P113 Effects of change in the gut microbiota on colon tumorigenesis in AOM-DSS model

Abstract

Background and Aim: The altered intestinal microbial profiles have been known to be associated with colorectal cancer as well as inflammatory bowel diseases. To determine the role of the commensal bacteria in the development of colitis-associated cancer (CAC), we investigated the effects of intestinal microbial change through antibiotics administration on colon tumorigenesis in the azoxymethane (AOM)-dextran sodium sulfate (DSS)-induced murine CAC model. Methods: CAC was induced in the C57BL/6 mice by injection of 10 mg/kg AOM followed by two rounds of 2% DSS exposure to elicit colitis. Four antibiotics combination (vancomycin, ampicillin, neomycin, and metronidazole) or each individual antibiotic were administered for 2 weeks prior to and throughout the duration of AOM/DSS administration. After sacrifice of the mice, colonic inflammation, proliferation, and tumorigenesis were evaluated. To characterize the change of intestinal microbiota, high throughput Illumina MiSeq sequencing for sequential feces was performed. Results: Antibiotics treatment, regardless of cocktail or individual, decreased AOM/DSS-induced tumor numbers, mean tumor size, histologic colitis and dysplasia scores, and pro-inflammatory and proliferatory cytokine expressions compared to AOM/DSS group without antibiotics treatment. Individual antibiotic treatment induced variable tumor burdens and degree of colitis, ranging between those of antibiotics cocktail-treated group and antibiotics nontreated group. Metagenomic sequencing analysis demonstrated that different antibiotics treatments generated different intestinal bacterial communities from each other. There was a positive correlation between the number of tumors and number of operational taxonomic units. The relative abundances of Proteobacteria and Tenericutes phylum were positively related to tumor burden, while sum of the relative abundances of Firmicutes and Bacteroidetes phylum, especially that of Clostridia class were negatively related to tumor burden. Conclusion: The change of intestinal microbiota through antibiotics administration attenuates colon tumorigenesis. Ecological interactions of the gut microbial community, rather than individual bacterial population, play an important role in the development of CAC.