Intestinal Permeability and Intestinal Microbiota in Irritable Bowel Syndrome

The Role of Intestinal Permeability and Intestinal Microbiota in the Development of the Irritable Bowel Syndrome and Functional Dyspepsia Symptoms

Patients with diarrhea-predominant irritable bowel syndrome (IBS) and functional dyspepsia (FD) were examined and received treatment in the study. Severity of complaints and quality of life patients were assessed according to questionnaires. The state of the intestinal barrier (analysis of the protein composition, intestinal mucin levels in biopsies, serum zonulin level in blood), the composition of the gut microbiota (16S rRNA gene sequencing), bacterial metabolic function (short-chain fatty acid levels in feces), and the presence of gut inflammation (levels of lymphocytes and eosinophils in biopsies) were assessed in the patients. Patients were divided into 3 treatment groups: trimebutin + placebo, rebamipide + placebo, trimebutin + rebamipide. The above parameters were compared in patients before and after treatment.

Study Overview

• Status: Active, not recruiting
• Conditions: Irritable Bowel Syndrome With Diarrhea
• Intervention / Treatment: Drug: prescribing anapproved drug, examination

Detailed Description

The study included 60 patients with an established diagnosis IBS and FD. Patients were randomized in toone of three groups. Patients in group 1 received Trimedat (trimebutine, marketing authorization number LP-005534/07 of 2007-12-28) for 2 months, patients in group 2 received Trimedat and Rebagit (rebamipide, marketing authorization number LP-001831 of 2012-09-12) for 2 months, patients in group 3 received Rebagit for 2 months. The patients were blinded to the treatment assignment. At inclusion and 1 month after the severity of complaints were assessed, 2 months after starting treatment, the severity of complaints, quality of life, state of tight junction proteins, mucin-2 expression level, serum zonulin level, histological investigation of the mucous membrane of the small and large intestine, state of the intestinal microbiota and short-chain fatty acid levels were assessed. After the end of the study, an interim analysis of the effect of the therapy on the parameters was carried out. In the case of a positive effect, a full analysis of all the aforementioned factors contributing to its development was to be performed.

In addition, all these parameters were also in the control group (15 healthy volunteers without complaints, matched for sex and age with the main group).

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation
    • Elena Poluektova

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent
• A man or woman aged 18-59.
• For women of childbearing age: mandatory use of contraceptive methods.
• Confirmed diagnosis of IBS-D and functional dyspepsia by clinical, instrumental and blood chemistry findings (according to the Clinical Guidelines of the Russian Gastroenterological Association and the Russian Association of Coloproctologists (2016)
• Absence of Helicobacter Pylori infection according to the urea breath test in the past 6 months before inclusion.
• Ability to understand and willingness to comply with all protocol details.

Exclusion Criteria:

