Prevention of Inflammatory Bowel Diseases in Persons at Risk The PIONIR (Preventing IBD Onset in Individuals at Risk) Trial

Study Overview
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Brief Summary
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The goal of this study is to explore in a cross over randomized controlled trial, the ability of the Tasty&Healthy dietary intervention (NCT04239248) to alter the parameters associated with future risk of developing Chron's disease (CD) using subjects identified in the Genetic Environmental Microbiome (GEM) Study as having a high-risk score. Specifically, the investigators aim to determine if the Tasty&Healthy dietary intervention can decrease the overall GEM Risk Score (GRS) and/or to alter the individual biological parameters that contribute to this score. The investigators hypothesize that the Tasty&Healthy dietary approach will alter the risk of CD as reflected by a decrease in the GRS.

Detailed Description
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Several important factors associated with CD onset have already been identified in the GEM analyses, such as elevated faecal calprotectin(FC),altered gut permeability, proteomics, anti-microbial serology, and microbiome composition. These parameters are combined into the GEM Risk Score (GRS). The first-line therapy in children with CD, according to ECCO/ESPGHAN guidelines, is exclusive enteral nutrition (EEN), meaning 8-12 weeks of exclusive liquid formula. Nutritional therapy may alter intestinal inflammation by several mechanisms, including modulation of the microbiome and an effect on intestinal permeability, both factors assessed in the GEM cohort. EEN is safe and effective, but it is challenging to implement. Several diets, based on solid foods, have been proposed as alternatives to EEN in an attempt to increase feasibility, three of which have the most data. Specific carbohydrate diet (SCD) restricts carbohydrates and processed foods and has been long used with variable reported effectiveness. The CD-TREAT diet induced a positive change to the microbiome, children with active CD entered clinical remission with decreased inflammatory markers. Crohn's Disease Exclusion Diet (CDED) is based on the exclusion of processed and pro-inflammatory foods, similar to Tasty&Healthy. A recent RCT of CDED diet with 50% liquid formula showed comparable effectiveness as EEN, including normalization of FC and positive effect on the microbiome. However, the allowed dietary components are not liberal, and the diet is rigid, making it unsuitable as a prevention measure. In 2014, a cook-book named Tasty&Healthy was published as a simple approach to dietary treatment based on the best available evidence. A steering committee of physicians experienced in IBD and nutrition, as well as leading IBD dieticians, reviewed results of dietary studies from animal models, humans and epidemiological cohorts. This review resulted in agreed-upon foods that may aggravate inflammation and thus should be excluded, including all processed and industrialized food, animal fat (dairy, meat), gluten and sugar. Overall, allowed foods in liberal quantities are those prepared at home from readily available ingredients such as fruits, vegetables, fish and shellfish, poultry, oats, eggs, non-gluten grains and legumes. Tasty&Healthy is not a specific diet; it is a dietary approach in which the allowed foods are not structured or restricted. This approach allows flexibility to increase adherence In this study, The Investigators hypothesize that the Tasty&Healthy dietary approach will alter the risk of CD as reflected by a decrease in the GEM CD risk score or alteration of its individual components.

Official Title
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Preventing IBD Onset in Individuals at Risk

Conditions
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Inflammatory Bowel Diseases

Intervention / Treatment
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* Other: Tasty&Healthy
* Other: Habitual diet


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Clinically healthy subjects (i.e. lack of symptoms that may suggest IBD) that are enrolled to the GEM project, with a high faecal calprotectin (FC)>70μg/g or chrons multiplex or elevated GRS score or increased microbiome risk score. Younger than 36 years of age, in order to maximize future risk of developing CD. No overt ulcerations (other than aphthous ulcerations) in the colon. Exclusion Criteria: Ulcerative colitis (UC) or IBD-unclassified (IBDU) diagnosis The use of antibiotics in the preceding month Prior intestinal resection Pregnancy (and up until six months after giving birth) Celiac disease or Diabetes Weight loss or weight gain by more than 20% body weight in the last 3 months Extraintestinal manifestations (Arthritis/arthralgia, iritis/uveitis, skin/mouth lesions, peri-anal disease, Other fistula). Underweight (children <3th BMI percentile, adult above the age of 18 years: BMI<18.5 kg/m2).

