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This crossover randomized controlled trial will evaluate the effects of purified gluten and whole wheat (gluten combined with amylase-trypsin inhibitors (ATIs)) on inducing intestinal and extra-intestinal symptoms in irritable bowel syndrome (IBS) patients. All participants will be put on a gluten-free diet and then challenged with muesli bars containing either purified gluten, whole wheat (gluten with ATIs), or gluten-free sham.
Irritable bowel syndrome (IBS) is a heterogenous, common gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits. Many IBS patients report symptom relief on a gluten-free diet (GFD), but it is uncertain whether gluten is the true culprit. The gluten-containing grains wheat, rye, and barley all contain amylase-trypsin inhibitors (ATIs), and a GFD is virtually ATI-free.
This double-blinded crossover randomized controlled trial aims to determine which IBS patients are affected by pure gluten and which are affected by gluten combined with ATIs. IBS patients who respond to and have been on a GFD for 3+ weeks will be randomized to receive a dietary challenge of muesli bars containing either 1) 10 g pure gluten, 2) whole wheat (containing 10 g gluten and wheat ATIs), 3) or gluten-free sham for a week followed by a 14 day washout. This will be repeated until all participants have had each dietary challenge.
The study will evaluate the effects and potential mechanisms of purified gluten and whole wheat (containing the same dose of non-purified gluten) on intestinal and extra-intestinal symptoms in IBS. It is likely that some IBS patients respond to gluten, while others respond to whole wheat containing gluten combined with wheat ATIs. Thus, this project may lead to better diagnosis and individualized dietary treatments for IBS.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Purified Gluten (10 g), Whole Wheat (containing 10 g Gluten and Wheat ATIs), Gluten-free Sham | Experimental | Participants will start on 1 week of muesli bars with 10 g purified gluten followed by 14 days washout. They will then take 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days of washout. Finally, they will have 1 week of gluten-free sham muesli bars (with nothing). |
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| Purified Gluten (10 g), Gluten-free Sham, Whole Wheat (containing 10 g Gluten and Wheat ATIs) | Experimental | Participants will start on 1 week of muesli bars with 10 g purified gluten followed by 14 days washout. They will then take 1 week of gluten-free sham muesli bars (with nothing) followed by 14 days of washout. Finally, they will have 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs). |
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| Whole Wheat (containing 10 g Gluten and Wheat ATIs), Purified Gluten (10 g), Gluten-free Sham | Experimental | Participants will start on 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days washout. They will then take 1 week of muesli bars with 10 g purified gluten followed by 14 days of washout. Finally, they will have 1 week of gluten-free sham muesli bars (with nothing). |
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| Whole Wheat (containing 10 g Gluten and Wheat ATIs), Gluten-free Sham, Purified Gluten (10 g) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Purified gluten | Other | 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. |
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| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Worsening Irritable Bowel Syndrome (IBS) Symptoms Based on IBS-SSS | Number of participants with a clinically meaningful worsening of symptoms during dietary challenge compared to sham, as defined by an increase of >50 points in the Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS). The IBS-SSS ranges from 0 to 500, with higher scores indicating greater symptom severity. A >50-point increase is considered a clinically significant worsening. | 1 week purified gluten or whole wheat (gluten+ATIs) intervention versus gluten-free sham. Outcomes were measured at baseline for Pre-Sham, Pre-Gluten and Pre-Wheat Arm/Groups and 1 week for Sham, Gluten and Wheat Arm/Groups. |
| Measure | Description | Time Frame |
|---|---|---|
| General Gastrointestinal Symptoms | Worsening of general gastrointestinal symptoms (using The Patient-Reported Outcomes Measurement Information System (PROMIS Scales) for belly pain, diarrhea, constipation, or gas & bloating) after dietary challenge compared to sham. Scores are calculated using the Scoring Service by Health Measures and range from 20-80, with medians set at 50 and a standard deviation of 10. Higher scores indicate greater symptom severity. Four PROMIS subscales are being used: Gas & Bloating, Diarrhea, Constipation, and Belly Pain. Each subscale follows the T-scale scoring range of 20-80 and will be measured independently. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Premysl Bercik, MD | McMaster University | Principal Investigator |
| Maria Ines Pinto-Sanchez, MD | McMaster University | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| McMaster University Medical Centre | Hamilton | Ontario | L8N 3Z5 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11694908 | Background | Boivin M. Socioeconomic impact of irritable bowel syndrome in Canada. Can J Gastroenterol. 2001 Oct;15 Suppl B:8B-11B. doi: 10.1155/2001/401309. | |