• Prematurely discontinuation of the consumption of tested drugs/placebo;
• Started taking antibiotics, other probiotics, or prebiotics during the follow-up period;
• Refusal to participate during the follow-up period, including refusal to come for re-examination 2 months after inclusion;
• Cancer or inflammatory bowel disease diagnosis during the follow-up period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A; a group of patients who, after the examination, were prescribed therapy with trimebutine 600 mg per day for 2 months	Drug: prescribing anapproved drug, examination; Blood test to assess serum zonulin levels;; Esophagogastroduodenoscopyand colonoscopy with biopsy from the small and large intestine followed by histological examination;; Stool sample collection to assess short-chain fatty acid levels and the composition of the gut microbiota. Then the patients were prescribed therapy with the approved drug trimebutin (trimedat) with placebo or trimebutine with rebamipide or rebamipide with placebo for 2 months.; Other Names: Trimedate, Rebagit
Experimental: Group B; a group of patients who, after the examination, were prescribed therapy with rebamipide 300 mg per day for 2 months	Drug: prescribing anapproved drug, examination; Blood test to assess serum zonulin levels;; Esophagogastroduodenoscopyand colonoscopy with biopsy from the small and large intestine followed by histological examination;; Stool sample collection to assess short-chain fatty acid levels and the composition of the gut microbiota. Then the patients were prescribed therapy with the approved drug trimebutin (trimedat) with placebo or trimebutine with rebamipide or rebamipide with placebo for 2 months.; Other Names: Trimedate, Rebagit
Experimental: Group C; a group of patients who, after the examination, were prescribed therapy with trimebutine 600 mg per day + rebamipide 300 mg per day for 2 months	Drug: prescribing anapproved drug, examination; Blood test to assess serum zonulin levels;; Esophagogastroduodenoscopyand colonoscopy with biopsy from the small and large intestine followed by histological examination;; Stool sample collection to assess short-chain fatty acid levels and the composition of the gut microbiota. Then the patients were prescribed therapy with the approved drug trimebutin (trimedat) with placebo or trimebutine with rebamipide or rebamipide with placebo for 2 months.; Other Names: Trimedate, Rebagit
No Intervention: Control; healthy volunteers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of complaints	The severity of complaints is assessed using "7×7" (7 symptoms per 7 days) questionnaire and GSRS (Gastrointestinal Symptom Rating Scale)	change from baseline points of questionnaires at 2 months
Low-grade inflammation	In biopsies of the small and large intestine, numbers of eosinophils and lymphocytes in the field of view were assessed by histological examination with hematoxylin-eosin staining	change from baseline numbers of eosinophils and lymphocytes at 2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tight junction protein level	In biopsies of the small and large intestine, tight junction proteins levels are assessed by two-dimensional electrophoresis	change from baseline tight junction proteins levels at 2 months
Mucin-2 expression	The level of Mucin-2 expression in biopsies of the small and large intestine is assessed by immunohistochemistry	change from baseline level of Mucin-2 at 2 months
Serum zonulin	The level of the permeability marker, serum zonulin, is assessed by enzyme-linked immunosorbent assay using an ELISA test kit (Immundiagnostik AG, Bensheim, Germany)	change from baseline level of serum zonulin at 2 months
Gut microbiome	The composition of the gut microbiota in feces is analyzed by 16S rRNA sequencing	change from baseline composition of the gut microbiota in feces at 2 months
Short-chain fatty acids	Short-chain fatty acid levels in feces are assessed by gas chromatography-mass spectrometry	change from baseline short-chain fatty acid levels at 2 months
Adverse events	Patients are notified of the need to report any adverse and unintended signs (any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product)	2 months after the start of the study
Quality of life (general health, limitation of activities, physical health problems, emotional health problems, social activities, pain, energy and emotions, social activities, general health)	Quality of life ((general health, limitation of activities, physical health problems, emotional health problems, social activities, pain, energy and emotions, social activities, general health) was assessed using the 36-Item Short Form Survey (SF-36) questionnaire	change from baseline points of questionnaire levels at 2 months
Severity of complaints	The severity of complaints is assessed using "7×7" (7 symptoms per 7 days) questionnaire and GSRS (Gastrointestinal Symptom Rating Scale)	baseline
Low-grade inflammation	In biopsies of the small and large intestine, numbers of eosinophils and lymphocytes in the field of view were assessed by histological examination with hematoxylin-eosin staining	baseline
Tight junction protein level	In biopsies of the small and large intestine, tight junction proteins levels are assessed by two-dimensional electrophoresis	baseline
Mucin-2 expression	The level of Mucin-2 expression in biopsies of the small and large intestine is assessed by immunohistochemistry	baseline
Serum zonulin	The level of the permeability marker, serum zonulin, is assessed by enzyme-linked immunosorbent assay using an ELISA test kit (Immundiagnostik AG, Bensheim, Germany)	baseline
Gut microbiome	The composition of the gut microbiota in feces is analyzed by 16S rRNA sequencing	baseline
Short-chain fatty acids	Short-chain fatty acid levels in feces are assessed by gas chromatography-mass spectrometry	baseline

Collaborators and Investigators

• Sponsor: I.M. Sechenov First Moscow State Medical University
• Investigators: Principal Investigator: Vladimir Ivashkin, I.M. Sechenov First Moscow State Medical University (Sechenov University)

Publications and helpful links

General Publications

• Ivashkin V, Poluektov Y, Kogan E, Shifrin O, Sheptulin A, Kovaleva A, Kurbatova A, Krasnov G, Poluektova E. Disruption of the pro-inflammatory, anti-inflammatory cytokines and tight junction proteins expression, associated with changes of the composition of the gut microbiota in patients with irritable bowel syndrome. PLoS One. 2021 Jun 11;16(6):e0252930. doi: 10.1371/journal.pone.0252930. eCollection 2021.

Helpful Links

• Kovaleva A.L., Poluektova E.A., Shifrin O.S. Intestinal Barrier, Permeability and Nonspecific Inflammation in Functional Gastrointestinal Disorders. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2020;30(4):52-59. (In Russ.)

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2021
• Primary Completion (Anticipated): May 31, 2022
• Study Completion (Anticipated): May 31, 2022

Study Registration Dates

• First Submitted: March 31, 2022
• First Submitted That Met QC Criteria: May 12, 2022
• First Posted (Actual): May 18, 2022

Study Record Updates

• Last Update Posted (Actual): May 18, 2022
• Last Update Submitted That Met QC Criteria: May 12, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Syndrome; Irritable Bowel Syndrome; Diarrhea
• Other Study ID Numbers: 116227

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data disclosure is not permitted by the local ethics committee. For more information about the study, please contact the principal investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No