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

Annaházi, Anitaa,b; Gecse, Krisztinab; Dabek, Martaa; Ait-Belgnaoui, Afifaa; Rosztóczy, Andrásb; Róka, Richárdb; Molnár, Tamásb; Theodorou, Vassiliaa; Wittmann, Tiborb; Bueno, Lionela; Eutamene, Helenea,*

doi: 10.1016/j.pain.2009.04.017
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ABSTRACT 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.

aUMR 1054 Institut National de la Recherche Agronomique/EI-Purpan Neurogastroenterology and Nutrition Unit, 180 Chemin de Tournefeuille, 31931 Toulouse Cedex 9, BP 3, France

bFirst Department of Internal Medicine, University of Szeged, Szeged, Hungary

*Corresponding author. Tel.: +33 5 61 28 51 59; fax: +33 5 61 28 51 45.

E-mail address:heutamen@toulouse.inra.fr

ARTICLE INFO

Article history:

Received December 22, 2008

Received in revised form and accepted April 17, 2009.

© 2009 Lippincott Williams & Wilkins, Inc.
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