Abstract A24: Lifetime use of antibiotics and risk of colorectal adenoma
Authors: Cao Yin , Wu Kana , Mehta Raaj , Drew David , Song Mingyang , Lochhead Paul , Izard Jacques , Fuchs Charles , Garrett Wendy , Huttenhower Curtis , Ogino Shuji , Giovannucci Edward , Chan Andrew 
Published: March 2017

Background: Antibiotics shift the gut microbiota to temporally quasi-stable or alternative stable states, marked by a loss of diversity, alternations in the abundance of specific taxa, shifts in metabolic capacity, and by reduced resistance to colonization against invading pathogens. Recent evidence suggests that antibiotic use may be associated with an increased risk of colorectal cancer. However, these prior studies may be confounded by symptoms associated with colorectal cancer or differential exposure to medical care. To address these potential concerns, we examined the association of chronic antibiotic exposure and recent antibiotic use with risk of colorectal adenomas, which are largely asymptomatic and the precursor of majority of colorectal cancers.

Methods: We prospectively evaluated the association between chronic lifetime antibiotic use at age 20-39 and age 40-59 (assessed in 2004), and recent antibiotic use (assessed in 2008) and risk of subsequent colorectal adenoma among women aged ≥60 in the Nurses' Health Study who underwent at least one lower endoscopy through 2010. Antibiotic use was categorized according to the total time using antibiotics (excluding skin creams, mouthwash or Isoniazid) during a specific time period (age 20-39, or age 40-59, or past 4 years). We also investigated the association between antibiotic exposure during each time period and risk of high-risk (adenoma ≥1cm, or with villous histology, or ≥3 adenomas) vs. low-risk adenoma, as well as risk of adenoma according to anatomic location. We used multivariate logistic regression adjusting for known and putative risk factors for adenoma to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Among 17,002 women aged ≥60 who reported their antibiotic exposure and then subsequently underwent at least one lower endoscopy, we documented 1,213 cases of adenoma over 6 years of follow-up. An increasing duration of antibiotic use at age 20-39 (Ptrend=0.002) and 40-59 (Ptrend=0.001) was significantly associated with an increased risk of colorectal adenoma. Compared to non-users, women who used antibiotics for ≥2 months between age 20-39 had a multivariable OR for adenoma of 1.37 (95% CI: 1.04-1.81). Women who used ≥2 months of antibiotics between age 40-59 had a multivariable OR of 1.71 (95% CI: 1.25-2.33). The associations were similar for high-risk compared to low-risk adenomas, but appeared somewhat stronger for adenomas of the proximal compared with distal colon. In contrast, recent antibiotic use within the past 4 years was not associated with risk of adenoma (Ptrend=0.44).

Conclusion: In this prospective study, exposure to antibiotics earlier in life (age 20-39 and 40-59) was significantly associated with an increased risk for colorectal adenoma. This increased risk was evident even after adjustment for known colorectal cancer risk factors. In contrast, more recent antibiotic use (within 4 years) was not associated with risk. To the best of our knowledge, this study is the first to link midlife antibiotic use, in a dose-dependent fashion, to colorectal adenoma. These data provide additional support for the association of the gut microbiome with colorectal neoplasia.

Citation Format: Yin Cao, Kana Wu, Raaj Mehta, David Drew, Mingyang Song, Paul Lochhead, Jacques Izard, Charles Fuchs, Wendy Garrett, Curtis Huttenhower, Shuji Ogino, Edward Giovannucci, Andrew Chan. Lifetime use of antibiotics and risk of colorectal adenoma. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A24.