| 18257767 | Background | Sanger GJ, Alpers DH. Development of drugs for gastrointestinal motor disorders: translating science to clinical need. Neurogastroenterol Motil. 2008 Mar;20(3):177-84. doi: 10.1111/j.1365-2982.2008.01084.x. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Purified Gluten (10 g), Whole Wheat (Containing 10 g Gluten and Wheat ATIs), Gluten-free Sham | Participants will start on 1 week of muesli bars with 10 g purified gluten followed by 14 days washout. They will then take 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days of washout. Finally, they will have 1 week of gluten-free sham muesli bars (with nothing). Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| FG001 | Purified Gluten (10 g), Gluten-free Sham, Whole Wheat (Containing 10 g Gluten and Wheat ATIs) | Participants will start on 1 week of muesli bars with 10 g purified gluten followed by 14 days washout. They will then take 1 week of gluten-free sham muesli bars (with nothing) followed by 14 days of washout. Finally, they will have 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs). Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| FG002 | Whole Wheat (Containing 10 g Gluten and Wheat ATIs), Purified Gluten (10 g), Gluten-free Sham | Participants will start on 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days washout. They will then take 1 week of muesli bars with 10 g purified gluten followed by 14 days of washout. Finally, they will have 1 week of gluten-free sham muesli bars (with nothing). Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| FG003 | Whole Wheat (Containing 10 g Gluten and Wheat ATIs), Gluten-free Sham, Purified Gluten (10 g) | Participants will start on 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days washout. They will then take 1 week of gluten-free sham muesli bars (containing nothing) followed by 14 days of washout. Finally, they will have 1 week of muesli bars with 10 g purified gluten. Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| FG004 | Gluten-free Sham, Whole Wheat (Containing 10 g Gluten and Wheat ATIs), Purified Gluten (10 g) | Participants will start on 1 week of gluten-free sham muesli bars (with nothing) followed by 14 days washout. They will then take 1 week of muesli bars containing whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days of washout. Finally, they will have 1 week of muesli bars with 10 g purified gluten. Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because we expect that participants will feel worse even though there is no potential irritant. |
| FG005 | Gluten-free Sham, Purified Gluten (10 g), Whole Wheat (Containg 10 g Gluten and Wheat ATIs) | Participants will start on 1 week of gluten-free sham muesli bars (with nothing) followed by 14 days washout. They will then take 1 week of muesli bars with 10 g purified gluten followed by 14 days of washout. Finally, they will have 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs). Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Purified Gluten (10 g), Whole Wheat (Containing 10 g Gluten and Wheat ATIs), Gluten-free Sham | Participants will start on 1 week of muesli bars with 10 g purified gluten followed by 14 days washout. They will then take 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days of washout. Finally, they will have 1 week of gluten-free sham muesli bars (with nothing). Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Worsening Irritable Bowel Syndrome (IBS) Symptoms Based on IBS-SSS | Number of participants with a clinically meaningful worsening of symptoms during dietary challenge compared to sham, as defined by an increase of >50 points in the Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS). The IBS-SSS ranges from 0 to 500, with higher scores indicating greater symptom severity. A >50-point increase is considered a clinically significant worsening. | Posted | Count of Participants | Participants | 1 week purified gluten or whole wheat (gluten+ATIs) intervention versus gluten-free sham. Outcomes were measured at baseline for Pre-Sham, Pre-Gluten and Pre-Wheat Arm/Groups and 1 week for Sham, Gluten and Wheat Arm/Groups. |
|
Adverse event data was collected during the main study (3 months including the run-in period) and was again assessed at the post-study follow-up. Overall this was 3 months regular monitoring and then follow-up monitoring up to 1 year.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Pre-Sham | Pooled from N=28 participants. | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Kitchen knife accident | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | 1 participant had an accident with a kitchen knife during the study, requiring an extended washout period when the participant had surgery and opioids for pain during muscle recovery. This was during the washout period a week after gluten challenge. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Premysl Bercik | McMaster University | 905-525-9140 | 73495 | bercikp@mcmaster.ca |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 6, 2022 | Jun 21, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D043183 | Irritable Bowel Syndrome |
| ID | Term |
|---|---|
| D003109 | Colonic Diseases, Functional |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D005767 | Gastrointestinal Diseases |
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| ID | Term |
|---|---|
| C005703 | salicylhydroxamic acid |
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Participants will be required to be on a gluten-free diet for a period of 3 weeks before starting the study. Participants will then be randomized to take muesli bars containing either 10 g purified gluten, whole wheat (containing 10 g non-purified gluten with wheat amylase trypsin inhibitors), or gluten-free sham for 1 week followed by 2 weeks of washout, and then repeated for the two remaining dietary challenges so that at the end all participants have been on all dietary challenges. At the beginning and end of each challenge period, participants will visit the clinic to be evaluated for changes in IBS symptoms.
