Clinical trial NCT06698601: Wild Blueberries in Colitis
Official title: Impact of Wild Blueberries (Vaccinium Myrtillus) on the Intestinal Barrier, Microbiome and Inflammation in Chronic Colitis - a Prospective Randomized Crossover Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Ulcerative Colitis (UC)
Crohn Disease (CD)
Keywords: ulcerative colitis
crohn disease
integrative medicine
intestinal barrier
inflammatory bowel disease
confocal laser endomicroscopy
wild blueberry
bilberry
nutrition
microbiome
inflammation
chronic colitis
Lead sponsor: Universität Duisburg-Essen
Sponsor class: OTHER
Collaborators: name: UniversitÃ¤t Duisburg-Essen
name: German Crohn's and Colitis Association (DCCV e.V.)
name: Wilhelm Doerenkamp Foundation
First posted: 2024-11-21
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: All participants undergo both study arms. This means that each participant is in the blueberry (intervention) group for a period of 3 months and is in the control group for 3 months. The order in which the participants receive the forms of therapy is determined randomly. Thus, half of the study participants start the supplementary blueberry intake directly after the inpatient stay, the second half three months later (crossover design).
Primary purpose: TREATMENT

Brief summary: The goal of this exploratory, prospective, monocentric randomized crossover study is to investigate the influence of a blueberry-rich diet compared to a blueberry-poor diet on the microbiome, the intestinal barrier and the inflammatory process in IBD patients with chronic colitis.

The main question the study aims to answer is:

* Does a diet rich in blueberries compared to a diet low in blueberries have an influence on disease activity, intestinal inflammation and symptoms in IBD patients with chronic colitis?

Ulcerative Colitis (UC) and Crohn's disease (MC) patients are recruited during an inpatient stay at the Clinic for Internal and Integrative Medicine in Bamberg, Germany. During their routine inpatient stay, patients are treated by an interdisciplinary team using a comprehensive multimodal integrative inpatient therapy concept that combines conventional medicine with a wide range of integrative non-pharmacological treatments, phytotherapy, lifestyle-modification and nutritional therapy. During this time, it is verified whether the patients can participate in the study.

The study consists of two study arms, which are conducted in a cross-over design:

* Intervention arm: in this study arm, participants receive 12 weeks of blueberry therapy in addition to the regular two weeks of inpatient care at the Clinic for Internal and Integrative Medicine in Bamberg. The blueberry therapy includes drinking around 35 g of blueberry powder stirred into water once a day for 12 weeks.
* Control arm: in this study arm, participants receive the standard therapy (integrative medical therapy concept described above) during the regular two-week hospital stay. There is no additional blueberry intake.

Due to the crossover study design, all participants undergo both study arms. This means that each participant takes the supplementary blueberry powder (intervention) for a period of 3 months and the control therapy for 3 months. The order in which the participants receive the forms of therapy is determined randomly. Thus, half of the study participants start the supplementary blueberry intake directly after the inpatient stay, the second half three months later (cross-over principle).

UC and MC patients will:

* initially receive a clinically indicated colonoscopy with confocal laser endomicroscopy (CLE) during their routine inpatient stay at the Clinic for Internal and Integrative Medicine in Bamberg
* return to the clinic for an optional sigmoidoscopy with CLE after 12 and 24 weeks
* answer questionnaires at study start as well as after 12 and 24 weeks 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 the colonoscopy/sigmoidoscopy at study start as well as after 12 and 24 weeks
* document their intake of blueberry powder as well as their symptoms and stool frequencies in a diary throughout the study participation

Detailed description: Background:

Chronic inflammatory bowel disease (IBD) affects the lives of millions of people worldwide due to recurrent, severe clinical symptoms, potential complications and ongoing medical interventions. The scientific community currently assumes a multicausal pathogenesis in IBD caused by an unfavorable constellation of genetic predisposition, imbalance of pathogenic to symbiotic gut bacteria (dysbiosis) and harmful environmental and lifestyle factors resulting in an excessive immune response.

The intestinal barrier and the microbiome play a key role in maintaining intestinal balance and health. The intestinal barrier protects our body from bacteria, viruses and fungi in the intestinal lumen, while it enables the absorption of nutrients at the same time. In case of a leaky gut, microbial pathogens or their components can enter the deeper cell layers of the intestine and cause acute and long-term inflammatory reactions. The composition of the gut microbiome, i.e. the community of billions of microorganisms living in the gut, has a significant influence on the intestinal barrier and gut health. Beneficial bacteria stabilize the intestinal barrier, strengthen local defenses (mucin and IgA production) and inhibit pro-inflammatory immune reactions and cell death. In contrast, harmful bacteria (pathobionts) disrupt the intestinal barrier, dysregulate cell death and proliferation, which leads to the release of pro-inflammatory signaling substancesand and an immune response causing inflammation.

While previous attempts to develop pharmacological therapies to improve gut barrier function have been unsuccessful, an increasing number of preclinical and clinical trial results highlight the significant impact of a plant-based diet through its modulatory effect on the gut microbiome and the gut barrier in IBD. However, further research is needed to evaluate the role of individual dietary components and complex dietary interventions with anti-inflammatory potential in the prevention and treatment of IBD.

The high levels of prebiotic food components in a plant-rich diet are of particular importance in the treatment of intestinal barrier disorders and the microbiome.

