Antibiotics Use and Subsequent Risk of Colorectal Cancer: A Swedish Nationwide Population-Based Study

Abstract

Background: Antibiotics use may increase colorectal cancer (CRC) risk by altering the gut microbiota, with suggestive evidence reported. Our study aims to investigate antibiotics use in relation to subsequent CRC risk.

Methods: This is a nationwide, population-based study with a matched case-control design (first primary CRC cases and 5 matched, cancer-free controls). Complete-population data, extracted from Swedish national registers for the period 2005-2016, were used to calculate odds ratios and 95% confidence intervals.

Results: We included 40 545 CRC cases and 202 720 controls. Using the full dataset, we found a positive association between more frequent antibiotics use and CRC, excluding antibiotics prescribed within 2 years of diagnosis attenuated results toward the null. In site-specific analyses, excluding the 2-year washout, the positive association was confined to the proximal colon (adjusted odds ratio for very high use vs no use = 1.17, 95% confidence interval = 1.05 to 1.31). For rectal cancer, an inverse association, which appears to be driven by women, was observed. Quinolones and sulfonamides and/or trimethoprims were positively associated with proximal colon cancer, whereas a more general inverse association, across antibiotics classes, was observed for rectal cancer. We found no association between methenamine hippurate, a urinary tract antiseptic not affecting the gut microbiota, and CRC risk.

Conclusions: This register-based study covering the entire population of Sweden found a robust association between antibiotics use and higher risk of proximal colon cancer and an inverse association with rectal cancer in women. This study strengthens the evidence from previous investigations and adds important insight into site-specific colorectal carcinogenesis.

Figure 1.

Flowchart of case and control selection. ^aThe Swedish colorectal cancer register was initiated in 1995 for rectal cancer and in 2007 for colon cancer. ^bCase first diagnosed before the start of the Swedish Colorectal Cancer Register. ^cThree cases had fewer than 5 eligible controls.

Figure 2.

Associations between antibiotics use and risk of colorectal cancer (CRC) by tumor subsites. Odds ratios (OR), conditioned on matching factors (age, sex, county) and adjusted for socioeconomic factors (level of education, country of birth, marital status) and health-care utilizations prior the 2 years preceding CRC diagnosis (number of specialist visits and hospitalizations). Antibiotics use during the 2 years preceding CRC diagnosis was excluded to account for possible reverse causation. CI = confidence interval.

Figure 3.

Associations between antibiotics classes and risk of site-specific colorectal cancer, stratified by sex. Odds ratios (OR), conditioned on matching factors (age, sex, county) and adjusted for socioeconomic factors (level of education, country of birth, marital status) and health-care utilizations prior the 2 years preceding colorectal cancer (CRC) diagnosis (number of specialist visits and hospitalizations). Antibiotics use during the 2 years preceding CRC diagnosis was excluded to account for possible reverse causation. Antibiotics with effect on both anaerobic and aerobic bacteria, and metrodinazoles and/or tinidazoles (which only affect anaerobic bacteria) were categorized as anti-anaerobic antibiotics. Antibiotics that primarily or only affect aerobic bacteria were categorized as anti-aerobic antibiotics. Any use of specific antibiotics class was compared with no use of the specific antibiotics class (reference category) during the study period. Results for all participants (A), men (B), and women (C) are shown. CI = confidence interval.

Figure 4.

Associations between methenamine hippurate use and risk of colorectal cancer (CRC). Odds ratios (OR), conditioned on matching factors (age, sex, county) and adjusted for socioeconomic factors (level of education, country of birth, marital status) and health-care utilizations prior the 2 years preceding CRC diagnosis (number of specialist visits and hospitalizations). Methenamine hippurate use during the 2 years preceding CRC diagnosis was excluded to account for possible reverse causation. The P_trend represents a trend test in which the 5 categories of antibiotics use were included in the model as a continuous variable. CI = confidence interval.