Antibiotics suppress colon tumorigenesis through inhibition of aberrant DNA methylation in an azoxymethane and dextran sulfate sodium colitis model

Abstract

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 that colonic microbiota modulates the inflammation response in the host and influences colon tumorigenesis. However, the influence of 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 < .01) and area of occupancy from 50.1 ± 57.4 to 0.5 ± 1.4 mm2 (P < .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%‐92% (P < .05) with antibiotic treatment. Microbiome analysis showed that this change was associated with a decrease of the Clostridium leptum subgroup. These data indicate that antibiotics suppressed tumorigenesis through inhibition of aberrant DNA methylation induced by chronic inflammation.

Role of Clostridium perfringens Enterotoxin on YAP Activation in Colonic Sessile Serrated Adenoma/Polyps with Dysplasia

“…Conversely, suppression of intestinal C. perfringens and C. difficile inhibits colon carcinogenesis in APC-deficient mice [26]. The mechanisms of carcinogenesis promotion by C. perfringens have been suggested, including increase in promoter DNA methylation [27] and induction of production of inflammatory cytokines such as tumor necrosis factor-α and interleukin-12 [28]. In this study, we attempted to clarify the mechanism of YAP activation by CPE.…”

Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer

“…Usually administered by gavage or drinking water, antibiotics are commonly used in in vivo models to study the impacts of gut microbiome on cancer or other inflammatory diseases. Indeed, antibiotic-mediated microbiome depletion was reported to attenuate CRC development in various studies [82][83][84], and such protective effect is suggested to be primarily through the elimination of the carcinogenic Bacteroides fragilis [85], as well as bacteria that are associated with mucin degradation [86], inflammation and DNA methylation [87].…”

Identification of Genes in Patients for Predicting Ulcerative Colitis-Associated Colorectal Cancer

“…In ammation has been regarded as a key factor contributing to IBD-CRC, and might promote cancer development via inducing DNA methylation mutation (11), and antibiotics could prevent colon epithelial cell proliferation by inhibiting DNA methylation and mutation (12). Runt-related transcription factor (RUNX) 3 was reported to loss activity in UC associated cancer (13), which might could be used for predict UC associated CRC.…”