Aberrant absorptive enterocyte differentiation is associated with altered ion transport and chronic inflammatory diahrea in IBD patients

Diarrhea is a hallmark of Crohn's disease (CD) and ulcerative colitis (UC), often linked to a leaky epithelial barrier and an impaired fluid and electrolyte absorption. This study investigates whether a defect in enterocyte differentiation contributed to reduced absorptive, but increased leak protein expression in patients with Inflammatory bowel disease (IBD). Segmental biopsies from the terminal ileum to the rectum were collected from IBD patients and healthy controls (HC). mRNA and protein levels of key absorptive ion transporters and markers of cell proliferation and differentiation were analyzed. Disease activity and diarrhea severity were assessed using clinical data, endoscopy, histopathology, and proinflammatory cytokine expression. In healthy subjects, ion transporters such as Na+/H+ exchanger NHE3 (SLC9a3), Cl-/HCO3- exchanger DRA (SLC26A3), short-chain fatty acid transporter MCT1 (SLC16A1), and epithelial Na+ channel ENaC showed distinct segment-specific expression patterns. Compared with HC, inflamed segments from IBD patients exhibited significantly reduced ion transporter expression, and increased expression of the leak-promoting tight junction protein claudin 2. Markers of absorptive enterocyte differentiation-including villin, intestinal alkaline phosphatase (iALP), and HES1-were reduced, whereas the proliferative marker KI67 was elevated. Goblet cell differentiation was also impaired in highly inflammed areas. High diarrhea scores correlated with lower transporter expression. Together, our findings suggest that inflammation-driven defects in epithelial differentiation may represent an important contributing mechanism to IBD-associated diarrhea, alongside other established mechanisms, including direct inflammation- and cytokine-mediated regulation of epithelial ion transporters. Mucosal healing restored normal segmental transporter expression, highlighting the reversibility of these defects.