{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:46:33Z","timestamp":1790383593616,"version":"4.1.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Den Danske Forskningsfond"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neutrophils play a significant role in sustaining chronic inflammation in Inflammatory Bowel Disease. The intestinal basement membrane acts as a barrier for immunological homeostasis, where the \u03b13 and \u03b14 chains of type IV collagen are expressed on the mucosal surface. We wanted to develop a biomarker reflecting early tissue injury, providing an opportunity for intervention. Two competitive enzyme-linked immunosorbent assays (ELISAs) quantifying human neutrophil elastase (HNE) degraded neo-epitopes of COL4A3 and COL4A4 were developed and investigated in two observational cohorts (n\u2009=\u2009161, n\u2009=\u2009100). A biomarker of MMP-mediated degradation of COL4A1 (C4M) was used for comparison. In Cohort 1, patients with mild endoscopic ulcerative colitis showed elevated levels of C4A3-HNE compared to those with severe disease. C4M had a strong positive correlation with disease activity. C4A3-HNE\/C4M provided superior discrimination between mild and severe endoscopic disease and negatively correlated to disease activity. In Cohort 2, C4A4-HNE and C4A4-HNE\/C4M showed similar trends. C4A3-HNE and C4A4-HNE possibly reflect early intestinal tissue injury. Combining the markers with a biomarker of another \u03b1-chain of the same collagen provides information on two distinct stages of mucosal damage. These biomarkers may be used to monitor disease flare-up in patients in remission, reducing the need for frequent endoscopic procedures.<\/jats:p>","DOI":"10.1038\/s41598-024-52208-y","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T15:03:55Z","timestamp":1705590235000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Neutrophil-mediated type IV collagen degradation is elevated in patients with mild endoscopic ulcerative colitis reflecting early mucosal destruction"],"prefix":"10.1038","volume":"14","author":[{"given":"Marta S.","family":"Alexdottir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Pehrsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Domislovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Line E.","family":"Godskesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Krag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Kjeldsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marko","family":"Brinar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Barisic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Christine","family":"Bay-Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten A.","family":"Karsdal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeljko","family":"Krznaric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim H.","family":"Mortensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"52208_CR1","unstructured":"McDowell, C., Farooq, U. & Haseeb, M. Inflammatory Bowel Disease. 2022. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30137275."},{"key":"52208_CR2","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1002\/ibd.20539","volume":"15","author":"MA McGuckin","year":"2009","unstructured":"McGuckin, M. A., Eri, R., Simms, L. A., Florin, T. H. J. & Radford-Smith, G. Intestinal barrier dysfunction in inflammatory bowel diseases. Inflamm. Bowel Dis. 15, 100\u2013113. https:\/\/doi.org\/10.1002\/ibd.20539 (2009).","journal-title":"Inflamm. Bowel Dis."},{"key":"52208_CR3","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.3748\/wjg.v20.i5.1165","volume":"20","author":"L Antoni","year":"2014","unstructured":"Antoni, L., Nuding, S., Wehkamp, J. & Stange, E. F. Intestinal barrier in inflammatory bowel disease. World J. Gastroenterol. 20, 1165\u20131179. https:\/\/doi.org\/10.3748\/wjg.v20.i5.1165 (2014).","journal-title":"World J. Gastroenterol."