Oral antibiotic use and risk of colorectal cancer in the United Kingdom, 1989-2012: a matched case-control study

Background: Microbiome dysbiosis predisposes to colorectal cancer (CRC), but a population-based study of antibiotic exposure and risk patterns is lacking. In this study, oral antibiotic use on CRC incidence was assessed.  Methods: A matched case-control study (incident CRC cases and up to 5 matched controls) was performed using the Clinical Practice Research Datalink (CPRD; January 1, 1989 to December 31, 2012). Conditional logistic regression was used to assess CRC association with oral antibiotic use, adjusting for potential confounders. Antibiotic exposure in categorical and continuous terms (spline) was investigated for pattern of risk, stratified by specific tumor location. Findings: 28,980 CRC cases and 137,077 controls were identified. Oral antibiotic use was associated with CRC risk, but effects differed by anatomic location. Antibiotic use was found to be associated with excess risk of colon cancer in a dose-dependent fashion (Ptrend<0·0001). The risk was observed after minimal antibiotic use, and was greatest in the proximal colon and with antibiotics with anti-anaerobic activity. In contrast, an inverse association was detected between antibiotic use and rectal cancers (Ptrend =0·003), particularly with length of antibiotic exposure >60 days (Adjusted Odds Ratio [AOR], 0·85, 95% CI 0·79–0·93) as compared with no antibiotic exposure. Penicillins were associated with increased risk of colon cancer (AOR,1·09, [1·05-1·13]) whereas tetracyclines were associated with risk reduction for rectal cancer (AOR, 0·90, [0·84-0·97]). Significant interactions were detected between antibiotic use and tumor location (colon vs rectum, Pinteraction <0·0001; proximal colon vs distal colon, Pinteraction =0·0194). The antibiotic-cancer association was found for antibiotic exposure occurring >ten years before diagnosis (AOR, 1·17, [1·06-1·31]). Interpretation: Oral antibiotic use is associated with an increased risk of colon cancer risk but a reduced risk for rectal cancer. This effect heterogeneity may suggest differences in gut microbiota and carcinogenesis mechanisms along the lower intestine tract.