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The statistician will also be masked from the treatments.
| Experimental |
Participants will start on 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days washout. They will then take 1 week of gluten-free sham muesli bars (containing nothing) followed by 14 days of washout. Finally, they will have 1 week of muesli bars with 10 g purified gluten. |
|
| Gluten-free Sham, Whole Wheat (containing 10 g Gluten and Wheat ATIs), Purified Gluten (10 g) | Experimental | Participants will start on 1 week of gluten-free sham muesli bars (with nothing) followed by 14 days washout. They will then take 1 week of muesli bars containing whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days of washout. Finally, they will have 1 week of muesli bars with 10 g purified gluten. |
|
| Gluten-free Sham, Purified Gluten (10 g), Whole Wheat (containing 10 g Gluten and Wheat ATIs) | Experimental | Participants will start on 1 week of gluten-free sham muesli bars (with nothing) followed by 14 days washout. They will then take 1 week of muesli bars with 10 g purified gluten followed by 14 days of washout. Finally, they will have 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs). |
|
| Non-purified gluten (containing ATIs) | Other | 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. |
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| Sham | Other | 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the identity of this gluten-free control and randomly assigned to it. |
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| 1 week purified gluten or whole wheat (gluten+ATIs) intervention compared to gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
| Orocecal Transit | Colonic transit assessed by SHAPE study (radiopaque markers). We measured orocecal transit time according to a modified SHAPE study using radiopaque markers, clinically used to identify patients with colonic inertia. Participants consumed 1 SITZARKS capsule (Konsyl Pharmaceuticals, Easton, MD) containing 24 markers, 48 hours prior to a plain abdominal film. A technician took a plain abdominal x-ray to provide images of the number and locations of the markers remaining in the gastrointestinal tract at 48 hours. A greater number of markers (up to 24) indicates slower gastrointestinal transit while less markers (or none) indicate faster transit. The outcome was assessed at the end of each 1-week intervention period (i.e., at Week 1 for Sham, Gluten, and Wheat Arms). Due to the COVID-19 pandemic, in-person study visits were limited and the SHAPE study was only conducted in N=13 participants. | Assessed at 1 week after each intervention period (Sham, Gluten, and Wheat). |
| Anti-gliadin Antibody (AGA) Levels | Change in AGA levels after purified gluten and whole wheat (gluten+wheat ATI) challenge will be assessed by ELISA NOTE: Due to the COVID-19 pandemic, in-person, non-essential blood withdrawals were paused. Blood collection occurred pre-pandemic and after in-person visits were allowed, in a total of N=14 participants. A post-study follow-up amendment, accepted by the Hamilton integrated Research Ethics Board (HiREB), allowed post-study collection of blood samples to assess the presence of AGAs and genetic markers. | Serum AGAs were measured at baseline. |
| Gut Microbiota Profiles | This outcome was intended to assess gut microbiota profiles using 16S rRNA Illumina sequencing of stool samples collected after each 1-week intervention period. However, data for this outcome are not available. | Stool samples collected at 1 week after each intervention period (Sham, Gluten, and Wheat) |
| Genetic Predisposition for Celiac Disease | Patient HLADQ2/8 status will be assessed at baseline NOTE: Due to the COVID-19 pandemic, in-person, non-essential blood withdrawals were paused. Blood collection occurred pre-pandemic and after in-person visits were allowed, in a total of N=14 participants. A post-study follow-up, accepted by the Hamilton integrated Research Ethics Board (HiREB), allowed post-study collection of blood samples to assess the presence of AGAs and genetic markers. | Patient HLA DQ2/8 status were measured at baseline |
| Depression, Anxiety and Stress | Worsening of depression, anxiety, and stress sub-scales during dietary challenge was assessed by Depression Anxiety Stress Scale (DASS-21). The DASS-21 has 21 questions. The three subscales (depression, anxiety, and stress) are reported independently and range from 0 to 42, with higher scores indicating greater symptom severity. | 1 week purified gluten or whole wheat (gluten+ATIs) intervention compared to gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
