Enteric bacterial proteases in inflammatory bowel disease- pathophysiology and clinical implications

Abstract

Numerous reports have identified a dysbiosis in the intestinal microbiota in patients suffering from inflammatory bowel diseases (IBD), yet the mechanism(s) in which this complex microbial community initiates or perpetuates inflammation remains unclear. The purpose of this review is to present evidence for one such mechanism that implicates enteric microbial derived proteases in the pathogenesis of IBD. We highlight and discuss studies demonstrating that proteases and protease receptors are abundant in the digestive system. Additionally, we investigate studies demonstrating an association between increased luminal protease activity and activation of protease receptors, ultimately resulting in increased intestinal permeability and exacerbation of colitis in animal models as well as in human IBD. Proteases are essential for the normal functioning of bacteria and in some cases can serve as virulence factors for pathogenic bacteria. Although not classified as traditional virulence factors, proteases originating from commensal enteric bacteria also have a potential association with intestinal inflammation via increased enteric permeability. Reports of increased protease activity in stools from IBD patients support a possible mechanism for a dysbiotic enteric microbiota in IBD. A better understanding of these pathways and characterization of the enteric bacteria involved, their proteases, and protease receptors may pave the way for new therapeutic approaches for these diseases.

Keywords: Protease, Proteinase, Protease associated receptor, Enteric microbiota, Epithelial barrier

Core tip: It is currently accepted that an enteric dysbiosis (alteration of the normal bacterial flora) is involved in the pathophysiology of inflammatory bowel diseases (IBD). One of the suggested mechanisms that ties an intestinal dysbiosis to the pathophysiology of IBD involves the release of enteric bacterial proteases that interact with protease activated receptors on epithelial cells, resulting in intestinal barrier dysfunction and exposure of the enteric immune system to luminal antigens. We have reviewed the literature that examined the role of microbial proteases and their enteric receptors in the pathogenesis of IBD, their suggested pathways of action, and discuss future therapeutic implications.