A new study suggests a connection between oral antibiotic use and increased risk of certain types of colorectal cancer.
The study, published this week in the journal Gut, found that the use of oral antibiotics was associated with a slightly increased risk of colon cancer, with the risk being observed even after minimal use of antibiotics, and the greatest effect observed with antibiotics that have anti-anaerobic activity. Penicillin antibiotics, in particular, were strongly associated with increased colon cancer risk.
At the same time, however, antibiotic use was also associated with a reduced risk of rectal cancer.
The authors of the study say the findings, which are observational and don't establish a causal relationship between oral antibiotic use and colorectal cancer, nonetheless provide additional evidence of potential links between antibiotic use, changes in the bacteria that inhabit the human digestive system, and the development of chronic disease.
"This is an area in microbiome research that's of particular interest: the potential associations between our gut microbiome, how it affects our metabolism, and what happens to us, disease-wise, over time," lead study author Cynthia Sears, MD, a professor of medicine at Johns Hopkins University School of Medicine and member of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, told CIDRAP News.
Increased risk in certain anatomic sites
The results come from a matched case-control analysis of data on more than 166,000 patients obtained from the United Kingdom's Clinical Practice Research Datalink, one of the world's largest electronic medical databases.
Using medical records dating from 1989 through 2012, Sears and her colleagues identified 28,980 patients with colorectal cancer and paired them with 137,770 patients, matched for age and gender, who didn't develop colorectal cancer. They then looked at all of the participants' exposure to oral antibiotics over time, from registration date to 1 year before the diagnosis of cancer, along with other risk factors.
The aim was to further explore an antibiotic-cancer association that had been found in previous studies, and investigate the role that gut microbes play in cellular changes in the colon and rectum. "There is an area of research on how the microbiome, and specific bacteria, may be contributing to colon cancer," Sears said. "So the question came up, if you modify the microbiome, is that a feature that's associated with colon cancer?"
Overall, antibiotics were prescribed to 70% of the colorectal cancer patients and 68.5% of the controls, and 59.5% of all participants were exposed to more than one class of antibiotics. Participants who developed colon cancer were slightly more likely to be exposed to antibiotics than the control patients (71.3% vs 69.1%), while patients with rectal cancer had similar exposure compared with controls (67.1% vs 67.2%).
The most commonly prescribed antibiotics were penicillins (80.7%), macrolides (30.4%), sulfa and trimethoprim (28.9%), cephalosporins (25.1%), tetracyclines (20.3%) and quinolones (14.3%).
Participants with either colon or rectal cancer were also more likely to have known risk factors for the disease, including obesity, tobacco and alcohol use, and diabetes. But after controlling their analysis for these factors, Sears and her colleagues found that an increased risk of colon cancer was associated with antibiotic use in a dose-dependent fashion.
Compared with no antibiotic use, the increased risk for colon cancer rose from 8% for patients who'd taken antibiotics for 1 to 15 days (adjusted odds ratio [aOR], 1.08; 95% confidence interval [CI], 1.04 to 1.13) to 17% for patients who'd been exposed to antibiotics for more than 60 days [aOR, 1.17; 95% CI, 1.10 to 1.23).
"With only 15 days or so of antibiotics, you start to see an uptick in association. That was a big surprise," said Sears.
The observed increased risk was highest in colon cancers that developed in the proximal colon—the first and middle parts of the colon—and in patients who were prescribed anti-anaerobic antibiotics, which target bacteria that predominate in the gut and as a result are more likely to disrupt the gut microbiota. No association was observed in distal colon cancer, and the observed increased risk was smaller with anti-aerobic (as opposed to anti-anaerobic) antibiotics.
Sears said the association between antibiotic use and increased risk of cancer in the proximal colon makes sense, since that's the first part of the colon exposed to antibiotics not absorbed in the small intestine.
"When you take an oral antibiotic, any carryover is going to hit the proximal part of the colon first, so any residual, unabsorbed antibiotics would have the greatest capacity to modify the proximal microbiome, before bacteria in the gut degrade those antibiotics," she said.
But antibiotic use was not associated with increased risk of rectal cancer. In fact, in patients exposed to antibiotics for more than 60 days, the risk of rectal cancer was reduced by 15% (aOR, 0.85; 95% CI, 0.79 to 0.93).
Link strongest in penicillins
When the researchers restricted their analysis to patients who had received a single class of antibiotics—versus those who received no antibiotics—penicillin antibiotics were consistently associated with increased risk of colon cancer, while tetracyclines were associated with a reduced risk of rectal cancer.
An analysis of patients with at least 15 years of follow-up showed that use of antibiotics more than 10 years before cancer diagnosis was associated with increased colon cancer risk, while use of antibiotics less than 10 years before cancer diagnosis was not. Sears said that fits with the biology of polyp formation in the gut, which is thought to take roughly 10 years from the time it begins until a tumor is visible.
Among the limitations of the study are missing data on lifestyle factors for 10% to 20% of the study participants, and no information on diet, physical activity, and family history—factors that could play a role in colorectal cancer.
Call for stewardship
While Sears stressed that the findings indicate only an association between oral antibiotic use and colon cancer, and that more research is needed, the take-home message for her is that antibiotics should be used judiciously. Between the concerns about antibiotic resistance and a growing body of research on how antibiotics affect the gut microbiota, Sears said, the public needs to understand that antibiotics have risks, should be taken only when necessary, and for only as long as needed.
"The infectious disease field, of which I'm a part, is keen on getting the message out there about the importance of using this class of medications well, and learning what is the best antibiotic for the shortest course," she said.
Sears said future research will focus on the specific microbes that play a role in the development of colon cancer, with the goal, ultimately, of improving prevention.
See also:
Aug 19 Gut study
