Background: Reduced short-chain fatty acids (SCFAs) has been reported in patients with ulcerative colitis, and increased intake of SCFAs has shown to be clinically beneficial for colitis. Whether SCFAs suppresses tumorigenesis in colitis-associated colorectal cancer remains unknown. The chemopreventive effect of SCFAs in colitis-associated colorectal cancer was evaluated in this study.
Methods: Model of colitis-associated colorectal cancer in male BALB/c mice was induced by azoxymethane (AOM) and dextran sodium sulphate (DSS). SCFAs mix (67.5mM acetate, 40mM Butyrate, 25.9mM Propionate) was administered in drink water during the study period. Macroscopic and histological studies were performed to examine the colorectal inflammation and tumorigenesis in AOM/DSS-induced mice treated with or without SCFA mix. The effects of SCFAs mix on colonic epithelial differentiation were also assessed using Ki67 immunohistochemistry and TUNEL staining.
Results: The administration of SCFAs mix significantly reduced the tumor incidence (4.0±1.6/mouse versus 8.3±2.4/mouse; p<0.001) and size (1.3±0.5mm versus 2.5±0.4mm; p<0.001) in mice with AOM/DSS-induced colitis associated colorectal cancer (Figure 1). SCFAs mix protected from AOM/DSS-induced colorectal cancer by improving colon inflammation (Severity score: 0.9±0.7 versus 2.0±0.8; p=0.005), disease activity index score (3.1±0.6 versus 5.6±1.9; p=0.002) as well as suppressed the expression of pro-inflammatory cytokines including IL-6 (mRNA relative expression: 1.9±0.7 versus 3.2±1.2; p=0.015), TNF-α (22.7±6.9pg/mg versus 33.9±6.1pg/mg; p=0.001), and IL-17 (mRNA relative expression: 1.8±0.8 versus 3.6±1.5; p=0.003). A decrease in cell proliferation markers (Ki67-positive: 3.5±1.0 versus 6.8±1.7; p<0.001) and an increase in TUNEL-positive tumor epithelial cells (0.9±0.2 versus 0.6±0.2; p<0.001) were also demonstrated in AOM/DSS mice treated with SCFAs mix.
Conclusions: SCFAs mix administration prevented development of tumor and attenuated the colonic inflammation in a mouse model of colitis-associated colorectal cancer. SCFAs mix may be a potential agent in the prevention and treatment of colitis-associated colorectal cancer.