Abstract
It has been suggested that manipulation of gut microbiota using antibiotics can inhibit colitis-associated colorectal cancer (CAC) in a mouse model. We investigated whether timing of gut microbial manipulation using antibiotics affects colon tumorigenesis in the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model. CAC was induced in C57BL/6 mice by injection of 12.5 mg/kg AOM followed by three rounds of 1.7% DSS exposure. There were six groups based on timing of antibiotic administration. Colonic inflammation, proliferation, and tumorigenesis were evaluated after animal sacrifice. High-throughput sequencing of the mice feces was performed to characterize changes in gut microbiota. Full-time antibiotic treatment significantly decreased the number and size of tumors, histological scores, and expression of pro-inflammatory cytokines compared to the AOM/DSS group without antibiotic treatment. The early and late antibiotic groups, antibiotic administration from the first and second rounds of DSS to the end of the study, showed significantly lower histological scores and tumor burden. In contrast, the pretreatment antibiotic group, antibiotic administration from 3 weeks prior to AOM to the first round of DSS, did not exhibit decreased tumorigenesis. Principal coordinate analysis showed similar gut microbial community structures among the full-time, early, and late antibiotic groups, whereas other groups showed distinct gut microbial profiles. There was a positive correlation between number of tumors and number of operational taxonomic units. Colonic tumorigenesis was attenuated by antibiotic administration, except for that only prior to DSS administration, suggesting that gut microbial changes should be maintained throughout the entire period of inflammation to suppress tumorigenesis.
Highlights
Inflammatory bowel disease (IBD), characterized by chronic relapsing inflammation of the gastrointestinal tract, has emerged as a substantial public health challenge worldwide [1]
We demonstrated that manipulation of the gut microbiota using antibiotics attenuates colon tumorigenesis in the AOM/dextran sodium sulfate (DSS)-induced murine CAC model
Attempts to suppress tumorigenesis have been made by manipulating gut microbiota, given that microorganisms are responsible for one axis of tumorigenesis, and the results have shown that manipulation of gut microbiota using antibiotics suppressed colon tumorigenesis in the AOM/DSS model [8, 9]
Summary
Inflammatory bowel disease (IBD), characterized by chronic relapsing inflammation of the gastrointestinal tract, has emerged as a substantial public health challenge worldwide [1]. IBD causes debilitating gastrointestinal symptoms and can cause colitis-associated cancer. Gut microbiota manipulation and colitis-associated cancer (CAC) over the long term [2]. The duration and severity of IBD are associated with development of CAC [3]. The pathogeneses of IBD and CAC are not completely understood, it is generally accepted that excessive immune responses to gut microbiota and subsequent chronic inflammation are involved [4]. Unlike sporadic CRC, mutations in the p53 gene are highly abundant at an early stage of dysplasia during development of CAC. Intestinal barrier dysfunction promotes bacterial invasion, sustains intestinal inflammation, and eventually results in mutations in the adenomatous polyposis coli (APC) gene and carcinoma development [5]. Several specific microbes, including Escherichia coli, Bacteroides fragilis, and Fusobacterium nucleatum, have been reported to be associated with colonic tumorigenesis; a single causative organism has not yet been identified [6]
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