The role of mucosal mediators and their effect on neuronal afferent signalling and intestinal permeability during postinflammatory visceral hypersensitivity: a translational study.

Visceral hypersensitivity and altered intestinal permeability are common key features of two major gastrointestinal disorders, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Alterations in the density of mucosal cells, such as enterochromaffin cells and mast cells, and in their activation status and mediator release (serotonin and proteases) have been described in IBS and IBD patients. Our first aim is to investigate whether these mediators can induce visceral hypersensitivity directly by activating the afferent nerve endings in the gut wall or indirectly via modulation of the intestinal barrier function. Increased permeability of the intestinal barrier facilitates the entrance of antigens, activating immune cells and other cell types in close proximity to afferent nerves. Therefore we will use an experimental model for postinflammatory visceral hypersensitivity that is routinely used in our lab and is based on a rat model of TNBS colitis. Visceral hypersensitivity and intestinal permeability will be extensively studied using a combination of validated in vivo and in vitro techniques: the in vivo visceromotor response and in vitro afferent neuronal activity to colonic distension (both indicators of visceral hypersensitivity) next to the Evans blue permeability method, all of which routinely used in our lab. In the first work package (WP1), the effect of pharmacological agents interfering with serotonin (5-HT) 2B and 5-HT4 receptors or with the serotonin synthesis will be assessed on visceral sensitivity and intestinal permeability. In WP2, newly developed potent protease inhibitors reducing tryptase and matriptase activity (in collaboration with ADDN) will be tested to define the contribution of these proteases to visceral sensitivity and intestinal barrier function. These two work packages will allows us to gain further insight in the incompletely elucidated pathophysiology underlying visceral hypersensitivity and impaired barrier function and to identify new drug targets for the treatment of IBS. The second aim of the project (WP3) is to validate the role of these serotonergic targets and proteases in a translational set-up using colonic biopsies from patients with IBS and quiescent IBD. The effect of the supernatant derived from these biopsies will be investigated on afferent neuronal signalling in the presence or absence of specific inhibitors identified in WP1 and WP2 to confirm their relevance in a clinically relevant context.

Keywords:INTESTINAL INFLAMMATION, HYPERSENSITIVITY, EXPERIMENTAL RESEARCH, PATHOPHYSIOLOGY OF PAIN

Disciplines:Gastro-enterology and hepatology, Physiology