Decreased Colonic Activin Receptor-Like Kinase 1 Disrupts Epithelial Barrier Integrity in Patients With Crohn’s DiseaseSummary

• Published in: Cellular and molecular gastroenterology and hepatology 2020-01, Vol.10 (4), p.779-796
• Main Authors: Takahiko Toyonaga, Erin C. Steinbach, Benjamin P. Keith, Jasmine B. Barrow, Matthew R. Schaner, Elisabeth A. Wolber, Caroline Beasley, Jennifer Huling, Yuli Wang, Nancy L. Allbritton, Nicole Chaumont, Timothy S. Sadiq, Mark J. Koruda, Animesh Jain, Millie D. Long, Edward L. Barnes, Hans H. Herfarth, Kim L. Isaacs, Jonathan J. Hansen, Michael T. Shanahan, Reza Rahbar, Terrence S. Furey, Praveen Sethupathy, Shehzad Z. Sheikh
• Format: Article
• Language: English
• Subjects: ALK1; Inflammatory Bowel Disease; Intestinal Epithelial Barrier; miR-31
• ISSN: 2352-345X; 2352-345X

Background & Aims: Intestinal epithelial cell (IEC) barrier dysfunction is critical to the development of Crohn’s disease (CD). However, the mechanism is understudied. We recently reported increased microRNA-31-5p (miR-31-5p) expression in colonic IECs of CD patients, but downstream targets and functional consequences are unknown. Methods: microRNA-31-5p target genes were identified by integrative analysis of RNA- and small RNA-sequencing data from colonic mucosa and confirmed by quantitative polymerase chain reaction in colonic IECs. Functional characterization of activin receptor-like kinase 1 (ACVRL1 or ALK1) in IECs was performed ex vivo using 2-dimensional cultured human primary colonic IECs. The impact of altered colonic ALK1 signaling in CD for the risk of surgery and endoscopic relapse was evaluated by a multivariate regression analysis and a Kaplan–Meier estimator. Results: ALK1 was identified as a target of miR-31-5p in colonic IECs of CD patients and confirmed using a 3’-untranslated region reporter assay. Activation of ALK1 restricted the proliferation of colonic IECs in a 5-ethynyl-2-deoxyuridine proliferation assay and down-regulated the expression of stemness-related genes. Activated ALK1 signaling increased colonic IEC differentiation toward colonocytes. Down-regulated ALK1 signaling was associated with increased stemness and decreased colonocyte-specific marker expression in colonic IECs of CD patients compared with healthy controls. Activation of ALK1 enhanced epithelial barrier integrity in a transepithelial electrical resistance permeability assay. Lower colonic ALK1 expression was identified as an independent risk factor for surgery and was associated with a higher risk of endoscopic relapse in CD patients. Conclusions: Decreased colonic ALK1 disrupted colonic IEC barrier integrity and was associated with poor clinical outcomes in CD patients.