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 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.
Annaházi
Anita
A
UMR 1054 Institut National de la Recherche Agronomique/EI-Purpan Neurogastroenterology and Nutrition Unit, 180 Chemin de Tournefeuille, 31931 Toulouse Cedex 9, BP 3, France.
Gecse
Krisztina
K
Dabek
Marta
M
Ait-Belgnaoui
Afifa
A
Rosztóczy
András
A
Róka
Richárd
R
Molnár
Tamás
T
Theodorou
Vassilia
V
Wittmann
Tibor
T
Bueno
Lionel
L
Eutamene
Helene
H
D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005243:Feces / Q000737:chemistry*; D005260:Female; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010465:Perception / Q000187:drug effects; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D012684:Sensory Thresholds / Q000187:drug effects; D012697:Serine Endopeptidases / Q000494:pharmacology*; D014781:Viscera / Q000187:drug effects* / Q000294:innervation*
D004791:Enzyme Inhibitors; D044462:Receptors, Proteinase-Activated; C481942:protease-activated receptor 4, mouse; D012697:Serine Endopeptidases