Background and purpose Chymotrypsin is a serine protease produced by the pancreas and secreted into the lumen of the small intestine, where it digests food proteins. Due to its presence in the gut lumen, we hypothesized that chymotrypsin activity may be found close to epithelial cells and signals to them via Protease-activated receptors (PARs). We deciphered molecular pharmacology mechanisms for chymotrypsin signaling in intestinal epithelial cells. Experimental approaches The presence and activity of chymotrypsin were evaluated by western blot (WB) and enzymatic activity tests in luminal and mucosal compartments of murine and human gut samples. The ability of chymotrypsin to cleave the extracellular domain of PAR1 or PAR2 was assessed using cell lines expressing N-terminally-tagged receptors. The cleavage site of chymotrypsin on PAR1 and PAR2 was determined by HPLC-MS analysis. To study the pharmacology of chymotrypsin signals, we investigated calcium signaling and ERK1/2 activation using calcium mobilization assays and WB in CMT93 intestinal epithelial cells. Key results We found that chymotrypsin was present and active in the vicinity of the murine and human colonic epithelium. Molecular pharmacology studies evidenced that chymotrypsin cleaved both PARs receptors. While chymotrypsin activated calcium and ERK1/2 signaling pathways through PAR2, it disarmed PAR1, preventing further activation by its canonical agonist thrombin. CONCLUSION Our work suggests that the function of chymotrypsin in the gut lumen goes well beyond a simple digestive role. Our results highlight the ability of chymotrypsin to signal to intestinal epithelial cells via PARs, which may have important physiological consequences in gut homeostasis.

Background: Several medicinal treatments for avoiding post-operative ileus (POI) after abdominal surgery have been evaluated in randomised controlled trials. This network meta-analysis aimed to explore the relative effectiveness of these different treatments on ileus outcome measures. Methods: A systematic literature review was performed to identify randomised controlled trials (RCTs) comparing treatments for post-operative ileus following abdominal surgery. A Bayesian network meta-analysis was performed. Direct and indirect comparisons of all regimens were simultaneously compared using random-effects network meta-analysis. Results: A total of 38 randomised controlled trials were included in this network meta-analysis reporting on 6371 patients. Our network meta-analysis shows that prokinetics significantly reduce the duration of first gas (Mean difference (MD) (hours) – 16; credible interval - 30, - 3.1; surface under the cumulative ranking curve (SUCRA) 0.418), duration of first bowel movements (Mean difference (MD) (hours) -25; credible interval - 39, - 11; SUCRA 0.25) and duration of post-operative hospitalisation (Mean difference (MD) (hours) – 1.9; credible interval – 3.8, - 0.040; SUCRA 0.34). Opioid antagonists are the only treatment that significantly improve the duration of food recovery (Mean difference (MD) (hours) - 19; credible interval - 26, - 14; SUCRA 0.163). Conclusion: Based on our meta-analysis, the two most consistent pharmacological treatments able to effectively reduce POI after abdominal surgery are prokinetics and opioid antagonists. The absence of clear superiority of one treatment over another highlights the limits of the pharmacological principles available.

Post-operative ileus (POI) is a frequent complication after abdominal surgery. The consequences of POI can be potentially serious such as bronchial inhalation or acute functional renal failure. Numerous advances in peri-operative management, particularly early rehabilitation, have made it possible to decrease POI. Despite this, the rate of prolonged POI ileus remains high and can be as high as 25% of patients in colorectal surgery. From a pathophysiological point of view, POI has two phases, an early neurological phase and a later inflammatory phase, to which we could add a “pharmacological” phase during which analgesic drugs, particularly opiates, play a central role. The aim of this review article is to describe the phases of the pathophysiology of POI, to analyse the pharmacological treatments currently available through published clinical trials and finally to discuss the different research areas for potential pharmacological targets.