| Somatic Symptoms | Worsening of somatic symptoms like fatigue, sleeping trouble, and pain were assessed using Patient Health Questionnaire (PHQ-15). Scores range from 0 to 30, with greater scores indicating greater severity. | 1 week purified gluten or whole wheat (gluten+ATIs) intervention compared to gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
| Stool Consistency | Stool consistency was assessed by Bristol Stool Scale. Types 1 and 2 indicate harder stools, types 3, 4, and 5 are normal, and types 6 and 7 indicate runnier, more liquid stool. | 1 week purified gluten or whole wheat (gluten+ATIs) intervention compared to gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
| Gluten Levels in Stool | Presence of gluten in stool samples was assessed to evaluate dietary compliance using an ELISA for gluten immunogenic peptides (GIP), measured in micrograms per gram of stool (μg/g). Stool samples were collected at the end of each 1-week intervention period (i.e., at Week 1 for Sham, Gluten, and Wheat). The values reported reflect GIP concentration at the end of each intervention. | Assessed at 1 week after each intervention period (Sham, Gluten, and Wheat). |
| Diet Assessment | This outcome was intended to assess dietary intake and compliance during each 1-week intervention period using the MealLogger app. Participants were instructed to take pictures of all meals during each intervention week to support dietary tracking and adherence monitoring. However, image analysis was not performed and data for this outcome are not available. | During each 1-week intervention period (Sham, Gluten, and Wheat). |
| IBS Symptom Duration | Evaluates symptom duration at the end of the diet challenge using the IBS-SSS. The overall score ranges from 0-500 in total, with each of the 5 questions ranging from 0 to 100. A higher score indicates higher symptom severity and the total score is summed. | Completed daily for 7 days after each diet challenge |
| Systemic Immune Reactivity | This outcome was intended to assess changes in pro-inflammatory cytokines (TNF-α, IL-8, and IFN-γ) using ex vivo peripheral blood mononuclear cell (PBMC) stimulation in a subset of participants. Blood was collected at baseline and after each 1-week dietary intervention (Sham, Gluten, and Wheat) to isolate PBMCs. However, due to the COVID-19 pandemic and the limited clinical phenotype observed, PBMC samples (N=11) were not analyzed. No outcome data are available. | Blood collected at baseline and post-intervention for each 1-week dietary period (Sham, Gluten, and Wheat). |
| Long-term Gluten-free Diet Adherence | At study completion and unblinding, the researchers compiled the study results (ex., worsening in IBS symptoms after gluten challenge) and provided this information to study participants after their study completion. An expert interview-based gluten-free diet assessment used previously in the study was conducted with study participants immediately prior and one month after. This amendment was approved by the Hamilton Ethics Board in June 2022 and was based on participant requests. We used the same gluten-free diet assessment as the primary study. We included new pre- and post-disclosure surveys to ask about current diet habits, beliefs surrounding wheat/gluten sensitivity, and how their behaviours would change after results disclosure. | At least 6-months (up to 41 months) after primary study completion, followed by 1+ months after study result disclosure. |
| Psychological and Gastrointestinal Symptoms After Learning Diet Triggers and Genetic Results (Unblinding Participants to Diet Triggers During Post-study Follow-up) | At study completion and unblinding, the team compiled the study results (ex., worsening in IBS symptoms after challenges) and provided this information to participants. Previous study surveys were sent to participants immediately prior and 1 month after. We used the following outcomes:
For greater detail, see above secondary outcome measure descriptions. | At least 6-months (up to 41 months) after primary study completion, followed by 1+ months after study result disclosure. |
| Irritable Bowel Syndrome (IBS) Symptoms (Continuous) | Worsening of IBS symptoms (using Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS)) during dietary challenge compared to sham. The overall score ranges from 0-500 in total, with each of the 5 questions ranging from 0 to 100. A higher score indicates higher symptom severity and the total score is summed. An increase in >50 points indicates worsening of symptoms. | 1 week purified gluten or whole wheat (gluten+ATIs) intervention versus gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
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| 22489905 | Background | McKenzie YA, Alder A, Anderson W, Wills A, Goddard L, Gulia P, Jankovich E, Mutch P, Reeves LB, Singer A, Lomer MC; Gastroenterology Specialist Group of the British Dietetic Association. British Dietetic Association evidence-based guidelines for the dietary management of irritable bowel syndrome in adults. J Hum Nutr Diet. 2012 Jun;25(3):260-74. doi: 10.1111/j.1365-277X.2012.01242.x. Epub 2012 Apr 10. |
