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

Abstract

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-α, IFN-γ, IL-1β 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.

Exploring the Contribution of Campylobacter jejuni to Post-Infectious Irritable Bowel Syndrome: A Literature Review

“…Enhanced macromolecule permeability was evidenced by a temperature-dependent augmentation in horseradish peroxidase (HRP) absorption within the PI-IBS group. This phenomenon indicates the activation of the transcytotic pathway in colonic mucosa functional assessments of PI-IBS patients, shown by increased HRP transport at 37 • C but not at 12 • C causing the immune activation [48]. Such macromolecule uptake signifies the translocation of antigens from the intestinal lumen to the mucosa, presenting significant pathological implications for mucosal balance when this process is prompted [1].…”

“…Specifically, individuals who experienced Campylobacter enteritis displayed an increase in enterochromaffin cells, intraepithelial lymphocytes and intestinal permeability, persisting for up to a year post-infection [7]. Disruption of the epithelial barrier often coincides with accentuated hypersensitivity in IBS, exacerbating abdominal pain symptoms within this condition [48] Prior clinical examination has demonstrated that patients with IBS-D and PI-IBS exhibit heightened permeability in the small intestine to 339 Da 51 -Cr-ethylenediaminetetraacetic acid (EDTA), in contrast to control subjects, which links the acute barrier disruption resulting from infection and the persistence of this barrier defect, aligning with the leaky gut concept, to the emergence of IBS symptoms [48].…”

“…It is significant to mention that these observations represent the inaugural set of paracellular ion permeability measurements in the context of PI-IBS. Beyond the role of active ion secretion, diarrhea observed in IBS-D may also arise from a malabsorptive mechanism [48]. The ENaC is the primary sodium absorption system in the distal colon and rectum.…”

“…The ENaC is the primary sodium absorption system in the distal colon and rectum. Prior research has shown that ENaC-dependent sodium absorption is notably diminished in cases of lymphocytic colitis, contributing to diarrhea [48]. This dysfunction of ENaC points to a significant pathomechanism within the large intestine, illustrating its involvement in conditions such as ulcerative colitis and campylobacteriosis, where impaired sodium absorption plays a pivotal role in the manifestation of diarrheal symptoms [48].…”

“…Prior research has shown that ENaC-dependent sodium absorption is notably diminished in cases of lymphocytic colitis, contributing to diarrhea [48]. This dysfunction of ENaC points to a significant pathomechanism within the large intestine, illustrating its involvement in conditions such as ulcerative colitis and campylobacteriosis, where impaired sodium absorption plays a pivotal role in the manifestation of diarrheal symptoms [48]. Functional and expression analyses of the sigmoid colon have identified claudins (1-5 and 8), occludin and tricellulin as crucial constituents of TJ that dictate the epithelial barrier's function in the colon [48].…”