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

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 Set-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. (C) 2009 International Association for the Study Of Pain. Published by Elsevier B.V. All rights reserved.