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Intestinal fibrosis is the excessive deposition of the extracellular matrix that obstructs intestinal movement. There is no approved medication to treat intestinal stricture. The roles of serum exosomal miRNAs in intestinal fibrosis are unknown. Serum exosomal miRNA sequencing was performed on samples of healthy donors and stricturing CD (CDS) patients. CDS patient-derived primary intestinal fibroblasts (CD-HIFs), CDS patient-derived serum exosomes (CDSE), human peripheral blood mononuclear cells (PBMCs), human colonic tissues, and mouse models of intestinal fibrosis were used. CDS patients had significantly lower serum exosomal miR205-5p levels than non-CDS patients and healthy donors. CDS patients had reduced miR205-5p expression in PBMCs. miR205-5p reduced its target Zinc finger E-box-binding homeobox 1 (ZEB1) and collagen protein expression in CDSE-treated CD-HIFs. In mouse models of intestinal fibrosis, overexpression of miR205-5p inhibited intestinal fibrosis, which was overcome by Zeb1 overexpression. Elafin, a human anti-fibrogenic protein, induced miR205-5p in intestinal fibroblasts. Inhibition of miR205-5p reversed the anti-fibrogenic effects of elafin in mice. Low serum exosomal anti-fibrogenic miR205-5p levels were associated with intestinal strictures in CD patients. miR205-5p can mediate the anti-fibrogenic effect of elafin by inhibiting ZEB1 and collagen expression.<\/jats:p>","DOI":"10.3390\/ijms26083778","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:48:46Z","timestamp":1744850926000},"page":"3778","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["MicroRNA Sequencing of Serum Exosomes Reveals miR205-5p as an Anti-Fibrogenic Factor Against Intestinal Fibrosis in Crohn\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0620-1519","authenticated-orcid":false,"given":"Ying","family":"Xie","sequence":"first","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"},{"name":"Department of Gastroenterology and Endoscopy, The First Hospital of China Medical University, Shenyang 110001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7521-3111","authenticated-orcid":false,"given":"Mieke","family":"van Daelen","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5442-3283","authenticated-orcid":false,"given":"Rebecca","family":"Park","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9218-5667","authenticated-orcid":false,"given":"Isabella","family":"Almaraz","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7430-5275","authenticated-orcid":false,"given":"Lindsey","family":"Fontenot","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9087-1568","authenticated-orcid":false,"given":"Florian","family":"Rieder","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases Institute, Department of Inflammation and Immunity, Lerner Research Institute, Program for Global Translational Inflammatory Bowel Diseases, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7590-4616","authenticated-orcid":false,"given":"Wendy","family":"Ho","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2714-6934","authenticated-orcid":false,"given":"Berkeley","family":"Limketkai","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1335-7044","authenticated-orcid":false,"given":"David Q.","family":"Shih","sequence":"additional","affiliation":[{"name":"F. 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