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Here, we use a microengineered human gut\u2010on\u2010a\u2010chip model that enables independent control of shear stress and mechanical strain under conditions of intact or impaired epithelial barrier function to interrogate fibroblast dynamics. Inflammation\u2010associated fibroblasts derived from an ulcerative colitis patient exhibit intrinsic tolerance to biomechanical stress, maintaining myofibroblast\u2010like phenotypes marked by hypertrophy and elevated \u03b1\u2010smooth muscle actin aligned with actin stress fibers. In contrast, normal fibroblasts from healthy donors are highly susceptible to fluid shear stress, undergoing matrix metalloproteinase\u2010dependent disruption of focal adhesion signaling, extracellular matrix remodeling, and apoptotic cell death, whereas mechanical strain alone exerts minimal effects. Importantly, an intact epithelial barrier is necessary and sufficient to protect fibroblasts from shear\u2010induced injury, suggesting that \u201cgood fences make good neighbors.\u201d Under barrier dysfunction, prolonged shear exposure promotes the emergence of stiff 3D aggregates composed of mechanoadaptive, myofibroblast\u2010like cells embedded within a complex fibrillar network. These findings identify that fluid shear stress contributes as a key driver of early profibrotic remodeling and highlight epithelial barrier integrity as a critical biomechanical safeguard in inflammatory bowel disease.<\/jats:p>","DOI":"10.1002\/advs.202516040","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T15:27:13Z","timestamp":1775834833000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanostimulatory Cues Determine Intestinal Fibroblast Fate and Profibrotic Remodeling in a Physiodynamic Human Gut\u2010on\u2010a\u2010Chip"],"prefix":"10.1002","volume":"13","author":[{"given":"Soyoun","family":"Min","sequence":"first","affiliation":[{"name":"Department of Inflammation and Immunity Cleveland Clinic Research Cleveland Clinic  Cleveland Ohio 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