EVIDENCE OF PROTEASE-MEDIATED PRO-NOCICEPTIVE EFFECTS IN INFLAMMATORY BOWEL DISEASE PATIENTS

• DOI: 10.1093/ibd/izae282.128
• Publication Date: 2025-03-04T21:38:29Z
• Authors: Hannah Wood; Kristyna Blazkova; Franco Faucher; Prameet M Sheth; Stephen J Vanner; David E Reed; Matthew Bogyo; Alan Lomax
• Keywords: Inflammatory Bowel Diseases

Abstract OBJECTIVE Abdominal pain poses a significant challenge for individuals with inflammatory bowel disease (IBD). Despite current treatments that target inflammation, IBD-associated abdominal often persists even in the absence of negatively impacting patients’ quality life. This persistence suggests factors other than inflammation may be contributing to pathology IBD. Our previous research bacterial proteases can directly influence excitability dorsal root ganglia neurons, many which are pain-sensing. Building on this, we hypothesize proteases, both host and origin, play role modulation during active remission phases METHODS The effects fecal supernatants (FS) from patients or remissive IBD healthy volunteers, pain-sensing neurons were assessed using ex-vivo single-unit afferent nerve recordings mouse colons. A protease inhibitor cocktail (PIC; 1:1000) protease-activated receptor (PAR)-2 antagonist (GB83; 10µM) independently applied bioassay determine whether these inhibited excitatory effect FS. In addition, participant FS tested proteolytic cleavage N-terminal domain PAR2 novel enzymatic assay. RESULTS volunteers [N=5] had no (p >0.05). [N=15] increased action potential discharge colonic nerves by 85% (p< 0.0001) selectively activation high-threshold units, putative nociceptors, 44% 0.01). >0.05) activity. contrast, [N=15], did not excite Interestingly, findings found consistent when was split into subtypes: Crohn’s ulcerative colitis. Furthermore, normalized total protein content, yielded significantly greater activity 0.05), while samples different participants correlated neuronal excitation (R2=0.4721, p< 0.001). CONCLUSION suggest leads generation luminal mediators, including acting PAR2, activate visceral nociceptive neurons. These mediators less abundant is remission. data targeting could offer promising therapeutic approach management