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Epithelial expression and function of trypsin-3 in irritable bowel syndrome.

  • Author(s): Rolland-Fourcade, Claire;
  • Denadai-Souza, Alexandre;
  • Cirillo, Carla;
  • Lopez, Cintya;
  • Jaramillo, Josue Obed;
  • Desormeaux, Cleo;
  • Cenac, Nicolas;
  • Motta, Jean-Paul;
  • Larauche, Muriel;
  • Taché, Yvette;
  • Vanden Berghe, Pieter;
  • Neunlist, Michel;
  • Coron, Emmanuel;
  • Kirzin, Sylvain;
  • Portier, Guillaume;
  • Bonnet, Delphine;
  • Alric, Laurent;
  • Vanner, Stephen;
  • Deraison, Celine;
  • Vergnolle, Nathalie
  • et al.


Proteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity.


Trypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells stimulated or not. These supernatants were also applied to cultures of primary afferents. mRNA isoforms of trypsin (PRSS1, 2 and 3) were detected by reverse transcription-PCR, and trypsin-3 protein expression was studied by western blot analysis and immunohistochemistry. Electrophysiological recordings and Ca2+ imaging in response to trypsin-3 were performed in mouse primary afferent and in human submucosal neurons, respectively. Visceromotor response to colorectal distension was recorded in mice administered intracolonically with trypsin-3.


We showed that stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In colons of patients with IBS, increased trypsin-like activity was associated with the epithelium. We identified that trypsin-3 was the only form of trypsin upregulated in stimulated intestinal epithelial cells and in tissues from patients with IBS. 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.


In IBS, the intestinal epithelium produces and releases the active protease trypsin-3, which is able to signal to enteric neurons and to induce visceral hypersensitivity.

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