Molecular Mechanisms Underlying Loss of Vascular and Epithelial Integrity in Irritable Bowel Syndrome

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 167; no. 6; pp. 1152 - 1166
• Main Authors: Barbaro, Maria Raffaella, Cremon, Cesare, Marasco, Giovanni, Savarino, Edoardo, Guglielmetti, Simone, Bonomini, Francesca, Palombo, Marta, Fuschi, Daniele, Rotondo, Luca, Mantegazza, Giacomo, Duncan, Robin, di Sabatino, Antonio, Valente, Sabrina, Pasquinelli, Gianandrea, Vergnolle, Nathalie, Stanghellini, Vincenzo, Collins, Stephen M., Barbara, Giovanni
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024; Elsevier
• Subjects: Cellular Biology; Endocrinology and metabolism; Food and Nutrition; Gut Vascular Barrier Permeability; Histone Deacetylase; Human health and pathology; Intestinal Barrier Permeability; Life Sciences; Plasmalemma Vesicle–Associated Protein 1; Protease-Activated Receptor 2; Subcellular Processes; Vascular Endothelial Cadherin; CD; AST; Protease-Activated Receptor 2; HDAC11; Plasmalemma Vesicle–Associated Protein 1; iPAR; ALT; Intestinal Barrier Permeability; PV1; L/M; UC; Histone Deacetylase; Gut Vascular Barrier Permeability; GVB; IBS-D; IBS-C; PAR2; VEC; Vascular Endothelial Cadherin; HRQOL; HUVEC; IBS-M; IBS; Associated Protein 1; Protease-Activated Receptor2; Plasmalemma Vesicle-Associate
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2024.07.004

The pathophysiology of irritable bowel syndrome (IBS) is multifactorial and includes epithelial barrier dysfunction, a key element at the interface between the gut lumen and the deeper intestinal layers. Beneath the epithelial barrier there is the vascular one representing the last barrier to avoid luminal antigen dissemination The aims of this study were to correlate morpho-functional aspects of epithelial and vascular barriers with symptom perception in IBS. Seventy-eight healthy subjects (controls) and 223 patients with IBS were enrolled in the study and phenotyped according to validated questionnaires. Sugar test was used to evaluate in vivo permeability. Immunohistochemistry, western blot, and electron microscopy were used to characterize the vascular barrier. Vascular permeability was evaluated by assessing the mucosal expression of plasmalemma vesicle–associated protein-1 and vascular endothelial cadherin. Caco-2 or human umbilical vein endothelial cell monolayers were incubated with soluble mediators released by mucosal biopsies to highlight the mechanisms involved in permeability alteration. Correlation analyses have been performed among experimental and clinical data. The intestinal epithelial barrier was compromised in patients with IBS throughout the gastrointestinal tract. IBS-soluble mediators increased Caco-2 permeability via a downregulation of tight junction gene expression. Blood vessel density and vascular permeability were increased in the IBS colonic mucosa. IBS mucosal mediators increased permeability in human umbilical vein endothelial cell monolayers through the activation of protease-activated receptor-2 and histone deacetylase 11, resulting in vascular endothelial cadherin downregulation. Permeability changes correlated with intestinal and behavioral symptoms and health-related quality of life of patients with IBS. Epithelial and vascular barriers are compromised in patients with IBS and contribute to clinical manifestations. [Display omitted] This study demonstrates that intestinal permeability alterations are involved in the development of intestinal and extra-intestinal symptoms in irritable bowel syndrome.