Biomarkers of intestinal fibrosis - one step towards clinical trials for stricturing inflammatory bowel disease

Abstract

Intestinal fibrosis, caused by an excessive deposition of extracellular matrix components, and subsequent stricture development are a common complication of inflammatory bowel disease. However, currently there are no biomarkers which reliably predict the risk of developing intestinal strictures or identify early stages of fibrosis prior to clinical symptoms. Candidate biomarkers of intestinal fibrosis, including gene variants (i.e. nucleotide-binding oligomerization domain-2 gene), serum microRNAs (miR-19, miR-29), serum extracellular matrix proteins (i.e. collagen, fibronectin) or enzymes (i.e. tissue inhibitor of matrix metalloproteinase-1), serum growth factors (i.e. basic fibroblast growth factor, YKL-40), serum anti-microbial antibodies (i.e. anti-Saccharomyces cerevisiae) and circulating cells (i.e. fibrocytes) have shown conflicting results on relatively heterogeneous patients' cohorts, and none of them was proven to be strictly specific for fibrostenosis, but rather predictive of a disease disabling course. In this review we critically reassess the diagnostic and prognostic value of serum biomarkers of intestinal fibrosis in inflammatory bowel disease.

Keywords: Anti-microbial antibody; Crohn’s disease; extracellular matrix; growth factor; microRNA.

Figure 1.

Pathogenic mechanisms and candidate molecular biomarkers for intestinal fibrosis. Picture shows pre-stenotic dilatation, stricture with fibrotic tissue, lumen, capillary and candidate biomarkers for intestinal fibrosis: genes (red panel), growth factors (purple panel), extracellular matrix (ECM) components (light blue panel), microRNAs (miRs) (yellow panel) and antibodies (green panel). Nucleotide-binding oligomerization domain (NOD)2 variants, which imply loss of binding between NOD2 and the bacterial cell wall component muramyl dipeptide (MDP), polymorphisms of the chemokine fractalkine receptor CX3CR1, variants in the toll like receptor (TLR)4, in the autophagy-related-16L1 (ATG16L1) and in the interleukin 23 receptor (IL23R) induce chronic inflammation leading to stricture development. Excessive deposition of ECM components, which consist of fibronectin, laminin, collagen and its propeptide or telopeptide – such as N-terminal propeptide of type III collagen (PIIINP), C-terminal propeptide of type I collagen (PICP) and C-terminal telopeptide of type I collagen (ITCP) – and alterated tissue remodelling are also due to a specific single nucleotide polymorphism in matrix metalloproteinase (MMP)-3 gene, which loses its proteolytic activity on ECM, and to abnormal expression of tissue inhibitor of matrix metalloproteinases (TIMP)-1. Myofibroblasts, whose proliferation is sustained by endothelial cell-released basic fibroblast growth factor (bFGF), produce increased amounts of collagen in a YKL-40-dependent fashion. YKL-40 is a growth factor secreted by activated macrophages and neutrophils. The production of collagen is also favoured by platelet-derived growth factor (PDGF), secreted by circulating platelets. Moreover, miR-29b, which is suppressed by myofibroblast-produced transforming growth factor (TGF)-β, inhibits the pro-fibrogenic effects of myofibroblasts themselves. These cells express on their surface fibroblast activation protein (FAP) and may be derived from circulating fibrocytes. The abnormal immune response underlying intestinal fibrosis is characterized by the plasma cell (PC)-mediated production of antibodies directed against bacterial components: anti-Escherichia coli outer membrane protein C antibodies (Anti-OmpC), anti-Pseudomonas-associated sequence I2 antibodies (Anti-I2), anti-bacterial flagellin CBir1 antibodies (Anti-CBir1) and anti-glycan antibodies, such as anti-Saccharomyces cerevisiae antibodies (ASCA), anti-chitobioside carbohydrate IgA antibodies (ACCA), anti-mannobioside carbohydrate IgG antibodies (AMCA), anti-laminaribioside IgG antibodies (ALCA), anti-laminarin carbohydrate antibodies (anti-L) and/or anti-chitin carbohydrate antibodies (Anti-C).