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 35 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Tasty&Healthy<br>Tasty&Healthy intervention: subjects will receive dietary advice to exclude pro-inflammatory dietary components | Other: Tasty&Healthy<br>* exclude pro-inflammatory dietary components<br>|
| Other: Habitual diet<br>Habitual diet: subjects will continue their habitual diet. | Other: Habitual diet<br>* subjects will continue their habitual diet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The likelihood to develop CD measured by the GRS scale. | Several important factors associated with CD onset have already been identified in the GEM analyses, such as elevated fecal calprotectin (FC), altered gut permeability, proteomics, anti-microbial serology, and microbiome composition. These parameters are potentially modifiable and will be combined into a model to construct the GEM Risk Score (GRS). The range of the GRS is 60.54682691 or higher. The higher the GRS score there is an increased chance of developing Chron's dis. | 8 weeks of Tasty&Healthy diet. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FC decreased by >30% at the end of the Tasty&Healthy intervention, compared to the FC before the intervention. | Decreased level of fecal calprotectin with at least 30% decline from baseline. fecal calprotectin is a test used to detect inflammation in the gastrointestinal tract and is associated with Crohn's disease onset. | 8 weeks of Tasty&Healthy diet. | 
| Microbiome risk score (MRS) Change in one standard deviation. | Decreased level of Microbiome risk score with at least one standard deviation decline from baseline. The Microbiome risk score is a test we develop to classify individuals according to their risk to develop Crohn's disease onset. | 8 weeks of Tasty&Healthy diet. | 
| Lactulose-Mannitol Ratio (LMR) Change in one standard deviation. | Decreased level of urinary fractional excretion ratio of Lactulose to Mannitol (LMR) with at least one standard deviation decline from baseline. The LMR is an in vivo test that allow quantification of intestinal barrier permeability that is associated with risk to develop Crohn's disease. | 8 weeks of Tasty&Healthy diet. | 
| Change in Serum Metabolomics pre and post-intervention | Change in levels of stool, urine, and serum metabolites with at least one standard deviation difference from baseline. Metabolomics allow assessment of host chemical processes involving metabolites, small molecule substrates, intermediates and products of cell or microbial metabolism. Unit of measure is raw area count rescaled to set the median equal to 1. | 8 weeks of Tasty&Healthy diet. | 
| Change in Serum Proteomics pre and post-intervention | Change in serum proteomics with at least one standard deviation different from baseline. Proteomics allows to assess initiators of most biological processes such as enzymes, cytokines, and transcription factors that contribute to Crohn's disease onset. Unit of measure is normalized protein expression. | 8 weeks of Tasty&Healthy diet. | 
| Change in Serology pre and post-intervention | Change in antimicrobial antibodies response with at least one standard deviation different from baseline. Serum antimicrobial antibodies allows to assess the immune response against commensal bacteria that are associated with risk of Crohn's disease onset. Unit of measure is titer. | 8 weeks of Tasty&Healthy diet. | 
| Ability to maintain a balanced diet as measured by food diaries. | Will be assessed by daily caloric intake and nutritional components. | 8 weeks of Tasty&Healthy diet. | 
| Adherence with the interventions, including assessment of faecal gluten. | Will be assessed using ELISA kit- Buhlman fCAL Elisa | 8 weeks of Tasty&Healthy diet. | 
| Satisfaction with the treatment received, as assessed by the Satisfaction with Food-Related Life (SFRL) questionnaire. | Will be assessed by the SFRL questionnaire - Grunert KG, Dean M, Raats MM, Nielsen NA, Lumbers M; Food in Later Life Team. A measure of satisfaction with food-related life. Appetite. 2007 Sep;49(2):486-93. doi: 10.1016/j.appet.2007.03.010. Epub 2007 Mar 24. PMID: 17481776. | 8 weeks of Tasty&Healthy diet. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chron