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| 21683077 | Background | Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011 Aug;141(2):599-609, 609.e1-3. doi: 10.1053/j.gastro.2011.04.052. Epub 2011 Apr 30. |
| 27426486 | Background | Volta U, Pinto-Sanchez MI, Boschetti E, Caio G, De Giorgio R, Verdu EF. Dietary Triggers in Irritable Bowel Syndrome: Is There a Role for Gluten? J Neurogastroenterol Motil. 2016 Oct 30;22(4):547-557. doi: 10.5056/jnm16069. |
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| 40706614 | Derived | Seiler CL, Rueda GH, Miranda PM, Nardelli A, Borojevic R, Hann A, Rahmani S, De Souza R, Caminero A, Curella V, Neerukonda M, Vanner S, Schuppan D, Moayyedi P, Collins SM, Verdu EF, Pinto-Sanchez MI, Bercik P. Effect of gluten and wheat on symptoms and behaviours in adults with irritable bowel syndrome: a single-centre, randomised, double-blind, sham-controlled crossover trial. Lancet Gastroenterol Hepatol. 2025 Sep;10(9):794-805. doi: 10.1016/S2468-1253(25)00090-1. Epub 2025 Jul 21. |
| BG001 | Purified Gluten (10 g), Gluten-free Sham, Whole Wheat (Containing 10 g Gluten and Wheat ATIs) | Participants will start on 1 week of muesli bars with 10 g purified gluten followed by 14 days washout. They will then take 1 week of gluten-free sham muesli bars (with nothing) followed by 14 days of washout. Finally, they will have 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs). Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| BG002 | Whole Wheat (Containing 10 g Gluten and Wheat ATIs), Purified Gluten (10 g), Gluten-free Sham | Participants will start on 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days washout. They will then take 1 week of muesli bars with 10 g purified gluten followed by 14 days of washout. Finally, they will have 1 week of gluten-free sham muesli bars (with nothing). Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| BG003 | Whole Wheat (Containing 10 g Gluten and Wheat ATIs), Gluten-free Sham, Purified Gluten (10 g) | Participants will start on 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days washout. They will then take 1 week of gluten-free sham muesli bars (containing nothing) followed by 14 days of washout. Finally, they will have 1 week of muesli bars with 10 g purified gluten. Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| BG004 | Gluten-free Sham, Whole Wheat (Containing 10 g Gluten and Wheat ATIs), Purified Gluten (10 g) | Participants will start on 1 week of gluten-free sham muesli bars (with nothing) followed by 14 days washout. They will then take 1 week of muesli bars containing whole wheat (containing 10 g non-purified gluten and wheat ATIs) followed by 14 days of washout. Finally, they will have 1 week of muesli bars with 10 g purified gluten. Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| BG005 | Gluten-free Sham, Purified Gluten (10 g), Whole Wheat (Containing 10 g Gluten and Wheat ATIs) | Participants will start on 1 week of gluten-free sham muesli bars (with nothing) followed by 14 days washout. They will then take 1 week of muesli bars with 10 g purified gluten followed by 14 days of washout. Finally, they will have 1 week of muesli bars with whole wheat (containing 10 g non-purified gluten and wheat ATIs). Purified gluten: 1 low FODMAPs, vegan muesli bar containing purified gluten per day for 1 week, for a total of 10 g purified gluten per day. Non-purified gluten (containing ATIs): 1 low FODMAPs, vegan muesli bar containing whole wheat flour with non-purified gluten per day for 1 week, for a total of 10 g non-purified gluten per day. Sham: 1 gluten-free, ATI-free, low FODMAPs, vegan muesli bar per day for 1 week. This is a sham because participants were blinded to the gluten-free control. |
| BG006 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Country of Birth | Count of Participants | Participants |
|
| Smoker status | Count of Participants | Participants |
|
| Gluten-free diet adherence | Count of Participants | Participants |
|
| Anti-gliadin antibodies IgG | Count of Participants | Participants |
|
| IBS-SSS (Continuous Score) | Change in IBS symptoms (using Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS) during dietary challenge compared to sham. The overall score ranges from 0-500 in total, with each of the 5 questions ranging from 0 to 100. A higher score indicates higher symptom severity and the total score is summed. Baseline IBS-SSS was collected for each participant before they were challenged with wheat, gluten, or gluten-free sham. | Mean | Standard Deviation | units on a scale |
|
| Gluten |
Pooled from N=28 participants. |
