Inhibitory Effects of Lactulose on Colitis-Associated Carcinogenesis by Restoration of the Gut Microbiota in AOM/DSS Mouse Model

In this study, we investigated the effect of lactulose on gastrointestinal inflammation and inflammation-related tumorigenesis in a mouse model of colorectal cancer. Eight week old female C57BL6 NCr Slc mice received a single intraperitoneal injection of azoxymethane, followed by oral administration of sodium dextran sulfateonce every 7 days per set in 3 sets. For lactulose treatment, mice were fed lactulose for 14 weeks after AOM/DSS treatment. Stool samples collected from mice were used for metagenomic analysis. Pathological progression and gene expression in tissues extracted 21 weeks after AOM injection were evaluated. AOM/DSS treatment induced colorectal tumorigenesis, enhanced the expression of tumor necrosis factor-alpha, interleukin-6 (IL-6), and transforming growth factor beta 1, and decreased intestinal flora diversity. Lactulose administration significantly suppressed tumor development, inhibited TNF and IL-6 upregulation, recovered the diversity in intestinal flora, and induced favorable modifications in intestinal bacterial composition. Starch degradation and amino acid metabolism upregulated by AOM/DSS treatment were suppressed by lactulose. These findings suggest that lactulose suppresses inflammatory tumorigenesis caused by inflammatory cytokines, potentially by modulating the diversity of the intestinal flora.