Irritable Bowel Syndrome (IBS) Clinical Trial
Official title:
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.
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.
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