Clinical trial NCT06719778: Impact of Diet and Lifestyle Modification on the Intestinal Barrier Integrity in Crohn's Disease
Official title: Prospective Interventional Study to Evaluate the Impact of Diet and Lifestyle Modification on the Intestinal Barrier Integrity in Crohn's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Crohn's Disease
Keywords: integrative medicine
lifestyle modification
intestinal barrier
Mediterranean diet
inflammatory bowel disease
Confocal Laser Endomicroscopy
Crohn Disease
microbiome
nutrition
irritable bowel
Lead sponsor: Universität Duisburg-Essen
Sponsor class: OTHER
Collaborators: name: Heidelberg University
name: German Crohn's and Colitis Association (DCCV e.V.)
First posted: 2024-12-06
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The goal of this prospective interventional study is to evaluate whether the targeted avoidance of a particular food that was diagnosed to be disruptive for the intestinal barrier during confocal laser endomicroscopy (CLE) contributes significantly to stabilizing the intestinal barrier and improving abdominal symptoms, quality of life and disease activity in Crohn's Disease patients with food-related symptoms.

The main questions the study aims to answer are:

* whether a food-induced intestinal barrier disorder in Crohn's disease patients can be detected by endoscopy using confocal laser endomicroscopy (CLE) and a causal relationship with certain foods can be established.
* whether a change in diet or a targeted elimination diet can restore the defective integrity of the intestinal barrier detected by CLE.
* to examine whether a targeted avoidance of a food that was identified by CLE to trigger intestinal barrier disruption leads to a relevant improvement in symptoms, quality of life and disease activity in patients with Crohn's disease.

Participants will undergo a two-stage nutritional therapy concept based on a two-week inpatient integrative medicinal lifestyle modification program that comprises nutritional therapy, stress management strategies, mind-body medicine, herbal medicine and exercise:

* Initially, participants learn how to employ the comprehensive lifestyle modification concept and receive nutritional training on a mostly vegetarian Mediterranean wholefood diet.
* In a first stabilization phase, lasting for 3 months, participants independently apply the taught Mediterranean diet and use strategies from the comprehensive lifestyle modification program.
* In a second elimination phase, lasting for another 3 months, participants additionally avoid the particular food that was identified by CLE to induce an intestinal barrier defect.

Crohn's disease patients will:

* initially receive a clinically indicated endoscopy with CLE and food challenge to examine whether a food-induced intestinal barrier disorder is present
* return to the clinic for an optional endoscopy with CLE and food challenge after the first (stabilization) phase as well as the second (elimination) phase
* answer questionnaires at study start as well as after the first and the second study phase to analyze their quality of life, the severity of their symptoms and their disease activity
* give samples of blood, urine, stool and bile fluid as well as intestinal biopsies during regular inpatient sampling at study start as well as after the first and the second study phase
* document their intake of food and their symptoms in an App-based diary throughout the study participation

Detailed description: Background: Chronic inflammatory bowel diseases (IBD) are multifactorial diseases in which diet can have both a positive and a negative influence. While, on the one hand, a switch to a Mediterranean plant-based wholefood diet has been shown to improve symptoms, quality of life and disease activity through a better supply of anti-inflammatory micronutrients and fatty acids, on the other hand diet is perceived by around two thirds of IBD patients as a symptom trigger. The leaky gut hypothesis offers a possible mechanistic explanation of this correlation. It describes how microbial pathogens or their components, but also food can reach deeper cell layers of the intestine through intestinal barrier disorders ("leaky gut"). There, they trigger immune reactions contributing to or driving food intolerances, allergies and IBD. To date, the functional relationship between food-induced intestinal barrier disorders and symptoms in Crohn's disease (MC) patients has not been investigated due to a lack of technical feasibility. Confocal laser endomicroscopy (CLE) is the first technology that makes it possible to observe the intestinal barrier on site in the intestine during routine endoscopy in real time at 1000x magnification and thus to functionally check whether the application of certain foods has an effect on the intestinal barrier.

Aim: The aim of the presented prospective interventional study is to investigate in an inpatient initiated two-stage nutritional therapy concept whether the targeted avoidance of a food that was identified by CLE to disrupt the intestinal barrier, contributes significantly to the stabilization of the intestinal barrier and improvement of abdominal symptoms, quality of life and disease activity in MC patients with food-related symptoms when compared to a pure lifestyle modification including a mostly vegetarian Mediterranean wholefood diet.

