319 Introduction Crohn’s disease (CD) is a chronic ulcerative inflammatory disease mainly affecting the gastrointestinal (GI) tract and is characterized by an inappropriate and uncontrolled immune response that is putatively triggered by the gut microbiome in genetically susceptible individuals.1 Longstanding (often subclinical) disease activity may progress to disease complications, including stricturing (i.e., intestinal stenosis) and penetrating (i.e., intestinal fistulae, abscesses, or perforations) disease phenotypes, which are already present in 30-50% of patients at the time of diagnosis and eventually occur in more than 70% of patients.2,3 Stricturing and/or penetrating disease complications are often classified according to the Montreal classification as disease behavior subtypes, which consist of non-stricturing, non-penetrating disease (B1), stricturing (B2), and penetrating (B3) disease.4 The intestinal (sub)mucosa is rich in extracellularmatrix (ECM) proteins, including collagens, which are very important to maintain epithelial integrity and structure and tensile strength of the intestinal tissue. The ECM can be divided into two layers, the basement membrane (BM) and interstitial matrix (IM). The most abundant collagen of the BM is type IV collagen, whereas type I and III collagens are the most abundant collagens of the IM, which are directly associated with the intestinal epithelium (Figure 1). At the interface between the BM and IM, type VI collagen is highly expressed and acts as an anchor of the BM, by interacting directly with type IV collagen and perlecan.5 Fibrosis is considered the primary pathophysiological mechanism underlying disease complications, in CD which is a result of excessive ECM deposition, mainly collagens, and abnormal remodeling due to chronic inflammation and impaired wound healing.6 This process is mediated by increased proliferation and differentiation of intestinal (myo) fibroblasts, and is considered to drive the development and progression of intestinal stricture formation.5,7 On the other hand, chronic intestinal inflammation may lead to ECM breakdown and remodeling, as many local cells secrete proteases and structural proteins.7,8 For example, inflammatory cells, e.g. macrophages and neutrophilic granulocytes, produce matrix metalloproteinases (MMPs), which are collagenases able to destroy ECM components. Moreover, T-lymphocytes express granzyme-B, resulting in epithelial barrier disruption, mucosal damage and giving rise to intestinal fistula formation.5,9 Fistulae may occur when healing of chronic ulcers is impaired due to increased activity of granulocytes and T-cells leading to increased protease activity, including MMPs, resulting in chronic tracts of granulation tissue between two epithelial-lined surfaces after re-epithelialisation of penetrating ulcers.5,10-12 Collagen biomarkers and Crohn’s disease behavior
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