Biomarkers of Diet-microbiota Interactions in Irritable Bowel Syndrome

Study Overview
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Brief Summary
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Most patients suffering from the irritable bowel syndrome (IBS) report that ingestion of certain foods is a major trigger of symptoms, but the reason is unclear. Previous studies have shown that foods containing poorly absorbed carbohydrates (FODMAPs) are fermented by the bacteria in our bowels and these cause symptoms in some but not all patients. Gut bacteria are capable of producing various products, such as neuroimmune mediator histamine, that may be related to IBS symptoms. Our recent data suggest that consumption of FODMAPs promotes production of bacterial histamine. The main objective of this study is to investigate bacterial production of histamine and its relationship to IBS symptoms. The study will involve 6 weeks on a low-FODMAP diet with three three-day interventions consisting of High- or Low-FODMAP drinks along with probiotics or placebo capsules. The patient's bacteria and metabolites will be analyzed at various time points.

Official Title
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Biomarkers of Diet-microbiota Interactions in Irritable Bowel Syndrome

Conditions
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Irritable Bowel Syndrome

Intervention / Treatment
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* Dietary Supplement: L-Histidine
* Dietary Supplement: High-FODMAP beverage
* Dietary Supplement: Low-FODMAP beverage
* Dietary Supplement: Lactobacillus acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2.
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged 18-75 with IBS (Rome IV criteria) who have self-reported previous improvement in their IBS symptoms while on a low FODMAP diet, or when excluding certain high-FODMAP foods, or patients in whom histamine is expected to play a key role (either diagnosed with high histamine producing bacteria, or improved IBS symptoms after using antihistamines). Individuals should be able to swallow size 00 capsules. Exclusion Criteria: Concurrent significant organic GI pathology (i.e. celiac, IBD, etc.) Concurrent systemic disease (such as diabetes) and/or laboratory abnormalities considered by investigators to be risky or that could interfere with data collection History of active cancer in the last 5 years, other than basal cell cancer Pregnant or breastfeeding women Active or recent participation (< 1 month) in a clinical study, except for SPOR IMAGINE Use of antibiotics, probiotics, or ACE inhibitors during, or one month prior to the study Use of new medications less than 4 weeks prior to the study. Allergies to any of the ingredients used in the study Any immune-compromising conditions

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Participants in group A will undergo challenges in the order: High-FODMAP beverage + placebo probiotic + L-Histidine Low-FODMAP beverage + placebo probiotic + L-Histidine High-FODMAP beverage + probiotic + L-Histidine Challenges each last 5 days, but the FODMAP drinks and the L-Histidine capsules are only taken for the last three days. There is a 10 day washout period between challenges. | Dietary Supplement: L-Histidine<br>* 1 capsule (0.6g) twice daily<br>Dietary Supplement: High-FODMAP beverage<br>* High-FODMAP beverage (10g of fermentable carbohydrates) consumed twice daily.<br>Dietary Supplement: Low-FODMAP beverage<br>* Low-FODMAP beverage (10g glucose) consumed twice daily.<br>Dietary Supplement: Lactobacillus acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2.<br>* Total of 50 billion CFU/capsule taken twice daily.<br>* Other names: Bio-K+ 50 Billion;Other: Placebo<br>* Enteric coated capsule with no active ingredient, taken twice daily<br>|
| Experimental: Group B<br>Participants in group A will undergo challenges in the order: Low-FODMAP beverage + placebo probiotic + L-Histidine High-FODMAP beverage + probiotic + L-Histidine High-FODMAP beverage + placebo probiotic + L-Histidine. Challenges each last 5 days, but the FODMAP drinks and the L-Histidine capsules are only taken for the last three days. There is a 10 day washout period between challenges. | Dietary Supplement: L-Histidine<br>* 1 capsule (0.6g) twice daily<br>Dietary Supplement: High-FODMAP beverage<br>* High-FODMAP beverage (10g of fermentable carbohydrates) consumed twice daily.<br>Dietary Supplement: Low-FODMAP beverage<br>* Low-FODMAP beverage (10g glucose) consumed twice daily.<br>Dietary Supplement: Lactobacillus acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2.<br>* Total of 50 billion CFU/capsule taken twice daily.<br>* Other names: Bio-K+ 50 Billion;Other: Placebo<br>* Enteric coated capsule with no active ingredient, taken twice daily<br>|
| Experimental: Group C<br>Participants in group A will undergo challenges in the order: High-FODMAP beverage + probiotic + L-Histidine High-FODMAP beverage + placebo probiotic + L-Histidine Low-FODMAP beverage + placebo probiotic + L-Histidine. Challenges each last 5 days, but the FODMAP drinks and the L-Histidine capsules are only taken for the last three days. There is a 10 day washout period between challenges. | Dietary Supplement: L-Histidine<br>* 1 capsule (0.6g) twice daily<br>Dietary Supplement: High-FODMAP beverage<br>* High-FODMAP beverage (10g of fermentable carbohydrates) consumed twice daily.<br>Dietary Supplement: Low-FODMAP beverage<br>* Low-FODMAP beverage (10g glucose) consumed twice daily.<br>Dietary Supplement: Lactobacillus acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2.<br>* Total of 50 billion CFU/capsule taken twice daily.<br>* Other names: Bio-K+ 50 Billion;Other: Placebo<br>* Enteric coated capsule with no active ingredient, taken twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolites in stool, urine and blood | Metabolites will be measured by LC-MS and ELISA at baseline and before and after each intervention. | six weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression of hdc gene by stool bacteria | Gram-positive and Gram-negative bacteria will be assessed by PCR using custom designed primers | six weeks | 
| Stool microbiota composition | 16S rRNA Illumina sequencing of stool samples with culture-enriched sequencing. | six weeks | 
| Worsening of IBS symptoms following High-FODMAP challenge | Increase by ≥50 points on IBS Symptom Severity Score (IBS-SSS). The score will be used as a dichotomous variable. The overall score ranges from 0 to 500, with higher scores indicating greater symptom severity. | six weeks | 
| Changes in IBS symptoms | IBS-SSS continuous data. The overall score ranges from 0 to 500, with higher scores indicating greater symptom severity. | six weeks | 
| Changes in general GI symptoms | Patient-Reported Outcomes Measurement Information System (PROMIS) for general GI symptoms. Four subscales will be used: Gas & Bloating, Diarrhea, Constipation, and Belly Pain. T-scores are calculated using the Scoring Service by Health Measures and range from 34.7 - 79.0 (Gas & Bloating), 39.9 - 75.2 (Diarrhea), 40.6 - 80.8 (Constipation), and 33.9 - 80.0 (Belly Pain). On this scale, 50 indicates the mean of the general population and a difference of 10 is a standard deviation. Higher scores indicate greater symptom severity. | six weeks | 
| Levels of anxiety, depression and stress | Depression Anxiety Stress Scale (DASS-21) to assess psychiatric comorbidity and stress. The scale scores range from 0 - 42 with higher scores indicating worse outcomes. | six weeks | 
| Changes in dietary intake | 5-day food diaries will be completed at 5 time points. FODMAP intake will be quantified using Monash University software and database | six weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FODMAP, microbiota, histamine