| OG002 | Wheat | Pooled from N=28 participants. |
|
|
| Secondary | General Gastrointestinal Symptoms | Worsening of general gastrointestinal symptoms (using The Patient-Reported Outcomes Measurement Information System (PROMIS Scales) for belly pain, diarrhea, constipation, or gas & bloating) after dietary challenge compared to sham. Scores are calculated using the Scoring Service by Health Measures and range from 20-80, with medians set at 50 and a standard deviation of 10. Higher scores indicate greater symptom severity. Four PROMIS subscales are being used: Gas & Bloating, Diarrhea, Constipation, and Belly Pain. Each subscale follows the T-scale scoring range of 20-80 and will be measured independently. | Posted | Median | 95% Confidence Interval | score on a scale | 1 week purified gluten or whole wheat (gluten+ATIs) intervention compared to gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
|
|
|
| Secondary | Orocecal Transit | Colonic transit assessed by SHAPE study (radiopaque markers). We measured orocecal transit time according to a modified SHAPE study using radiopaque markers, clinically used to identify patients with colonic inertia. Participants consumed 1 SITZARKS capsule (Konsyl Pharmaceuticals, Easton, MD) containing 24 markers, 48 hours prior to a plain abdominal film. A technician took a plain abdominal x-ray to provide images of the number and locations of the markers remaining in the gastrointestinal tract at 48 hours. A greater number of markers (up to 24) indicates slower gastrointestinal transit while less markers (or none) indicate faster transit. The outcome was assessed at the end of each 1-week intervention period (i.e., at Week 1 for Sham, Gluten, and Wheat Arms). Due to the COVID-19 pandemic, in-person study visits were limited and the SHAPE study was only conducted in N=13 participants. | Posted | Median | 95% Confidence Interval | number of radiopaque markers at 48h | Assessed at 1 week after each intervention period (Sham, Gluten, and Wheat). |
|
|
|
| Secondary | Anti-gliadin Antibody (AGA) Levels | Change in AGA levels after purified gluten and whole wheat (gluten+wheat ATI) challenge will be assessed by ELISA NOTE: Due to the COVID-19 pandemic, in-person, non-essential blood withdrawals were paused. Blood collection occurred pre-pandemic and after in-person visits were allowed, in a total of N=14 participants. A post-study follow-up amendment, accepted by the Hamilton integrated Research Ethics Board (HiREB), allowed post-study collection of blood samples to assess the presence of AGAs and genetic markers. | Posted | Count of Participants | Participants | Serum AGAs were measured at baseline. |
|
|
|
| Secondary | Gut Microbiota Profiles | This outcome was intended to assess gut microbiota profiles using 16S rRNA Illumina sequencing of stool samples collected after each 1-week intervention period. However, data for this outcome are not available. | Stool samples were collected for gut microbiota analysis; however, due to resource limitations and shifting study priorities, these samples were not analyzed and will not be analyzed in the future. As a result, no data are available for this outcome. | Posted | Count of Participants | Participants | Stool samples collected at 1 week after each intervention period (Sham, Gluten, and Wheat) |
|
|
| Secondary | Genetic Predisposition for Celiac Disease | Patient HLADQ2/8 status will be assessed at baseline NOTE: Due to the COVID-19 pandemic, in-person, non-essential blood withdrawals were paused. Blood collection occurred pre-pandemic and after in-person visits were allowed, in a total of N=14 participants. A post-study follow-up, accepted by the Hamilton integrated Research Ethics Board (HiREB), allowed post-study collection of blood samples to assess the presence of AGAs and genetic markers. | Posted | Count of Participants | Participants | Patient HLA DQ2/8 status were measured at baseline |
|
|
|
| Secondary | Depression, Anxiety and Stress | Worsening of depression, anxiety, and stress sub-scales during dietary challenge was assessed by Depression Anxiety Stress Scale (DASS-21). The DASS-21 has 21 questions. The three subscales (depression, anxiety, and stress) are reported independently and range from 0 to 42, with higher scores indicating greater symptom severity. | Posted | Median | 95% Confidence Interval | score on a scale | 1 week purified gluten or whole wheat (gluten+ATIs) intervention compared to gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
|
|
|
| Secondary | Somatic Symptoms | Worsening of somatic symptoms like fatigue, sleeping trouble, and pain were assessed using Patient Health Questionnaire (PHQ-15). Scores range from 0 to 30, with greater scores indicating greater severity. | Posted | Median | 95% Confidence Interval | score on a scale | 1 week purified gluten or whole wheat (gluten+ATIs) intervention compared to gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
