Creatine Suppressed Colitis-Associated Colorectal Cancer in C57BL/6 Mice through Regulating M1/M2 Macrophage Polarization and Gut Microbial Homeostasis

Colitis-associated colorectal cancer (CAC) is a serious complication of inflammatory bowel disease (IBD) with complex etiology involving chronic inflammation, immune dysregulation, and gut microbiota dysbiosis. Creatine, a natural nitrogenous compound, possesses anti-inflammatory and immunomodulatory properties, but its role in CAC remains unclear. We utilized a mouse model of CAC induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) in male C57BL/6 mice, and supplemented mice with creatine in drinking water. We assessed the effects of creatine on colitis severity, tumor burden, and histopathology. Additionally, we investigated the impact of creatine on gut barrier function, macrophage polarization, and gut microbiota composition. Creatine supplementation significantly alleviated DSS-induced colitis, reduced tumor burden, and delayed CAC progression in mice. Mechanistically, creatine improved gut barrier function by protecting tight junction proteins from degradation induced by the modeling stimulus, influenced macrophage polarization, and maintained gut microbiota diversity, promoting the abundance of beneficial bacteria while reducing harmful ones. Our findings suggest that creatine supplementation may represent a promising supportive therapy for IBD and CAC.