Fibrosis in IBD: from pathogenesis to therapeutic targets

Abstract

Background: Intestinal 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.

Objective: We herein describe the current state of stricture pathogenesis, measuring tools and clinical trial endpoints development.

Design: Data presented and discussed in this review derive from the past and recent literature and the authors' own research and experience.

Results and conclusions: Significant progress has been made in better understanding the pathogenesis of fibrosis, but additional studies and preclinical developments are needed to define specific therapeutic targets.

Keywords: fibrosis; inflammatory bowel disease; myofibroblasts.

Figure 1.

Model for progressive accumulation of extracellular matrix and thickening of the muscularis propria, despite a relapsing and remitting chronic inflammatory disease course. Initial inflammation dependent pathways given way to inflammation independent pathways and then both likely occur in parallel. Abbreviations: ECM, extracellular matrix.

Figure 2.

Cellular sources of activated intestinal mesenchymal cells and their capability to transdifferentiate into fibroblasts, myofibroblasts and smooth muscle cells. Abbreviations: EMT, epithelial-to-mesenchymal transition; EndMT, endothelial-to-mesenchymal transition

Figure 3.

Recently described mechanisms of intestinal fibrogenesis. For clarity of presentation the lamina propria and muscularis mucosa were not delineated separately, which is not meant to diminish their contribution to the process of intestinal fibrosis. Abbreviations: IL, interleukin; TLR, Toll-like receptor; LOX, lysyl oxidases; TNFSF14, tumor necrosis factor superfamily member 14; PDPN, podoplanin; CTHRC1, collagen triple-helix repeat-containing 1; CHI3L1, chitinase-3-like 1.

Figure 4.

Model for the disconnect of inflammation and fibrosis/extracellular matrix changes. Depicted is a period of active intestinal inflammation before and after treatment.

Figure 5.

Deciphering mechanisms of fibrosis using multi-omics approaches. Recent advances in the omics field allow assessment of the transcriptome, genome, epigenome, cell ontogeny and Proteome. Identified cell types and pathways can be spatially located using spatial transcriptomics. Integration of these multi-omics datasets allows high-resolution assessments of cells and their state and already available datasets from other fibrotic disease can inform rational drug development strategies.

Figure 6.

Necessary steps for developing a pathway to testing anti-fibrotic drugs: Combination of preclinical development, clinical trial endpoint development and the critical step for engaging industry in early drug development, such as first in human studies, to reach the stage of proof of concept clinical trials.