|
|
|
| Secondary | Stool Consistency | Stool consistency was assessed by Bristol Stool Scale. Types 1 and 2 indicate harder stools, types 3, 4, and 5 are normal, and types 6 and 7 indicate runnier, more liquid stool. | Posted | Median | 95% Confidence Interval | units on a scale (Bristol stool scale) | 1 week purified gluten or whole wheat (gluten+ATIs) intervention compared to gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
|
|
|
| Secondary | Gluten Levels in Stool | Presence of gluten in stool samples was assessed to evaluate dietary compliance using an ELISA for gluten immunogenic peptides (GIP), measured in micrograms per gram of stool (μg/g). Stool samples were collected at the end of each 1-week intervention period (i.e., at Week 1 for Sham, Gluten, and Wheat). The values reported reflect GIP concentration at the end of each intervention. | Posted | Median | 95% Confidence Interval | micrograms per gram of stool | Assessed at 1 week after each intervention period (Sham, Gluten, and Wheat). |
|
|
|
| Secondary | Diet Assessment | This outcome was intended to assess dietary intake and compliance during each 1-week intervention period using the MealLogger app. Participants were instructed to take pictures of all meals during each intervention week to support dietary tracking and adherence monitoring. However, image analysis was not performed and data for this outcome are not available. | Dietary images were collected using the MealLogger app; however, due to resource limitations and changing study priorities, the images were not analyzed and will not be analyzed in the future. No outcome data are available. | Posted | Count of Participants | Participants | During each 1-week intervention period (Sham, Gluten, and Wheat). |
|
|
| Secondary | IBS Symptom Duration | Evaluates symptom duration at the end of the diet challenge using the IBS-SSS. The overall score ranges from 0-500 in total, with each of the 5 questions ranging from 0 to 100. A higher score indicates higher symptom severity and the total score is summed. | Posted | Mean | Standard Deviation | score on a scale | Completed daily for 7 days after each diet challenge |
|
|
|
| Secondary | Systemic Immune Reactivity | This outcome was intended to assess changes in pro-inflammatory cytokines (TNF-α, IL-8, and IFN-γ) using ex vivo peripheral blood mononuclear cell (PBMC) stimulation in a subset of participants. Blood was collected at baseline and after each 1-week dietary intervention (Sham, Gluten, and Wheat) to isolate PBMCs. However, due to the COVID-19 pandemic and the limited clinical phenotype observed, PBMC samples (N=11) were not analyzed. No outcome data are available. | PBMC samples were collected from 11 participants at baseline and after each intervention; however, due to the limited clinical changes observed and high cost of analysis, cytokine stimulation assays were not performed and will not be completed in the future. As such, no data are available for this outcome. | Posted | Count of Participants | Participants | Blood collected at baseline and post-intervention for each 1-week dietary period (Sham, Gluten, and Wheat). |
|
|
|
| Secondary | Long-term Gluten-free Diet Adherence | At study completion and unblinding, the researchers compiled the study results (ex., worsening in IBS symptoms after gluten challenge) and provided this information to study participants after their study completion. An expert interview-based gluten-free diet assessment used previously in the study was conducted with study participants immediately prior and one month after. This amendment was approved by the Hamilton Ethics Board in June 2022 and was based on participant requests. We used the same gluten-free diet assessment as the primary study. We included new pre- and post-disclosure surveys to ask about current diet habits, beliefs surrounding wheat/gluten sensitivity, and how their behaviours would change after results disclosure. | We used the gluten-free diet adherence survey (PMID: 19268725) with expert-assessed gluten-free diet adherence grouped into: excellent, good, fair, poor, very poor, and no gluten-free diet adherence. | Posted | Count of Participants | Participants | At least 6-months (up to 41 months) after primary study completion, followed by 1+ months after study result disclosure. |
|
|
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| Secondary | Psychological and Gastrointestinal Symptoms After Learning Diet Triggers and Genetic Results (Unblinding Participants to Diet Triggers During Post-study Follow-up) | At study completion and unblinding, the team compiled the study results (ex., worsening in IBS symptoms after challenges) and provided this information to participants. Previous study surveys were sent to participants immediately prior and 1 month after. We used the following outcomes:
