Epithelial Barrier Dysfunction in Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D) via Downregulation of Claudin-1

Background: In patients with diarrhea-predominant irritable bowel syndrome (IBS-D), the diarrheal mechanisms are largely unknown, and they were examined in this study on colon biopsies. Methods: Electrophysiological measurements were used for monitoring functional changes in the diarrheic colon specimens. In parallel, tight junction protein expression was analyzed by Western blot and confocal laser-scanning microscopy, and signaling pathway analysis was performed using RNA sequencing and bioinformatics. Results: Epithelial resistance was decreased, indicating an epithelial leak flux diarrheal mechanism with a molecular correlate of decreased claudin-1 expression, while induction of active anion secretion and impairment of active sodium absorption via the epithelial sodium channel, ENaC, were not detected. The pathway analysis revealed activation of barrier-affecting cytokines TNF-alpha, IFN-gamma, IL-1 beta and IL-4. Conclusions: Barrier dysfunction as a result of epithelial tight junction changes plays a role in IBS-D as a pathomechanism inducing a leak flux type of diarrhea.