Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases

Abstract

Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors (PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.

Identification of an epithelial member of the protease family, supporting the potential diagnostic and therapeutic role of serine proteases in IBS

“…Regarding the mechanism of action, a PAR2-mediated pathway has been suggested for several proteases. In their present study, Rolland-Fourcade et al seem to exclude the involvement of PAR1 and PAR4 as the main receptor targets of trypsin-3 2. However, we cannot exclude a role for different PAR receptors when other (serine) proteases are involved.…”

“…One of these mechanisms is visceral hypersensitivity, resulting from a disturbed neuronal signalling at the peripheral and/or central levels 1 2. Rolland-Fourcade et al 3 show, in this issue of Gut , that intestinal epithelial cells (Caco-2 cells) release a trypsin-like activity at the basolateral side of the cells after stimulation with a classical inflammatory stimulus (lipopolysaccharide) or with a stress-related stimulus (epinephrine), and they identified it as trypsin-3.…”

“…Protease inhibition has been suggested as a therapeutic option in both IBS and IBD since an increased trypsin-like activity and enhanced tryptase contents have been shown in tissues from patients with IBS. In preclinical studies, PAR2-antagonists and (serine) protease inhibitors indeed have shown beneficial effects on inflammation, intestinal permeability and recently on visceral hypersensitivity (for reviews, see refs 2 7 8). One has to be aware that besides mast cells releasing different serine proteases, such as tryptase and chymase, and inflammatory cells, the pancreas and the microbiome encompass an important source of proteases.…”

“…We generally assume that these luminal proteases derived from the microbiome, pancreas or even food substances will remain in the GI lumen without crossing the mucosal barrier. However, we do not know exactly what happens in circumstances of impaired barrier dysfunction—as evidenced in many GI diseases—taking into account that proteases themselves are able to alter the intestinal permeability 2 8…”

Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

“…In the gut, these PAR‐2 agonists, among other effects, impact on gut nociception and cause visceral hypersensitivity through PAR‐2 signaling, but whether these agonists can mediate effects through Mrgprc11 is currently unknown. Therefore, our finding that Mrgprc11 can be considered a mediator of visceral hypersensitivity opens new directions to explore its role in protease‐mediated signaling in the bowel, especially given the importance of such signaling pathways in chronic abdominal pain disorders …”