Genetic Determinism of Epithelial Barrier Defects in Irritable Bowel Syndrome (PROTIBS)

Genetic Determinism of Epithelial Barrier Defects Induced by Increase in Proteases Activity in Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) profoundly affects the quality of life. Mucosal micro-inflammation, epithelial permeability disorder and proteases activity increase have been demonstrated in the patients' gastrointestinal tract. Protease activity increase could be subjected to a genetic determinism (decrease in proteases inhibitors genes expression). Objectives: 1/ To study relations between proteases activity (in stool and colonic biopsies supernatants), proteases inhibitors genes expression and mucosal cellular infiltrate (IBS patients and healthy subjects). 2/ Establishing a correlation between proteases activity, mucosal micro-inflammation and symptoms. 3/ To evaluate proteases inhibitors therapeutic potential. Expected results: 1/ Decreased expression of proteases inhibitors genes in subjects with IBS. 2/ Correlation of symptoms with proteases activity intensity. 3/ Demonstration of restorative potential of proteases inhibitors.

Study Overview

• Status: Withdrawn
• Conditions: Irritable Bowel Syndrome (IBS)
• Intervention / Treatment: Genetic: Analysis on colorectal biopsy

Detailed Description

Irritable bowel syndrome (IBS) is the first reason for consultation in gastroenterology and his prevalence reach 5% of the general population. IBS is characterized by abdominal discomfort, diarrhea or constipation and decreased quality of life.

Recent facts on IBS pathophysiology show association between mucosal immunity activation (mast cells and their proteases) and epithelial permeability disorder. Permeability disorder can be reproduced by application of colonic biopsies cultures supernatants on in-vitro cell cultures. In parallel, tight junctions proteins mRNA (ZO-1, Occludin) decrease is observed ex-vivo in biopsies and in-vitro.

Gut bacterial proteases (cystein and serin proteases) may also play a role. In human, proteases activity is correlated with IBS symptoms severity. Proteases activity increase (cystein and serin proteases) is poorly understood, and this increase could be subjected to a genetic determinism (decrease in proteases inhibitors genes expression - Serpin A1/E1).

Objectives: 1/ To study relations between proteases activity (in stool and colonic biopsies supernatants), proteases inhibitors genes expression and mucosal cellular infiltrate (IBS patients and healthy subjects). 2/ Establishing a correlation between proteases activity, mucosal micro-inflammation and symptoms. 3/ To evaluate proteases inhibitors therapeutic potential.

Method: Subjects will be recruited in gastroenterology consultation. IBS patients will answer to Rome III criteria. Patients coming for screening colonoscopy will be defined as healthy subjects.

Colonic biopsies will be sent in real time to the research laboratory (EA 6302) for supernatants collecting, mRNA expression studies (Serpins, ZO-1, occludin, cytokines), proteases activity / permeability measurements and proteases inhibitors reversibility tests. Histologic study will also be performed.

Expected results: 1/ Decreased expression of proteases inhibitors genes in subjects with IBS. 2/ Correlation of symptoms with proteases activity intensity. 3/ Demonstration of restorative potential of proteases inhibitors.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Nice, France, 06002
    • Department of gastroenterology, Hopital Archet 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient with irritable bowel syndrome (IBS), defined by Rome III criteria (patient group)
• Patients coming for screening colonoscopy (control group)

Patients exclusion criteria :

• Active inflammatory bowel disease
• Infectious bowel disease or other cause that could explain digestive symptoms

Healthy subjects inclusion criteria :

• Patients coming for screening colonoscopy without inflammatory bowel disease or IBS

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: analysis on colorectal biopsy; Proteases activity (cystein and serin proteases); Proteases inhibitors genes expression (Serpins A1 / E1); Colonic biopsies permeabilityTight junctions genes expression; Cytokines genes expression (TNFalpha, interleukines); Cellularity on histologic sections	Genetic: Analysis on colorectal biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical criteria	Abdominal Pain : Francis scoring	at the medical visit
Clinical criteria	Transit disorders : Rome III criteria questionnaire	at day one
Clinical criteria	Quality of life alteration (questionnaires)	at day one

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Experimental criteria	Proteases activity (cystein and serin proteases) Tight junctions genes expression Cytokines genes expression (TNFalpha, interleukines) Cellularity on histologic sections	at day one
Experimental criteria	Proteases inhibitors genes expression (Serpins A1 / E1)	at day one
Experimental criteria	Colonic biopsies permeability	at day one

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nice
• Investigators: Principal Investigator: Thierry PICHE, MD, Nice University Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2016
• Primary Completion (Anticipated): September 1, 2018
• Study Completion (Anticipated): September 1, 2018

Study Registration Dates

• First Submitted: August 24, 2015
• First Submitted That Met QC Criteria: July 19, 2016
• First Posted (Estimate): July 22, 2016

Study Record Updates

• Last Update Posted (Actual): February 22, 2018
• Last Update Submitted That Met QC Criteria: February 15, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Syndrome; Irritable Bowel Syndrome
• Other Study ID Numbers: 14-PP-20