Antibiotics may raise colon cancer risk, massive study suggests

 
Taking antibiotic drugs may raise the risk of developing colon cancer five to 10 years down the line, according to a new study of more than 40,000 cancer cases in Sweden.

Past studies hinted that antibiotics can cause lasting changes to the gut microbiome — the community of microbes that live in the digestive tract — and that these changes may be linked to a heightened risk of colon cancer. Now, in the largest epidemiological study to ever explore this link, researchers report that the heightened risk may be specific to cancers in the so-called proximal colon, the part of the colon that connects to the small intestine and starts in the lower-right abdomen.

"It's very clear, when we looked at the data, that it's very confined to the proximal, or right-sided colon," senior author Sophia Harlid, a cancer researcher at Umeå University in Sweden, told Live Science. And in fact, the antibiotic-related cancer risk was greatest at the start of the proximal colon, called the "ascending colon," which extends from the lower- to upper-right abdomen.

People who took antibiotics for more than six months bore the highest cancer risk, according to the research, published Wednesday (Sept. 1) in the Journal of the National Cancer Institute. Compared with people who'd taken no antibiotics, these individuals had a 17% higher chance of developing cancer in the ascending colon.

That said, even short courses of antibiotics carried an associated cancer risk, albeit a far smaller one than what was seen with the months-long regimens, the team found. This data may provide yet another reason to rein in the overprescription of antibiotics, besides preventing the emergence of antibiotic-resistant superbugs, Harlid said.

These new findings echo the results of a similar, but smaller, U.K.-based study, published in 2019 in the journal Gut. The Swedish study "came right in line with other data that was emerging … which actually improves confidence that there's an association," Dr. Cynthia Sears, senior author of the U.K. study, who was not involved in the newest research, told Live Science.

It's important to note that these studies only identify a correlation; they don't show that antibiotics directly cause the subsequent colon cancer, said Sears, who is a professor of medicine and oncology at the Johns Hopkins University School of Medicine and a professor of molecular microbiology and immunology at the Bloomberg School of Public Health. That said, there are theories as to how the drugs may make the proximal gut more vulnerable to cancer growth.

"Our thinking is that you're disrupting the balance of the microbiota," and this may allow infectious bugs like Escherichia coli and Klebsiella pneumoniae to gain prominence where they'd usually be outcompeted by other microbes, Sears said. This in turn may ramp up inflammation in the colon, generating reactive chemicals that could damage DNA and generate tumors. In addition, the inner lining of the intestine may then become more permeable, allowing bacteria to infiltrate the colon walls and join together in slimy structures called biofilms. Studies suggest that almost all proximal colon cancers — nearly 90% — are associated with such biofilms, Sears said.

The proximal colon may be particularly vulnerable to these changes because it endures the greatest spillover of antibiotic drugs from the small intestine, Sears said. Then, as the drugs move through the colon, their molecules steadily break down. That said, these potential mechanisms still need to be studied further, but for now, the new study strengthens the case that some link exists between antibiotics and colon cancer, she said.

The new study used data from the Swedish Colorectal Cancer Registry to identify tens of thousands of colorectal cancer patients who had been diagnosed between 2010 and 2016. Data from the Swedish Prescribed Drug Register allowed the team to track these patients' antibiotic use between 2005 to 2016, to see if any patterns emerged. They also compared the cancer patients to more than 200,000 cancer-free people from the wider Swedish population.

While the team uncovered a clear link between antibiotics use and cancer in the ascending colon, they found no such link to cancers in any part of the distal colon or rectum.  

The team wanted to pin down why the drugs might drive cancer in the proximal colon. To do so, they searched the prescribed drug register for methenamine hippurate — a medicine that helps prevent urinary tract infections in people who get them frequently.

Although it has antibacterial effects, the drug doesn't alter the gut microbiome because it can only be activated by the high acidity of urine, Harlid explained. So based on the theory that antibiotics raise the risk of cancer by messing with gut bugs, methenamine hippurate should not be linked to the same increased risk. And in sifting through all their data, the team found that this was the case: only antibiotics that affect gut bugs, not methenamine hippurate, showed a link to colon cancer.

These results further support the antibiotics-cancer link, but the study still has its limitations. For instance, the datasets didn't include any information on individuals' diets, smoking habits or alcohol use, all of which can also raise the risk of colon cancer. Similarly, the authors could not determine which patients might be taking antibiotics for an underlying condition like inflammatory bowel disease, also linked to colon cancer. In addition, the Swedish Prescribed Drug Register provides information on drug prescriptions, but cannot reflect whether individuals finished their complete course of antibiotics, for instance.

But because the study is so large, it "definitely hints in the right direction," Harlid said.

In a few years time, the team hopes to perform an even larger follow-up study, when more data has accumulated, and they're interested in seeing whether specific colon cancer subtypes show a stronger association with antibiotics. Cancers can be split into subtypes based on the behavior of their tumor cells and what genetic mutations they carry, and these subtle differences affect where the cancer grows and how it responds to treatments, according to the National Cancer Institute.

Meanwhile, Sears and her colleagues are currently collecting data on the microbiomes of individuals with early-stage colon cancer, to pinpoint specific gut bugs that are unusually depleted or overgrown. As scientists continue to study why microbes make a difference in colon cancer, for now, doctors should be selective in when and how they prescribe antibiotics, Sears said.

In theory, for those who do have to take antibiotics, dietary supplements could potentially be designed to help bring their microbiome back into balance, Sears said. One such supplement was recently trialed in malnourished children and helped them cultivate a diverse assortment of gut bugs, Live Science previously reported. But again, for now, the best course of action is simply to avoid taking antibiotics when they're not needed, she said.

https://www.livescience.com/colon-cancer-antibiotic-use-link.html