Abstract
<jats:p>Ulcerative colitis is characterized by relapsing-remitting phases and impaired intestinal barrier integrity. Creatine supplementation ameliorates colitis severity and intestinal barrier damage; however, the mechanisms underlying its protective effects remain poorly understood. We investigated whether creatine prevents inflammation and preserves epithelial architecture and the proper expression and localization of proteins involved in intestinal barrier integrity, with attention to sex-specific effects. Using a dextran sulfate sodium-induced chronic colitis model in male and female rats, we evaluated classical readouts together with novel structural and vascular parameters. In both sexes and during both disease phases, creatine attenuated clinical symptoms and colonic damage while preventing pro-inflammatory cytokine upregulation, epithelial mucin-2 depletion, mislocalization and dysregulated expression of ZO-1, claudin-5, E-cadherin, and β-catenin, as well as alterations in endothelial caveolin-1 and plasmalemma vesicle-associated protein-1. Furthermore, creatine preserved epithelial scutoid geometry. Overall, it benefited both sexes, with greater efficacy during the active phase and more pronounced effects in males. These findings identify anti-inflammatory action and preservation of epithelial and vascular barrier integrity as key mechanisms underlying creatine-mediated protection, sustaining key parameters at normal levels throughout the active and remission phases of colitis, promoting the recovery of gut homeostasis, and supporting creatine as a safe and accessible adjuvant therapy for ulcerative colitis.</jats:p>