Abstract
Extracellular matrix (ECM) remodeling is a hallmark of the pathology of gastrointestinal disorders. Collagen type VI (COL6) is produced by fibroblasts, and the COL6 α3-chain has shown to be elevated in patients with ulcerative colitis (UC), Crohn’s disease (CD) and colorectal cancer (CRC). Measuring COL6α3 in serum may therefore have potential as a biomarker for gastrointestinal disorders. The aims of this study were to develop and validate a competitive ELISA targeting a specific neo-epitope of COL6α3 and evaluate its associations with the gastrointestinal disorders UC, CD and CRC, in comparison to healthy controls. A monoclonal antibody was raised against a matrix metalloproteinase-2 and -9 specific cleavage site of COL6α3 (C6Mα3) and employed in a competitive enzyme-linked immunosorbent assay (ELISA). The assay was developed and technically validated. Levels of C6Mα3 were measured in serum from patients with UC (n = 58), CD (n = 44) and CRC (n = 39) and compared to healthy controls (n = 32). The levels of C6Mα3 were elevated in patients with UC, CD and CRC patients compared to healthy controls (all p < 0.0001). The area under the receiver operating characteristics (AUROC) curve for separation of patients with UC from healthy controls was 0.972 (95% CI: 0.925–1.020, p < 0.0001), with CD from healthy controls was 0.947 (95% CI: 0.885–1.009, p < 0.0001) and with CRC from healthy controls was 0.890 (95% CI: 0.809–0.972, p < 0.0001). We developed a technically robust assay targeting a fragment of COL6, which was elevated in serum from patients with UC, CD and CRC.
Highlights
Inflammatory bowel diseases (IBD) are a group of idiopathic gastrointestinal chronic inflammatory conditions, encompassing ulcerative colitis (UC) and Crohn’s disease (CD), characterized by a dysregulated excessive immune response and tissue damage affecting the mucosa and submucosa of the gastrointestinal tract[1,2,3,4,5]
In IBD COL6α1, COL6α2 and COL6α3 chains are elevated in the intestinal tissue in patients with CD and UC, and COL6 has been demonstrated to be involved in the integrity of the epithelial barrier[20,21]
It has previously been demonstrated that COL6 turnover was elevated in luminal CD and stricturing CD compared to fistulizing CD22
Summary
Inflammatory bowel diseases (IBD) are a group of idiopathic gastrointestinal chronic inflammatory conditions, encompassing ulcerative colitis (UC) and Crohn’s disease (CD), characterized by a dysregulated excessive immune response and tissue damage affecting the mucosa and submucosa of the gastrointestinal tract[1,2,3,4,5]. The extracellular matrix (ECM) is responsible for maintaining tissue architecture in the gastrointestinal tract, and plays an important part of the pathophysiology of UC, CD and colon cancer (CRC)[4,6]. Novel biomarkers reflecting altered ECM remodeling may be an important tool for evaluating pathologically relevant disruptions in intestinal tissue. In cancer and IBD, the turnover of COL6 is altered due to an accumulation of fibroblasts and increased matrix metalloprotease (MMP) activity[9,10,11,12,13]. Based on the function of COL6 and MMPs in cancer and IBD, we hypothesized that a specific MMP-generated COL6α3 fragment could function as a biomarker in gastrointestinal disorders
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