},{"issue":"Suppl 2","key":"52208_CR4","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1097\/00054725-200810001-00077","volume":"14","author":"H Vogelsang","year":"2008","unstructured":"Vogelsang, H. Do changes in intestinal permeability predict disease relapse in Crohn\u2019s disease?. Inflamm. Bowel Dis. 14(Suppl 2), 162\u2013163. https:\/\/doi.org\/10.1097\/00054725-200810001-00077 (2008).","journal-title":"Inflamm. Bowel Dis."},{"key":"52208_CR5","first-page":"S50","volume":"34","author":"R D\u2019Inca","year":"1993","unstructured":"D\u2019Inca, R. et al. Can permeability to sugars predict relapses in Crohn\u2019s disease?. Gut 34, S50\u2013S73 (1993).","journal-title":"Gut"},{"key":"52208_CR6","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1053\/j.gastro.2020.08.005","volume":"159","author":"W Turpin","year":"2020","unstructured":"Turpin, W. et al. Increased intestinal permeability is associated with later development of Crohn\u2019s disease. Gastroenterology. 159, 2092\u20132100. https:\/\/doi.org\/10.1053\/j.gastro.2020.08.005 (2020).","journal-title":"Gastroenterology."},{"key":"52208_CR7","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.jcmgh.2021.03.002","volume":"12","author":"B Drury","year":"2021","unstructured":"Drury, B., Hardisty, G., Gray, R. D. & Ho, G. Neutrophil extracellular traps in inflammatory bowel disease: Pathogenic mechanisms and clinical translation. Cell. Mol. Gastroenterol. Hepatol. 12, 321\u2013333. https:\/\/doi.org\/10.1016\/j.jcmgh.2021.03.002 (2021).","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"52208_CR8","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1111\/1751-2980.12540","volume":"18","author":"GX Zhou","year":"2017","unstructured":"Zhou, G. X. & Liu, Z. J. Potential roles of neutrophils in regulating intestinal mucosal inflammation of inflammatory bowel disease. J. Dig. Dis. 18, 495\u2013503. https:\/\/doi.org\/10.1111\/1751-2980.12540 (2017).","journal-title":"J. Dig. Dis."},{"key":"52208_CR9","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1159\/000199473","volume":"37","author":"W Fischbach","year":"1987","unstructured":"Fischbach, W. et al. Leucocyte elastase in chronic inflammatory bowel diseases: A marker of inflammatory activity?. Digestion 37, 88\u201395. https:\/\/doi.org\/10.1159\/000199473 (1987).","journal-title":"Digestion"},{"key":"52208_CR10","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1039\/c8mo00239h","volume":"15","author":"S Kirov","year":"2019","unstructured":"Kirov, S. et al. Degradation of the extracellular matrix is part of the pathology of ulcerative colitis. Mol. Omics J. 15, 67\u201376. https:\/\/doi.org\/10.1039\/c8mo00239h (2019).","journal-title":"Mol. Omics J."},{"key":"52208_CR11","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/nm.4294","volume":"23","author":"SK Jorch","year":"2017","unstructured":"Jorch, S. K. & Kubes, P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat. Med. 23, 279\u2013287. https:\/\/doi.org\/10.1038\/nm.4294 (2017).","journal-title":"Nat. Med."},{"key":"52208_CR12","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1080\/17474124.2019.1673729","volume":"13","author":"JH Mortensen","year":"2019","unstructured":"Mortensen, J. H. et al. The intestinal tissue homeostasis\u2013the role of extracellular matrix remodeling in inflammatory bowel disease. Expert Rev. Gastroenterol. Hepatol. 13, 977\u2013993. https:\/\/doi.org\/10.1080\/17474124.2019.1673729 (2019).","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"52208_CR13","doi-asserted-by":"publisher","unstructured":"B\u00e4chinger, H. P., Mizuno, K., Vranka, J. A. & Boudko, S. P. Collagen Formation and Structure. in Comprehensive Natural Products II, 469\u2013530 (Elsevier, 2010). https:\/\/doi.org\/10.1016\/B978-008045382-8.00698-5.","DOI":"10.1016\/B978-008045382-8.00698-5"},{"key":"52208_CR14","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1046\/j.1440-1746.2002.02789.x","volume":"17","author":"Y Oka","year":"2002","unstructured":"Oka, Y. et al. Distribution of collagen type IV \u03b11-6 chains in human normal colorectum and colorectal cancer demonstrated by immunofluorescence staining using chain-specific epitope-defined monoclonal antibodies. J. Gastroenterol. Hepatol. 