Study design: For this purpose, 30 MC patients with suspected food-related symptoms are initially examined via CLE (during a routine esophagogastroduodenoscopy of the inflammation-free duodenum) to determine whether they react to the five most common food allergens wheat, yeast, milk, soy and egg white ("food challenge") with an intestinal barrier disorder. If a food-related intestinal barrier disorder is detected, a 2-stage nutritional therapy concept is applied. The 2-stage nutritional therapy concept consists of a stabilization phase (Phase 1) and an elimination phase (Phase 2). Phase 1 comprises a 3-month period during which the participants apply a mostly vegetarian Mediterranean whole-food diet and use strategies from an integrative medicinal lifestyle modification program that comprises nutritional therapy, stress management strategies, mind-body medicine, herbal medicine and exercise initially taught during detailed initial training at the clinic for internal and integrative medicine in Bamberg. Phase 2 comprises another 3-month period during which the participants particularly avoid the food that was identified by CLE to induce an intestinal barrier defect while they stay on the diet and apply the comprehensive lifestyle modification concept taught and applied during Phase 1. Throughout the study, participants document their nutrition and symptoms in a digital food and symptom diary with integrated questionnaire query via app. At the end of the first and the second phase, a CLE is used to check whether there is still a food-induced intestinal barrier disorder.

To assess the effect of the two therapy phases, clinical questionnaires are collected at the beginning and end of each phase (at week 0, W12, W24) to record IBD-specific, nutrition-related and general quality of life, symptoms, disease activity, fatigue and stress levels, as well as dietary behavior. In addition, blood, stool, urine, bile and biopsy samples are taken for examination. These serve to clarify mechanistic relationships between the intestinal barrier function, the microbiome, its metabolic products (metabolome), the systemic allergy status, the immune system and the inflammatory process (inflammation markers, immune cells and cytokines), and thus for the potential identification of diagnostic markers that can be used on an outpatient basis. The statistical comparison of the two phases is intended to examine whether the additional, targeted avoidance of foods identified by CLE as disruptive to the intestinal barrier can make a substantial contribution to stabilizing the intestinal barrier and improving abdominal symptoms, quality of life and disease activity in MC patients with food-related symptoms compared to a pure Mediterranean plant-based wholefood diet.

Eligibility criteria: Inclusion Criteria:

* age more than 18 years
* Crohn's Disease for at least 6 months (date of initial diagnosis)
* with suspected food-induced symptoms or irritable bowel syndrome-like symptoms (fulfils IBS-Rom-IV criteria) for at least 3 months with moderate to severe symptom severity
* stable IBD-specific medication dosage for at least 3 months \[such as 5-aminosalicylates (5-ASA), thiopurines or biologicals (therapeutic antibodies such as infliximab, adalimumab, vedolizumab, etc.)\].
* inpatient admission to the clinic for internal and integrative medicine in Bamberg for regular treatment
* clinical indication and performance of an initial esophagogastroduodenoscopy with confocal laser endomicroscopy with detection of a food-induced intestinal barrier disorder
* signed informed consent form

Exclusion Criteria:

* severe flare of Crohn's disease
* artificial intestinal outlet
* IgE-mediated type 1 allergy to CLE-tested foods (egg white, soy, milk, yeast, wheat)
* macroscopic inflammation of the duodenum (detected via endoscopy)
* pregnancy or breastfeeding
* chronic alcohol or drug abuse
* treatment with antibiotics within one month before the start of the study
* Acute or chronic infectious, inflammatory or autoimmune intestinal diseases (such as coeliac disease, Whipples disease, lambliasis, eosinophilia, ulcerative colitis, infectious enterocolitis) or other organs (such as chronic hepatitis, autoimmune hepatitis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis)
* malignant diseases affecting internal organs within the last 5 years (such as colorectal cancer, stomach cancer, pancreatic cancer, liver cancer, lung cancer, breast cancer)
* severe mental disorders that impair the participant's ability to understand or follow the study protocol (e.g. uncontrolled schizophrenia, severe bipolar disorder, severe depression)
* inability to give written consent or follow study protocols
* participation in another therapeutic study within the last 30 days (except health services research)

