihood ratios were used to calculate the positive predictive value of the no-biopsy approach across different pretest probabilities of celiac disease. The methodological quality of the included studies was evaluated using the QUADAS-2 tool. This study was registered with PROSPERO, number CRD42023398812. RESULTS A total of 18 studies comprising 12,103 participants from 15 countries were included. The pooled prevalence of biopsy-proven celiac disease in the included studies was 62% (95% confidence interval [CI], 40%-83%). The proportion of patients with IgA-tTG ≥10×ULN was 32% (95% CI, 24%-40%). The summary sensitivity of IgA-tTG ≥10×ULN was 51% (95% CI, 42%-60%), and the summary specificity was 100% (95% CI, 98%-100%). The area under the summary receiver operating characteristic curve was 0.83 (95% CI, 0.77 - 0.89). The positive predictive value of the no-biopsy approach to identify patients with celiac disease was 65%, 88%, 95%, and 99% if celiac disease prevalence was 1%, 4%, 10%, and 40%, respectively. Between-study heterogeneity was moderate (I2 =30.3%), and additional sensitivity analyses did not significantly alter our findings. Only 1 study had a low risk of bias across all domains. CONCLUSION The results of this meta-analysis suggest that selected adult patients with IgA-tTG ≥10×ULN and a moderate to high pretest probability of celiac disease could be diagnosed without undergoing invasive endoscopy and duodenal biopsy.
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Updates in the diagnosis and management of coeliac disease.
Shiha, MG, Chetcuti Zammit, S, Elli, L, Sanders, DS, Sidhu, R
Best practice & research. Clinical gastroenterology. 2023;:101843
Abstract
Coeliac disease is a common autoimmune disorder induced by ingesting gluten, the protein component of wheat, barley, and rye. It is estimated that one-in-hundred people worldwide have coeliac disease, of whom the majority remain undiagnosed. Coeliac disease is characterized by a wide range of gastrointestinal and extraintestinal symptoms but can also present asymptomatically. Diagnosing coeliac disease depends on the concordance of clinical, serological and histopathological data. However, the diagnosis can be challenging and frequently overlooked. Undiagnosed coeliac disease is associated with an increased risk of complications and detrimental effects on quality of life. Early diagnosis and treatment of coeliac disease are necessary to reduce the risk of long-term complications.
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Efficacy and Acceptability of Dietary Therapies in Non-Constipated Irritable Bowel Syndrome: A Randomized Trial of Traditional Dietary Advice, the Low FODMAP Diet, and the Gluten-Free Diet.
Rej, A, Sanders, DS, Shaw, CC, Buckle, R, Trott, N, Agrawal, A, Aziz, I
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022;20(12):2876-2887.e15
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Plain language summary
Irritable bowel syndrome (IBS) is a common disorder characterised by stomach pain, bloating, and altered bowel movements. Dietary therapy is a way to manage IBS, with 3 diets becoming popular amongst health care professionals and those who suffer from IBS. Traditional dietary advice (TD), which involves adopting healthy, sensible eating patterns with adequate hydration, is the first line recommendation in the UK. The low-FODMAP diet (LFD) is the avoidance of carbohydrates, which tend to ferment in the stomach and are found in certain fruits and vegetables. The gluten free diet (GFD) is the avoidance of foods which contain gluten such as bread and pasta. All three diets have little evidence to support their use in IBS and this randomised control trial of 101 individuals with IBS aimed to determine whether the GFD and LFD are superior in relieving IBS symptoms compared to TD. The results showed that GFD, LFD and TD were all effective in the management of non-constipated IBS, but that TD was easier to follow and cheaper compared to the other two diets. It was concluded that TD should be used as first-line therapy for people with non-constipated IBS and that GFD and LFD should be reserved for specific patients under the care of a health care professional.
Expert Review
Conflicts of interest:
None
Take Home Message:
- TDA, LFD and GFD can all lead to significant improvements in non-constipation IBS with no statistically significant difference in effectiveness between the diets.
- Most patients find a TDA easier and cheaper to implement than a LFD or GFD.
- TDA is therefore recommended as a first line approach in non-constipation IBS.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
The aim of this study was to compare the effectiveness and patient acceptability of traditional dietary advice (TDA) vs a low FODMAP diet (LFD) vs a gluten-free diet (GFD, cross-contamination allowed) in patients with non-constipation irritable bowel syndrome (IBS).
TDA definition: healthy, sensible eating pattern, including regular meals, not eating too little/too much, adequate hydration, and reducing the intake of: alcohol/caffeine/fizzydrinks/fatty/spicy/ processed foods; fresh fruit (maximum of 3 per day); fibre/gas-producing foods and perceived food intolerances.
Methods
This was a randomised dietary trial over 4 weeks. Dietary advice was provided by a specialist dietitian in a session lasting 45-60 minutes. 99 patients completed the study (33 in each group). Stool analysis was performed in “around half“ (study authors terminology) of participants due to disruption of trial caused by COVID-19.
Results:
- Primary endpoint (reduction of 50 points or more on IBS symptom severity score) was met by 42% of patients on the TDA, 55% on LFD and 58% on GFD. The differences between groups were not statistically significant, p=0.43.
- Patients on the LFD had greater improvements in mood compared to the other diets under examination, reaching statistical significance (p=0.03) for Hospital Anxiety and Depression scale and (p<0.01) for dysphoria score on IBS-QOL scale.
- Patients on TDA found their diet cheaper (p<0.01), less time consuming to shop (p<0.01) and easier to follow when eating out with family and friends (p=0.03), whilst TDA and GFD were considered easier to incorporate into daily diet than LFD (p=0.02).
- No significant differences were found between groups in changes to macro- and micronutrient composition, except a trend to lower fibre intake with LFD (p=0.06).
- There was a significant reduction in intake of FODMAPs in all groups, with greatest reduction in LFD (27.7 to 7.6 g/day, p<0.01), followed by TDA (24.9 to 15.2 g/day, p<0.01) and GFD (27.4 to 22.4 g/day, p=0.03). Differences between groups were statistically significant (p<0.01).
- No differences were noted in change to the dysbiosis index between groups.
- Neither clinical characteristics nor dysbiosis index predicted response to any of the diets.
Conclusion
- TDA, LFD and GFD are all effective approaches for non-constipation IBS.
- TDA should be first-line dietary advice due to being the most patient-friendly.
Clinical practice applications:
- When working with clients with non-constipation IBS, a TDA approach may be favoured over LFD and GFD as a first line intervention if the patient has not already tried a TDA diet.
- Patient preferences, budget, time and living situation should be taken into account when deciding on best dietary advice for IBS.
Considerations for future research:
- As all 3 approaches led to reduction in FODMAPs, trials comparing different levels of FODMAP exclusion could lead to valuable information, as a strict FODMAP exclusion, which is commonly recommended in IBS, is difficult and may not be necessary.
- Studies of longer duration would be valuable to confirm that benefits observed with the 3 approaches are not short-term only.
- Comparing individual approaches to appropriate control group would ensure that improvements are not due to a placebo effect.
Abstract
BACKGROUND & AIMS Various diets are proposed as first-line therapies for non-constipated irritable bowel syndrome (IBS) despite insufficient or low-quality evidence. We performed a randomized trial comparing traditional dietary advice (TDA) against the low FODMAP diet (LFD) and gluten-free diet (GFD). METHODS Patients with Rome IV-defined non-constipated IBS were randomized to TDA, LFD, or GFD (the latter allowing for minute gluten cross-contamination). The primary end point was clinical response after 4 weeks of dietary intervention, as defined by ≥50-point reduction in IBS symptom severity score (IBS-SSS). Secondary end points included (1) changes in individual IBS-SSS items within clinical responders, (2) acceptability and food-related quality of life with dietary therapy, (3) changes in nutritional intake, (4) alterations in stool dysbiosis index, and (5) baseline factors associated with clinical response. RESULTS The primary end point of ≥50-point reduction in IBS-SSS was met by 42% (n = 14/33) undertaking TDA, 55% (n = 18/33) for LFD, and 58% (n = 19/33) for GFD (P = .43). Responders had similar improvements in IBS-SSS items regardless of their allocated diet. Individuals found TDA cheaper (P < .01), less time-consuming to shop (P < .01), and easier to follow when eating out (P = .03) than the GFD and LFD. TDA was also easier to incorporate into daily life than the LFD (P = .02). Overall reductions in micronutrient and macronutrient intake did not significantly differ across the diets. However, the LFD group had the greatest reduction in total FODMAP content (27.7 g/day before intervention to 7.6 g/day at week 4) compared with the GFD (27.4 g/day to 22.4 g/day) and TDA (24.9 g/day to 15.2 g/day) (P < .01). Alterations in stool dysbiosis index were similar across the diets, with 22%-29% showing reduced dysbiosis, 35%-39% no change, and 35%-40% increased dysbiosis (P = .99). Baseline clinical characteristics and stool dysbiosis index did not predict response to dietary therapy. CONCLUSIONS TDA, LFD, and GFD are effective approaches in non-constipated IBS, but TDA is the most patient-friendly in terms of cost and convenience. We recommend TDA as the first-choice dietary therapy in non-constipated IBS, with LFD and GFD reserved according to specific patient preferences and specialist dietetic input. CLINICALTRIALS gov: NCT04072991.
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Links between celiac disease and small intestinal bacterial overgrowth: A systematic review and meta-analysis.
Shah, A, Thite, P, Hansen, T, Kendall, BJ, Sanders, DS, Morrison, M, Jones, MP, Holtmann, G
Journal of gastroenterology and hepatology. 2022;(10):1844-1852
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BACKGROUND AND AIM Symptoms of small intestinal bacterial overgrowth (SIBO) and celiac disease (CeD) often overlap, and studies suggest a link between SIBO and CeD. We thus conducted a systematic review and meta-analysis to compare SIBO prevalence in CeD patients and controls and assessed effects of antimicrobial therapy on gastrointestinal symptoms in SIBO positive CeD patients. METHODS Electronic databases were searched until February 2022 for studies reporting SIBO prevalence in CeD. Prevalence rates, odds ratio (OR), and 95% confidence intervals (CI) of SIBO in CeD and controls were calculated. RESULTS We included 14 studies, with 742 CeD patients and 178 controls. The pooled prevalence of SIBO in CeD was 18.3% (95% CI: 11.4-28.1), with substantial heterogeneity. Including case-control studies with healthy controls, SIBO prevalence in CeD patients was significantly increased (OR 5.1, 95% CI: 2.1-12.4, P = 0.0001), with minimal heterogeneity. Utilizing breath tests, SIBO prevalence in CeD patients was 20.8% (95% CI: 11.9-33.7), almost two-fold higher compared with culture-based methods at 12.6% (95% CI: 5.1-28.0), with substantial heterogeneity in both analyses. SIBO prevalence in CeD patients nonresponsive to a gluten free diet (GFD) was not statistically higher as compared with those responsive to GFD (OR 1.5, 95% CI: 0.4-5.0, P = 0.511). Antibiotic therapy of SIBO positive CeD patients resulted in improvement in gastrointestinal symptoms in 95.6% (95% CI: 78.0-99.9) and normalization of breath tests. CONCLUSIONS This study suggests a link between SIBO and CeD. While SIBO could explain nonresponse to a GFD in CeD, SIBO prevalence is not statistically higher in CeD patients non-responsive to GFD. The overall quality of the evidence is low, mainly due to substantial "clinical heterogeneity" and the limited sensitivity/specificity of the available diagnostic tests.
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Anti-SARS-CoV-2 immunoglobulin profile in patients with celiac disease living in a high incidence area.
Elli, L, Facciotti, F, Lombardo, V, Scricciolo, A, Sanders, DS, Vaira, V, Barisani, D, Vecchi, M, Costantino, A, Scaramella, L, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2022;(1):3-9
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BACKGROUND AND AIM How symptoms and antibodies related to SARS-CoV-2 infection develop in patients with celiac disease (CD) is unclear. We aimed to investigate the impact of SARS-CoV-2 infection in CD patients. METHODS CD patients were interviewed about the development of COVID-19 symptoms, compliance with anti-virus measures and adherence to a gluten-free diet (GFD). The presence of anti-SARS-CoV-2 IgG and IgA (anti-RBD and N proteins) was compared to that in non-CD subjects. Expression of the duodenal ACE2 receptor was investigated. When available, data on duodenal histology, anti-tissue transglutaminase IgA (tTGA), comorbidities and GFD adherence were analyzed. RESULTS Of 362 CD patients, 42 (12%) reported COVID-19 symptoms and 21% of these symptomatic patients presented anti-SARS-CoV-2 Ig. Overall, 18% of CD patients showed anti-SARS-CoV-2 Ig versus 25% of controls (p = 0.18). CD patients had significantly lower levels of anti-N IgA. tTGA, duodenal atrophy, GFD adherence or other comorbidities did not influence symptoms and/or antibodies. The ACE2 receptor was detected in the non-atrophic duodenal mucosa of patients; atrophy was associated with lower expression of the ACE2 receptor. CONCLUSION CD patients have an anti-SARS-CoV-2 Ig profile similar to non-celiac controls, except for anti-N IgA. No risk factors were identified among CD parameters and GFD adherence.
