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Project

Therapeutic modulation of the gastrointestinal permeability-inflammation-pain axis.

Gastrointestinal barrier disturbances are postulated to play an important role in the pathogenesis of a wide range of diseases characterised by underlying inflammation and ranging from metabolic disorders (obesity) over gastrointestinal diseases (inflammatory bowel diseases such as Crohn's disease) towards infection (sepsis). 1./ In this translational project we first want to investigate the effect of pharmacological modulation of gastrointestinal barrier dysfunction in three animal models representing different conditions of clinically relevant inflammation; more precisely irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD) and sepsis. The target molecules were chosen based on their proposed role on the epithelial barrier. The role of intestinal alkaline phosphatase, a membrane-bound brush-border enzyme with anti-inflammatory properties, will be investigated on the interplay between intestinal permeability, inflammation and visceral pain. We will also investigate the effect of newly developed serine protease inhibitors on this 'permeability-inflammation-pain' axis because proteases too, being abundantly present both in the gastrointestinal tract and the gastrointestinal lumen, have been proposed as important mediators in permeability, inflammation and visceral pain. 2./ In close parallel with the experimental part and based on the outcome data obtained in our animal models, we will perform a translational study in which human biopsies and/or surgical specimens of patients with IBS, IBD or sepsis will be collected for the validation of the biomarkers identified in the experimental part. The combination of data on the patient's clinical background, his/her immune response and the severity of intestinal permeability disturbances will generate a unique patient profile that might help stratifying patients allowing a personalized treatment. Moreover, as no approved therapeutic agents are currently targeting the epithelial barrier, more research on the gastrointestinal permeability-inflammation-visceral pain axis is eagerly awaited.
Date:1 Jan 2018 →  31 Dec 2021
Keywords:GASTROINTESTINAL PHYSIOLOGY, INFLAMMATION, PAIN, BARRIERS
Disciplines:Gastro-enterology and hepatology, Physiology