17, 980\u2013986. https:\/\/doi.org\/10.1046\/j.1440-1746.2002.02789.x (2002).","journal-title":"J. Gastroenterol. Hepatol."},{"key":"52208_CR15","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1679\/aohc.70.313","volume":"70","author":"H Sato","year":"2007","unstructured":"Sato, H. et al. The differential distribution of type IV collagen \u03b1 chains in the subepithelial basement membrane of the human alimentary canal. Arch. Histol. Cytol. 70, 313\u2013323. https:\/\/doi.org\/10.1679\/aohc.70.313 (2007).","journal-title":"Arch. Histol. Cytol."},{"key":"52208_CR16","doi-asserted-by":"publisher","first-page":"004","DOI":"10.1093\/nargab\/lqz004","volume":"2","author":"N Maillet","year":"2020","unstructured":"Maillet, N. Rapid peptides generator: Fast and efficient in silico protein digestion. NAR Genom. Bioinform. 2, 004. https:\/\/doi.org\/10.1093\/nargab\/lqz004 (2020).","journal-title":"NAR Genom. Bioinform."},{"key":"52208_CR17","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/BF01551818","volume":"3","author":"ML Gefter","year":"1977","unstructured":"Gefter, M. L., Margulies, D. H. & Scharff, M. D. A simple method for polyethylene glycol-promoted hybridization of mouse myeloma cells. Somatic Cell Genet. 3, 231\u2013236. https:\/\/doi.org\/10.1007\/BF01551818 (1977).","journal-title":"Somatic Cell Genet."},{"key":"52208_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0084934","volume":"8","author":"JM Sand","year":"2013","unstructured":"Sand, J. M. et al. MMP mediated degradation of type IV collagen alpha 1 and alpha 3 chains reflects basement membrane remodeling in experimental and clinical fibrosis\u2014Validation of two novel biomarker assays. PLoS One 8, 1\u201312. https:\/\/doi.org\/10.1371\/journal.pone.0084934 (2013).","journal-title":"PLoS One"},{"key":"52208_CR19","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11195907","author":"V Domislovic","year":"2022","unstructured":"Domislovic, V. et al. Inflammatory biomarkers of extracellular matrix remodeling and disease activity in Crohn\u2019s disease and ulcerative colitis. J. Clin. Med. https:\/\/doi.org\/10.3390\/jcm11195907 (2022).","journal-title":"J. Clin. Med."},{"key":"52208_CR20","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/978-3-319-59856-7_3","volume-title":"Biomarkers for Endometriosis: State of the Art","author":"AH Katsanos","year":"2017","unstructured":"Katsanos, A. H. et al. Biomarker Development in Chronic Inflammatory Diseases. In Biomarkers for Endometriosis: State of the Art (ed. D\u2019Hooghe, T.) 41\u201375 (Springer, 2017). https:\/\/doi.org\/10.1007\/978-3-319-59856-7_3."},{"key":"52208_CR21","doi-asserted-by":"publisher","first-page":"3134","DOI":"10.1007\/s10620-019-05676-6","volume":"64","author":"M Lindholm","year":"2019","unstructured":"Lindholm, M. et al. Extracellular matrix fragments of the basement membrane and the interstitial matrix are serological markers of intestinal tissue remodeling and disease activity in dextran sulfate sodium colitis. Dig. Dis. Sci. 64, 3134\u20133142. https:\/\/doi.org\/10.1007\/s10620-019-05676-6 (2019).","journal-title":"Dig. Dis. Sci."},{"key":"52208_CR22","doi-asserted-by":"publisher","first-page":"e00217","DOI":"10.14309\/ctg.0000000000000217","volume":"11","author":"WT van Haaften","year":"2020","unstructured":"van Haaften, W. T. et al. Serological biomarkers of tissue turnover identify responders to anti-TNF therapy in crohn\u2019s disease: A pilot study. Clin. Transl. Gastroenterol. 11, e00217. https:\/\/doi.org\/10.14309\/ctg.0000000000000217 (2020).","journal-title":"Clin. Transl. Gastroenterol."},{"key":"52208_CR23","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23158137","author":"MS Alexdottir","year":"2022","unstructured":"Alexdottir, M. S. et al. Serological biomarkers of extracellular matrix turnover and neutrophil activity are associated with long-term use of vedolizumab in patients with Crohn\u2019s disease. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms23158137 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"52208_CR24","doi-asserted-by":"publisher","first-page":"S260","DOI":"10.1093\/ecco-jcc\/jjz203.364","volume":"14","author":"J Mortensen","year":"2020","unstructured":"Mortensen, J. et al. P235 serological biomarkers of interstitial matrix and basement membrane remodelling correlate the modified mayo endoscopic score (mMES) for ulcerative colitis. J. Crohns Colitis 14, S260\u2013S261. https:\/\/doi.org\/10.1093\/ecco-jcc\/jjz203.364 (2020).","journal-title":"J. Crohns Colitis"},{"key":"52208_CR25","doi-asserted-by":"publisher","first-page":"i458","DOI":"10.1093\/ecco-jcc\/jjac190.0448","volume":"17","author":"J Mortensen","year":"2023","unstructured":"Mortensen, J. et al. P318 Protein FingerPrint assays reflecting neutrophil activity, mucosal damage, and tissue fibrosis are surrogate biomarkers for mucosal healing in pediatric Crohn\u2019s disease. J. Crohns Colitis 17, i458\u2013i459. https:\/\/doi.org\/10.1093\/ecco-jcc\/jjac190.0448 (2023).","journal-title":"J. Crohns Colitis"},{"key":"52208_CR26","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1139\/o86-054","volume":"64","author":"T Nakano","year":"1986","unstructured":"Nakano, T. & Scott, P. G. Purification and characterization of a gelatinase produced by fibroblasts from human gingiva. Biochem. Cell Biol. 64, 387\u2013393. https:\/\/doi.org\/10.1139\/o86-054 (1986).","journal-title":"Biochem. Cell Biol."},{"key":"52208_CR27","doi-asserted-by":"publisher","unstructured":"E. Arthur Z., S. Susanta K., Neuman, K. C. & G. Gregory I. Matrix Metallopeptidase 9\/Gelatinase B. in Handbook of Proteolytic Enzymes. 1, 754\u2013763 (2013). https:\/\/doi.org\/10.1016\/B978-0-12-382219-2.00157-5.","DOI":"10.1016\/B978-0-12-382219-2.00157-5"},{"key":"52208_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2022.1067950","volume":"13","author":"K Mei","year":"2023","unstructured":"Mei, K. et al. The role of intestinal immune cells and matrix metalloproteinases in inflammatory bowel disease. Front. Immunol. 13, 1\u201315. https:\/\/doi.org\/10.3389\/fimmu.2022.1067950 (2023).","journal-title":"Front. Immunol."},{"key":"52208_CR29","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1053\/gast.1997.v113.pm9352851","volume":"113","author":"A Nusrat","year":"1997","unstructured":"Nusrat, A., Parkos, C. A., Liang, T. W., Carnes, D. K. & Madara, J. L. Neutrophil migration across model intestinal epithelia: Monolayer disruption and subsequent events in epithelial repair. Gastroenterology 113, 1489\u20131500. https:\/\/doi.org\/10.1053\/gast.1997.v113.pm9352851 (1997).","journal-title":"Gastroenterology"},{"key":"52208_CR30","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1093\/ecco-jcc\/jjab177","volume":"16","author":"A Spinelli","year":"2022","unstructured":"Spinelli, A. et al. ECCO guidelines on therapeutics in ulcerative colitis: Medical treatment. J. Crohns Colitis 16, 179\u2013189. https:\/\/doi.org\/10.1093\/ecco-jcc\/jjab177 (2022).","journal-title":"J. Crohns Colitis"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-52208-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-52208-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-52208-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T15:07:57Z","timestamp":1705590477000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-52208-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,18]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["52208"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-52208-y","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,18]]},"assertion":[{"value":"28 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"MA, MP, ACBJ, MK, and JHM are employees of Nordic Bioscience. MK and ACBJ own stocks in Nordic Bioscience. This study was funded by The Danish Research Foundation. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. All other authors have no conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1641"}}