Highly Ca ²⁺ -permeable Transient Receptor Potential Vanilloid 6 Contributes to the Protection against Colitis by Regulating Epithelial Barrier Function

Transient receptor potential vanilloid 6 (TRPV6) is a highly Ca 2+ -permeable cation channel predominantly expressed in the intestinal epithelium. It plays a crucial role in maintaining systemic calcium homeostasis by regulating Ca 2+ absorption in the intestine. However, its local physiological and pathophysiological roles in the intestine remain unexplored. The exact cause of inflammatory bowel disease is not fully understood; however, disruption of the intestinal epithelial barrier is a key pathogenic mechanism. In this study, we aimed to elucidate the role of TRPV6 in the pathogenesis of colitis. Experimental colitis was induced in TRPV6-deficient (KO) and wild-type (WT) mice by administering 2% dextran sulfate sodium solution (DSS) in drinking water for 7 days. DSS treatment resulted in weight loss, diarrhea/bloody stool, histological colonic injury, and colon shortening. The systemic symptoms and colonic injury were significantly worse in TRPV6KO mice than in WT mice. DSS treatment increased tumor necrotic factor-α, interleukin-1β, interleukin-6 mRNA expressions, and myeloperoxidase activity, and these responses were significantly enhanced in TRPV6KO mice compared with WT mice. Under normal (no-DSS-treated) conditions, TRPV6KO mice exhibited increased intestinal permeability compared with WT mice. No difference was observed in the number of goblet cells between WT and TRPV6KO mice; however, the expression of intercellular junction proteins, including E-cadherin, claudin-3, and occludin, was significantly suppressed in TRPV6KO mice compared with WT mice. These findings suggest that TRPV6 protects against DSS-induced colitis, potentially by regulating epithelial barrier function through intracellular junction protein expressions.