Preclinical and clinical studies highlight the modulatory effect of berries, especially blueberries (Vaccinium myrtillus), on the microbiome, gut health and inflammation due to their richness in prebiotically active polyphenols, flavonoids, anthocyanins and fiber.

However, the influence of blueberries on the intestinal barrier and the microbiome in colitis patients has not yet been investigated. Mechanistically oriented clinical studies are needed to confirm the prebiotic and preclinical findings in the clinic. Through a targeted combination of clinical testing on patients, ex vivo examination of biopsy material and cell biological studies at protein and transcriptome level, it should be possible to develop a comprehensive picture of the influence of a blueberry-rich diet, but also of the underlying pathomechanisms affected.

Aim of the study:

Determination of the influence of a three-month blueberry-rich diet compared to a diet with a low blueberry content on disease activity, intestinal inflammation and symptoms in patients with chronic colitis - initiated as part of a routine inpatient stay during which patients are treated with a comprehensive multimodal integrative therapy concept with dietary changes.

Exploratory study design:

This is an exploratory, prospective, monocentric, randomized, crossover study. 60 IBD patients are randomized into two groups of 30 subjects each. During a period of 6 months, which follows the inpatient-initiated integrative medical lifestyle modification program, participants undergo two consecutive phases of 3 months each marked by a blueberry-rich and a blueberry-poor diet. Dependent on the study group, half of the study participants start the supplementary blueberry intake directly after the inpatient stay, the second half three months later (cross-over principle).

Before the start of the study (W0), the colon of the participants is initially examined for macroscopic inflammation and for intestinal barrier disorders using confocal laser endomicroscopy as part of regular inpatient care. In order to investigate the influence of the integrative therapy with or without blueberry intake on the intestinal barrier and colonic inflammation, this will be checked after the end of the first 3 months (W12) and after 6 months (W24) in a voluntary control sigmoidoscopy with confocal laser endomicroscopy (CLE) as part of a short inpatient stay.

During the endoscopy, biopsies, bile, stool, urine and blood samples important for the study are taken for examination. These serve to clarify mechanistic relationships between the intestinal barrier function, the microbiome, its metabolic products (metabolome), the immune system, the oxidative stress profile, the antioxidative capacity and the inflammatory process (inflammation markers, immune cells and cytokines). In addition, participants will receive questionnaires at all three time points (W0, W12, W24) to evaluate their IBD-specific and general quality of life, symptoms, disease activity, fatigue and stress levels.

Eligibility criteria: Inclusion Criteria:

* age \> 18 years
* diagnosis of Crohn's Disease (CD) or Ulcerative Colitis (UC) with mild to moderate colitis for at least 6 months (CD: Harvey-Bradshaw-Index Score 5-16; UC: Partial Mayo Score 2-6)
* 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 Department for Internal and Integrative Medicine at the Sozialstiftung Bamberg, Germany for regular treatment
* clinical indication and performance of an initial colonoscopy with confocal laser endomicroscopy (CLE)
* signed informed consent form

Exclusion Criteria:

* IBD without inflammation of the colon (e.g. Crohn's Disease without colitis)
* active flare of IBD
* CRP ≥ 100 mg/l
* artificial bowel outlet in front of the colon (ileostomy)
* high regular consumption of blueberries (≥ 300 g cultivated blueberries or ≥ 150 g wild blueberries per week) or administration of blueberry therapy in the last 3 months
* participation in another therapeutic study within the last 30 days
* Known intolerance to blueberries or their ingredients such as contained anthocyanins or fructose (e.g. fructose malabsorption)
* presence of known serious infectious diseases e.g. of the liver such as HIV, hepatitis B and C infection

Primary outcomes:
measure: Improvement of the intestinal inflammation status evaluated via fecal calprotectin levels
timeFrame: week 0, 12, 24
Secondary outcomes:
measure: Improvement of Crohn's disease severity evaluated by Harvey-Bradshaw-Index (HBI)
timeFrame: week 0, 12, 24
measure: Improvement of ulcerative colitis disease severity evaluated by MAYO-Score
timeFrame: week 0, 12, 24
measure: Evaluation of IBD-SI (Inflammatory Bowel Disease Symptom Inventory)
timeFrame: week 0, 12, 24
measure: Evaluation of disease-specific quality of life by IBD-Q (Inflammatory Bowel Disease Questionnaire)
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: Colonoscopy/Sigmoidoscopy with confocal laser endomicroscopy (CLE)
timeFrame: week 0, 12, 24
measure: Histopathological analysis of ileo-colorectal biopsies
timeFrame: week 0, 12, 24
measure: Immunohistochemical analysis of ileo-colorectal biopsies
timeFrame: week 0, 12, 24
measure: Gene expression analysis of ileo-colorectal 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: 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: Analysis of inflammatory markers in the stool
timeFrame: week 0, 12, 24
measure: Analysis of fecal biomarkers to evaluate the integrity of the intestinal barrier
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 and 24
measure: Metabolite profiling in the urine
timeFrame: week 0, 12 and 24
measure: Analysis of oxidative stress in the urine
timeFrame: week 0, 12, 24
measure: Analysis of the antioxidant capacity in the serum
timeFrame: week 0, 12, 24
measure: Analysis of the thiol status in the serum
timeFrame: week 0, 12, 24
measure: Analysis of the peroxidation of lipids in the serum
timeFrame: week 0, 12, 24
measure: Analysis of the composition of bile fluid
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
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: