Changes in Intestinal Permeability 4 Hours After Gluten Challenge

Study Overview
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Brief Summary
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This study evaluates why people with celiac disease and non-celiac gluten/wheat sensitivity develop rapid onset symptoms within hours of gluten exposure. Half of subjects will be given gluten and half will not.

Detailed Description
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When a person with celiac disease is exposed to gluten, their immune system attacks their bowel and causes abdominal pain, bloating, and diarrhea. This process takes 24-72 hours to occur. Some people without celiac disease develop similar symptoms when they eat gluten or wheat. Doctors and scientists do not know what causes this sensitivity to gluten. People with celiac disease and non-celiac gluten sensitivity report symptoms within hours of being exposed to gluten. This study evaluates why this occurs by looking at changes in blood, urine, stool, and the bowel after being given gluten.

Official Title
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The Innate Response to and Changes in Intestinal Permeability 4 Hours After a Gluten Challenge in Subjects With Celiac Disease and Non Celiac Gluten Sensitivity

Conditions
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Celiac Disease, Wheat Hypersensitivity, Gluten Sensitivity, Gluten Enteropathy, Immune System and Related Disorders, Duodenal Diseases

Intervention / Treatment
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* Dietary Supplement: Gluten
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for subjects with Celiac Disease: Biopsy proven celiac disease diagnosed at least 2 years prior to recruitment Attest to following a gluten free diet to the best of their ability Quiescent symptoms on a gluten free diet Negative tissue transglutaminase at time of recruitment (to be collected with baseline blood work) A prior endoscopy with small bowel biopsies reviewed by a gastrointestinal pathologist revealing healing Inclusion Criteria for subjects with Non-Celiac Gluten Sensitivity: Meet diagnostic consensus criteria as defined by Ludvigsson et al in The Oslo definitions for coeliac disease and related terms Attest to following a gluten free diet to the best of their ability Quiescent symptoms on a gluten free diet Prior negative evaluation for celiac disease (including tissue transglutaminase IgA with total IgA or small bowel biopsies) If subjects have had a small bowel biopsies revealing increased intraepithelial lymphocytes (IELs), they will be reviewed as a separate subgroup Inclusion Criteria for Normal Subjects: No gastrointestinal diagnosis (reflux, eosinophilic esophagitis, inflammatory bowel disease, or irritable bowel syndrome) No gastrointestinal symptoms (diarrhea, abdominal pain, nausea, vomiting, weight loss) No family history of celiac disease Will not be required to have a baseline biopsy Exclusion Criteria: Tobacco use Symptomatic coronary disease Active, severe pulmonary disease Baseline oxygen requirement Coagulopathy (INR>1.5) Mastocytosis Active H. pylori infection Treated celiac disease with neutrophilia or eosinophilia secondary to infection Diabetes (type 1 and type 2) Crohn's disease or Ulcerative colitis Microscopic colitis Dermatitis herpetiformis Gastroparesis Pregnant women Subjects exposed to the following medications during their respective time frames will be excluded: NSAIDs (24 hours) Leukotriene inhibitors (24 hours) Mast cell stabilizers (24 hours) Benzodiazepines (24 hours) H2 blockers (2 days) H1 blockers (7 days) Steroids (systemic or topically active within gastrointestinal tract) (30 days) Topical steroids (14 days) Intermittent (up to once weekly) tranquilizer (trazodone, doxepin) use (7 days) Chronic tricyclic antidepressant or tranquilizer use (trazodone, doxepin) Use of these medications will also be prohibited during the study duration (AAAAI and AAOA).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blinded, placebo-controlled oral gluten challenge
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Normal Subjects, Gluten Drink<br>Normal subjects will drink a solution containing 6 grams of gluten one time. | Dietary Supplement: Gluten<br>* Six grams of gluten will be mixed with water and Tang flavoring. Subjects will drink the mixture one time.<br>|
| Placebo Comparator: Normal Subjects, Placebo Drink<br>Normal subjects will drink a solution without gluten one time. | Dietary Supplement: Placebo<br>* Subjects will drink a mixture of rice water and Tang flavoring one time.<br>|
| Active Comparator: Celiac Subjects, Gluten Drink<br>Subjects with celiac disease will drink a solution containing 6 grams of gluten one time. | Dietary Supplement: Gluten<br>* Six grams of gluten will be mixed with water and Tang flavoring. Subjects will drink the mixture one time.<br>|
| Placebo Comparator: Celiac Subjects, Placebo Drink<br>Subjects with celiac disease will drink a solution without gluten one time. | Dietary Supplement: Placebo<br>* Subjects will drink a mixture of rice water and Tang flavoring one time.<br>|
| Active Comparator: Gluten Sensitivity, Gluten Drink<br>Subjects with non-celiac gluten sensitivity will drink a solution containing 6 grams of gluten one time. | Dietary Supplement: Gluten<br>* Six grams of gluten will be mixed with water and Tang flavoring. Subjects will drink the mixture one time.<br>|
| Placebo Comparator: Gluten Sensitivity, Placebo Drink<br>Subjects with non-celiac gluten sensitivity will drink a solution without gluten one time. | Dietary Supplement: Placebo<br>* Subjects will drink a mixture of rice water and Tang flavoring one time.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Activation of the Mucosal Innate Immune System after Oral Gluten Challenge | Small bowel biopsies will be assessed for markers of innate immune system activation: presence of granulocytes, granulocyte degranulation, products of degranulation, interleukins and cytokines involved in the innate immune system response, inflammatory mediators. | 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Mucosal Permeability after Oral Gluten Challenge | Mucosal permeability will be measure before and after oral gluten or placebo challenge with C13-mannitol lactulose urinary excretion testing. In addition, mucosal permeability will also be measured along the duodenum with a mucosal impedance probe. | Baseline and up to eight hours after gluten or placebo exposure | 
| Detection of Gluten Peptides in Urine and Stool | Urine and stool samples will be assessed for the presence of gluten peptides. This will help assess how long these tests are positive after a known gluten exposure. | Baseline and up to 72 hours after gluten or placebo exposure | 
| Rapid Onset Symptom Development after Gluten Exposure | Subjects will record the symptoms they experience after gluten or placebo exposure. The will complete a simple symptom diary every 30 minutes for the first 2 hours. | Baseline and up to 72 hours after gluten or placebo exposure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized, double-blinded, placebo-controlled trial, Oral food challenge