Fibrosis in IBD: from pathogenesis to therapeutic targets

Abstract

BackgroundIntestinal fibrosis resulting in stricture formation and obstruction in Crohn’s disease (CD) and increased wall stiffness leading to symptoms in ulcerative colitis (UC) is among the largest unmet needs in inflammatory bowel disease (IBD). Fibrosis is caused by a multifactorial and complex process involving immune and non-immune cells, their soluble mediators and exposure to luminal contents, such as microbiota and environmental factors. To date, no antifibrotic therapy is available. Some progress has been made in creating consensus definitions and measurements to quantify stricture morphology for clinical practice and trials, but approaches to determine the degree of fibrosis within a stricture are still lacking.ObjectiveWe herein describe the current state of stricture pathogenesis, measuring tools and clinical trial endpoints development.DesignData presented and discussed in this review derive from the past and recent literature and the authors’ own research and experience.Results and conclusionsSignificant progress has been made in better understanding the pathogenesis of fibrosis, but additional studies and preclinical developments are needed to define specific therapeutic targets.

Inflammation accelerating intestinal fibrosis: from mechanism to clinic

“…The majority of transcriptional changes were observed in the mucosal and submucosal layers of stenotic CD, with fewer changes observed in the lamina propria compared to controls. In particular, specific fibroblast populations, such as CXCL14 + and MMP/WNT5A + fibroblasts, exhibited either increased numbers or enhanced transcriptional activity in stenotic CD compared with non-stenotic but inflamed and non-inflamed tissue from the same patients [ 30 ]. Nevertheless, clinical observations have indicated that chronic intestinal inflammation does not invariably result in intestinal fibrosis.…”

Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies

“…Current therapeutic strategies to combat intestinal fibrosis are limited, since anti-inflammatory and immunosuppressive strategies often fail to prevent or reverse this complication. Moreover, there is a lack of translation of recent experimental results into the development of new drugs, while there continues to be a lack of consensus defining clinical trial endpoints [ 26 ]. In fact, the only way to remove fibrotic tissue at the present date is surgical intervention involving resection or strictureplasty.…”