Fecal proteases from diarrheic-IBS and ulcerative colitis patients exert opposite effect on visceral sensitivity in mice

Pain. 2009 Jul;144(1-2):209-17. doi: 10.1016/j.pain.2009.04.017. Epub 2009 May 17.


Elevated colonic luminal serine-protease (Ser-P) activity of diarrhea-predominant IBS (IBS-D) patients evokes a proteinase-activated receptor (PAR)-2-mediated colonic hypersensitivity in mice. Despite similarly elevated Ser-P levels in feces, patients with IBD exhibit visceral hypo- or normosensitivity to rectal distension, as opposed to IBS-D. To explain these discrepancies we studied the effect of colonic infusion of fecal supernatants from ulcerative colitis (UC) patients to colorectal mechanical sensitivity of mice and explored the involvement of PAR-4 and its activator Cathepsin-G (Cat-G). Fecal protease activities were assayed in healthy subjects, IBS-D and UC patients in presence or not of antiproteases or Cat-G inhibitor. Following intracolonic infusion of fecal supernatants from healthy subjects, IBS-D and UC patients or PAR-4 activating peptide (PAR-4-AP) or Cat-G, EMG response to colorectal balloon distension was recorded in mice. This nociceptive response was also determined after treatment with pepducin (PAR-4 antagonist) on UC supernatant or after a preincubation with antiproteases or Cat-G inhibitor. In contrast to IBS-D supernatant, UC supernatant promoted colonic hyposensitivity to distension, an effect mimicked by PAR-4-AP or Cat-G. UC supernatant-induced hypoalgesia was inhibited by a cocktail of antiproteases. However, blockade of PAR-4 or Cat-G inhibition resulted in colonic hypersensitivity similar to that observed after IBS-D supernatant infusion. Despite similarly elevated Ser-P activities, IBS-D and UC fecal supernatant display visceral pro- and antinociceptive effects in mice, respectively. Visceral hyposensitivity induced by fecal supernatant from UC patients results from PAR-4 activation by cathepsin-G, counterbalancing the pronociceptive effect of simultaneous PAR-2 activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analysis of Variance
  • Animals
  • Colitis, Ulcerative / metabolism*
  • Colitis, Ulcerative / physiopathology
  • Enzyme Inhibitors / pharmacology
  • Feces / chemistry*
  • Female
  • Humans
  • Irritable Bowel Syndrome / metabolism*
  • Irritable Bowel Syndrome / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Perception / drug effects
  • Receptors, Proteinase-Activated / metabolism
  • Sensory Thresholds / drug effects
  • Serine Endopeptidases / pharmacology*
  • Viscera / drug effects*
  • Viscera / innervation*


  • Enzyme Inhibitors
  • Receptors, Proteinase-Activated
  • protease-activated receptor 4, mouse
  • Serine Endopeptidases