{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T11:48:15Z","timestamp":1782906495841,"version":"3.54.5"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":29,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Boehringer-Ingelheim"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,7]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Perianal fistulas remain a major complication in Crohn\u2019s disease, profoundly impacting quality of life. Although often therapy refractory, strong heterogeneity exists between patients, both in clinical behavior and therapy response. In this study, we aimed to identify biological factors involved in the clinical behavior of perianal fistulas, allowing better stratification.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Forty-nine patients were included (Crohn\u2019s n\u2009=\u200936, cryptoglandular n\u2009=\u200913). Gene expression was analyzed in internal fistula openings and tracts by RNA sequencing. Data were verified using spatial transcriptomics and functionally in human adult organoid cultures. A gene-module score for keratinization activity was calculated and correlated to the Crohn\u2019s TOpClass classification as well as to long-term fistula outcomes.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Perianal fistulas were associated with the development of stratified squamous epithelium, expressing specific keratins (KRT5, KRT7, and KRT13). In human organoid models, exposing intestinal mucosa to a pro-inflammatory cytokine mixture partially induced similar changes, supporting rectal mucosal redifferentiation in response to perianal wounding. A gene-module score based on the keratinization-associated markers showed a decreasing gradient from cryptoglandular to mild Crohn-related to severe Crohn-related fistula (0.448 vs. \u20130.125 vs. \u20130.448, P\u2009=\u2009.018). Interestingly, the score was also predictive of long-term outcomes: Patients with low keratinization often showed progressive disease (14\/20 patients), whereas this was not seen in the high keratinization group (0\/16, P\u2009&lt;\u2009.001).<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n We identify an epithelial redifferentiation process characterized by a keratinization-associated gene module as part of the healing process in perianal fistula. The extent of the keratinization not only distinguished Crohn-related from cryptoglandular fistulas but also aligned with disease severity and healing potential.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/ecco-jcc\/jjag092","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T12:32:12Z","timestamp":1781613132000},"source":"Crossref","is-referenced-by-count":0,"title":["Impaired keratinization activity in perianal Crohn\u2019s fistulas is associated with poor prognosis"],"prefix":"10.1093","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7881-4958","authenticated-orcid":false,"given":"Marte A J","family":"Becker","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]},{"name":"Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pim J","family":"Koelink","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Ouahoud","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander M","family":"Meisner","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanesa","family":"Muncan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]},{"name":"Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Nabozny","sequence":"additional","affiliation":[{"name":"Department of Immunology and Respiratory Diseases Research, Research and Development Boehringer-Ingelheim , Ridgefield, CT,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Global Computational Biology and Data Sciences, Research and Development Boehringer-Ingelheim , Ridgefield, CT,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Job","family":"Saris","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem A","family":"Bemelman","sequence":"additional","affiliation":[{"name":"Department of Surgery, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert R","family":"D\u2019Haens","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9425-8683","authenticated-orcid":false,"given":"Christianne J","family":"Buskens","sequence":"additional","affiliation":[{"name":"Department of Surgery, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon E","family":"Wildenberg","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The Netherlands"]},{"name":"Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["The 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