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Biomarkers for the diagnosis and monitoring of celiac disease: can you count on me?
Topa, M, Sanders, DS, Elli, L
Current opinion in gastroenterology. 2022;(3):263-269
Abstract
PURPOSE OF REVIEW Different markers are available to diagnose and monitor celiac disease (CeD); however, the concordance among them and their efficacy are still controversial. We aim at defining the efficacy of CeD biomarkers, their advantages and limits. RECENT FINDINGS CeD diagnostic criteria are widely accepted, being a positive serology and duodenal atrophy (according to the Marsh-Oberhuber score) the main hallmarks. Flow cytometry and other molecular biomarkers support the diagnosis of refractory CeD. On the other side, CeD monitoring is less defined, as the biomarkers are not always reliable. To date, the reference standard to detect mucosal healing is represented by duodenal histology, but its timing and significance are debated. Novel scores may better define the trend of mucosal damage and MicroRNAs are among the innovative noninvasive biomarkers. The assessment of a correct gluten-free diet (GFD) is another aspect of CeD monitoring, based upon questionnaires and recently developed tools such as dosage of urinary or faecal gluten immunogenic peptides. SUMMARY Clinicians lack of a widely acknowledged tools to monitor CeD and GFD. Here, we present the efficacy of the most used markers.
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Diet and irritable bowel syndrome: an update from a UK consensus meeting.
Rej, A, Avery, A, Aziz, I, Black, CJ, Bowyer, RK, Buckle, RL, Seamark, L, Shaw, CC, Thompson, J, Trott, N, et al
BMC medicine. 2022;(1):287
Abstract
There has been a renewed interest in the role of dietary therapies to manage irritable bowel syndrome (IBS), with diet high on the agenda for patients. Currently, interest has focussed on the use of traditional dietary advice (TDA), a gluten-free diet (GFD) and the low FODMAP diet (LFD). A consensus meeting was held to assess the role of these dietary therapies in IBS, in Sheffield, United Kingdom.Evidence for TDA is from case control studies and clinical experience. Randomised controlled trials (RCT) have demonstrated the benefit of soluble fibre in IBS. No studies have assessed TDA in comparison to a habitual or sham diet. There have been a number of RCTs demonstrating the efficacy of a GFD at short-term follow-up, with a lack of long-term outcomes. Whilst gluten may lead to symptom generation in IBS, other components of wheat may also play an important role, with recent interest in the role of fructans, wheat germ agglutinins, as well as alpha amylase trypsin inhibitors. There is good evidence for the use of a LFD at short-term follow-up, with emerging evidence demonstrating its efficacy at long-term follow-up. There is overlap between the LFD and GFD with IBS patients self-initiating gluten or wheat reduction as part of their LFD. Currently, there is a lack of evidence to suggest superiority of one diet over another, although TDA is more acceptable to patients.In view of this evidence, our consensus group recommends that dietary therapies for IBS should be offered by dietitians who first assess dietary triggers and then tailor the intervention according to patient choice. Given the lack of dietetic services, novel approaches such as employing group clinics and online webinars may maximise capacity and accessibility for patients. Further research is also required to assess the comparative efficacy of dietary therapies to other management strategies available to manage IBS.
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Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.
Rostami, K, Ensari, A, Marsh, MN, Srivastava, A, Villanacci, V, Carroccio, A, Asadzadeh Aghdaei, H, Bai, JC, Bassotti, G, Becheanu, G, et al
Nutrients. 2022;(12)
Abstract
Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.