| abstract |
The invention is in the field of therapy of gut diseases associated with intestinal permeability such as, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Diseases (IBD), celiac disease or pouchitis. In particular, the invention relates to inhibitors of Trypsin-3, for use in the treatment of Irritable Bowel Syndrome (IBS) including gluten hypersensitivity. The inventors demonstrate that, stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In IBS patient colons, increased trypsin-like activity was associated with the epithelium. Inventors identified that Trypsin-3 was the only form of trypsin up-regulated in stimulated intestinal epithelial cells and in IBS patient tissues. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a Protease-Activated Receptor-2-dependent mechanism. |