Antibiotics Suppress Colon Tumorigenesis Through Inhibition of Aberrant DNA Methylation in an AOM/DSS Colitis Model

Summary

Chronic inflammation is involved in the development of colon cancer by inducing mutations and aberrant DNA methylation in colon epithelial cells. Furthermore, there is growing evidence showing that the colonic microbiota modulates the inflammation response in the host and influences colon tumorigenesis. However, the influence of the colonic microbiota on aberrant DNA methylation remains unknown. Here, we show the effect of colonic microbes on DNA methylation and tumorigenicity using a mouse model of human ulcerative colitis. Mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS) showed an increase in degree of colitis, as estimated by body weight, occult blood, and stool consistency/diarrhea at 2 weeks after treatment, but treatment with antibiotics markedly reduced the severity of the colitis. Although mucosal hyperplasia and increased inflammation‐related genes were observed in the colonic epithelial cells of the AOM/DSS‐treated mice, treatment with antibiotics abrogated these changes. In addition, treatment with antibiotics significantly decreased the number of mucosal nodules from 5.9 ± 5.3 to 0.2 ± 0.6 (P < 0.01) and area of occupancy from 50.1 ± 57.4 to 0.5 ± 1.4 mm² (P < 0.01). Aberrant DNA methylation of three marker CpG islands (Cbln4, Fosb and Msx1) was induced by AOM/DSS treatment in colonic mucosae, but this increase was suppressed by 50% to 92% (P < 0.05) with antibiotic treatment. Microbiome analysis showed that this change was associated with a decrease of the Clostridium leptum subgroup. These data demonstrate that antibiotics suppressed tumorigenesis through inhibition of aberrant DNA methylation induced by chronic inflammation.

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