For greater detail, see above secondary outcome measure descriptions. | Posted | Mean | Standard Deviation | score on a scale | At least 6-months (up to 41 months) after primary study completion, followed by 1+ months after study result disclosure. |
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| Secondary | Irritable Bowel Syndrome (IBS) Symptoms (Continuous) | Worsening of IBS symptoms (using Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS)) during dietary challenge compared to sham. The overall score ranges from 0-500 in total, with each of the 5 questions ranging from 0 to 100. A higher score indicates higher symptom severity and the total score is summed. An increase in >50 points indicates worsening of symptoms. | Posted | Median | 95% Confidence Interval | score on a scale (IBS-SSS) | 1 week purified gluten or whole wheat (gluten+ATIs) intervention versus gluten-free sham. Outcomes were measured at 1 week for Sham, Gluten and Wheat Arm/Groups. |
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| Post-Hoc | Post-hoc Comparison by Participant Believed Challenges | We collected participant beliefs of what they consumed post-challenges to assess that they were effectively blinded. After challenges, participants reported whether they believed they consumed: (1) whole wheat; (2) purified gluten; (3) gluten-free sham; or (4) an unknown challenge (they were unsure what they consumed). | The total number of responses was for 28 participants times 3 challenges = 84 reported beliefs after challenges. Of these, 43/84=51% were unsure what challenge they took, 13/84=15% believed they took a gluten-free sham, 16/84=19% believed they took a purified gluten challenge, and 12/84=14% believed they took a whole wheat challenge. The participants were confirmed to be blinded. | Posted | Count of Participants | Participants | 1 week purified gluten or whole wheat (gluten+ATIs) intervention compared to gluten-free sham. Outcomes were measured at baseline for Pre-Sham, Pre-Gluten and Pre-Wheat Arm/Groups and 1 week for Sham, Gluten and Wheat Arm/Groups. |
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| 28 |
| 0 |
| 28 |
| 0 |
| 28 |
| EG001 | Sham | Pooled from N=28 participants. | 0 | 28 | 0 | 28 | 0 | 28 |
| EG002 | Pre-Gluten | Pooled from N=28 participants. | 0 | 28 | 0 | 28 | 0 | 28 |
| EG003 | Gluten | Pooled from N=28 participants. | 0 | 28 | 1 | 28 | 0 | 28 |
| EG004 | Pre-Wheat | Pooled from N=28 participants. | 0 | 28 | 0 | 28 | 0 | 28 |
| EG005 | Wheat | Pooled from N=28 participants. | 0 | 28 | 0 | 28 | 0 | 28 |
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Not provided
Not provided
| D004066 | Digestive System Diseases |
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| Constipation |
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| Diarrhea |
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| HLA DQ7 |
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| HLA DQ8 heterozygous |
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| Negative |
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| Not measured |
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| Stress |
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| Post-challenge (Day 8) |
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| Post-challenge (Day 9) |
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| Post-challenge (Day 10) |
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| Post-challenge (Day 11) |
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| Post-challenge (Day 12) |
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| Post-challenge (Day 13) |
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| Post-challenge (Day 14) |
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| Fair |
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| Poor |
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| Very Poor |
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| No gluten-free diet |
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| PROMIS (Diarrhea) |
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| PROMIS (Constipation) |
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| PROMIS (Bloating & Gas) |
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| DASS-Depression |
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| DASS-Anxiety |
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| DASS-Stress |
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| PHQ15 (Somatization) |
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| Guessed Gluten-Free Sham Challenge |
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| Unsure guess |
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