Primary outcomes:
measure: Improvement of the integrity of the duodenal intestinal barrier analyzed by confocal laser endomicroscopy (CLE)
timeFrame: week 0, 12, 24
Secondary outcomes:
measure: Severity of IBS symptoms by IBS-SSS (Irritable Bowel Severity scoring system)
timeFrame: week 0, 12, 24
measure: Severity of IBD-SI (Inflammatory Bowel Disease Symptom Inventory)
timeFrame: week 0, 12, 24
measure: Severity of HBI (Harvey-Bradshaw-Index)
timeFrame: week 0, 12, 24
measure: Disease-specific quality of life by IBD-Q (Inflammatory Bowel Disease Questionnaire)
timeFrame: week 0, 12, 24
measure: Diagnosis of functional bowel disorders using Rome IV criteria
timeFrame: week 0, 12, 24
measure: Assessment of health-related quality of life with the Short Form 12 Health Survey (SF-12)
timeFrame: week 0, 12, 24
measure: Assessment of the severity of the fatigue syndrome with the Multidimensional Fatigue Inventory (MFI-20)
timeFrame: week 0, 12, 24
measure: Assessment of perceived stress using the Perceived Stress Scale (PSS-10)
timeFrame: week 0, 12, 24
measure: Assessment of anxiety and depression using the Hospital Anxiety and Depression Scale (HADS)
timeFrame: week 0, 12, 24
measure: Assessment of food-related quality of life using the FR-QoL-29 questionnaire
timeFrame: week 0, 12, 24
measure: Assessment of frequency of consumption and usual portion sizes of particular food groups using the DEGS-Food Frequency Questionnaire
timeFrame: week 0, 4, 8, 12, 16, 20, 24
measure: Patient diary
timeFrame: week 0 to week 24
measure: Oesophagogastroduodenoscopy (OGD) with confocal laser endomicroscopy (CLE)
timeFrame: week 0, 12, 24
measure: Histopathological analysis of duodenal biopsies
timeFrame: week 0, 12, 24
measure: Immunohistochemical analysis of duodenal biopsies
timeFrame: week 0, 12, 24
measure: Gene expression analysis of duodenal biopsies
timeFrame: week 0, 12, 24
measure: Evaluation of the systemic inflammatory status by analysis of serum-cytokine concentrations
timeFrame: week 0, 12, 24
measure: Evaluation of the complete blood count
timeFrame: week 0, 12, 24
measure: C-reactive protein (CRP) in the blood
timeFrame: week 0, 12, 24
measure: Erythrocyte Sedimentation Rate (ESR)
timeFrame: week 0, 12, 24
measure: IgE and IgG/IgG4 screening of antibodies against typical food allergens in the serum
timeFrame: week 0
measure: anti-ASCA (anti-Saccharomyces-cerevisiae antibodies)
timeFrame: week 0
measure: Lymphocyte-transformation test (LTT)
timeFrame: week 0
measure: Flow CAST
timeFrame: week 0
measure: Phenotypic analysis of PBMCs (peripheral blood mononuclear cells) isolated from the blood
timeFrame: week 0, 12, 24
measure: Analysis of inflammatory markers in the stool (Calprotectin)
timeFrame: week 0, 12, 24
measure: Analysis of fecal biomarkers to evaluate the integrity of the intestinal barrier (Zonulin)
timeFrame: week 0, 12, 24
measure: Determination of the I-FABP concentration in the serum
timeFrame: week 0, 12, 24
measure: Determination of the fecal β-Defensin concentration
timeFrame: week 0, 12, 24
measure: Fecal microbiome analysis
timeFrame: week 0, 12, 24
measure: Analysis of fecal metabolites
timeFrame: week 0, 12, 24
measure: Metabolite profiling in the urine
timeFrame: week 0, 12, 24
measure: Analysis of the composition of bile fluid
timeFrame: week 0, 12, 24
measure: Metabolome analysis of serum samples
timeFrame: week 0, 12, 24
measure: Anamnesis
timeFrame: week 0, 12, 24
measure: Concomitant medication
timeFrame: week 0, 12, 24
measure: Medical history
timeFrame: week 0, 12, 24
measure: Social demographics
timeFrame: week 0, 12, 24
measure: Evaluation of the iron status in the blood
timeFrame: week 0, 12, 24
measure: Evaluation of the liver status in the blood
timeFrame: week 0, 12, 24
measure: Analysis of inflammatory markers in the stool (Lactoferrin)
timeFrame: week 0, 12, 24
measure: Analysis of inflammatory markers in the stool (EDN)
timeFrame: week 0, 12, 24
measure: Analysis of inflammatory markers in the stool (PMN-Elastase)
timeFrame: week 0, 12, 24
measure: Analysis of fecal biomarkers to evaluate the integrity of the intestinal barrier (α-1-Antitrypsin)
timeFrame: week 0, 12, 24
Other outcomes:
Locations:
city: Bamberg
country: Germany
facility: Sozialstiftung Bamberg
state: Bavaria
Study officials:
affiliation: Universität Duisburg-Essen
name: Jost Langhorst, Univ. Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: