Gut microbiome may yield clues to serious colon cancer drug reactions

Last Updated: 2017-11-06

By Marilynn Larkin

NEW YORK (Reuters Health) - Variations in the gut microbiome may influence how patients respond to the colon cancer drug irinotecan and could help to predict which people may experience serious adverse effects, researchers suggest.

Irinotecan (CPT-11) is one of the few drugs for which there is a mechanistic understanding of how the gut microbiome influences drug metabolism, note Dr. Libusha Kelly of Albert Einstein College of Medicine in New York City and colleagues.

Irinotecan is given intravenously in an inactive form, and liver enzymes metabolize it into an active form to combat cancer cells. Other enzymes convert the drug back into its inactive form for elimination from the body.

However, the gut bacteria of some people feed off inactivated irinotecan using enzymes called beta-glucuronidases. That activity can reactivate the inactive metabolite of the drug, causing adverse drug responses such as severe diarrhea.

To investigate the connection between gut microbiota and irinotecan reactivation, Dr. Kelly and colleagues recruited 20 healthy young adults with no exposure to antibiotics within six months before enrollment.

As reported in npj Biofilms and Microbiomes, online November 1, after examining participants' fecal samples using various assays, the team found that some were "high metabolizers" of the drug, meaning their gut microbiome was more prone to reactivate it. Further analyses showed the microbiomes of those individuals had significantly higher levels of previously unreported types of beta-glucuronidases.

"Future work is necessary to determine whether fecal turnover correlates with irinotecan-induced toxicity and whether the microbiome might therefore serve as an accurate predictor of patient (adverse drug response) risk," the authors conclude.

Reuters Health asked Dr. Kelly whether the gut microbiome response to irinotecan might differ from day to day or week to week.

"Temporal differences are absolutely a concern," Dr. Kelly said. "An important next step is to ask how stable the drug metabolism phenotype of an individual's gut is."

"This study looked only at a single time point, and it is absolutely possible that people could have changes in their gut microbiota over time that would influence how they metabolize irinotecan and other drugs," she acknowledged.

Might the microbiome response to irinotecan differ between healthy individuals compared to those with cancer?

"Other studies show that cancer patients can have significantly different microbiome features than healthy individuals," Dr. Kelly said. "This suggests that it is important to test a cancer patient's metabotype right before they are administered a drug like irinotecan because a sample taken when they were healthy could be different."

Could factors such as other treatments affect how the gut microbiome responds to irinotecan?

"Iriniotecan is often given in combination with other drugs," Dr. Kelly responded. "Microbiome interactions with those other drugs could absolutely influence patient response. It is possible that features such as the patient's diet could also influence the profile of microbial proteins that drive irinotecan metabolism in the gut."

"We've known for a long time that the gut microbiome can metabolize drugs," she observed. "What has been lacking is an understanding of when and how gut metabolism of compounds influences patient outcomes."

"Our work, and that of many other groups, is a small step moving in this direction," she concluded.

Dr. Louis Cohen, assistant professor of gastroenterology at the Icahn School of Medicine at Mount Sinai, said in an email to Reuters Health, "The belief is that identifying microbial populations associated with CPT-11 metabolism may allow for the targeted manipulation of bacterial cohorts in the future to prevent CPT-11 toxicity."

"It will be some time before work like this begins to materialize in the clinic," he noted, "as we are still far away from the ability to fine-tune specific microbial populations in the gut to achieve a therapeutic outcome."

"This will be especially challenging for some of the enzymes involved in CPT-11 metabolism, which can be present in fairly ubiquitous microbes and will require a better knowledge about how bacteria metabolize CPT-11," he noted.

"With these caveats," he added, "this study begins to start chipping away at some of these challenges."

"With a better mechanistic understanding of CPT-11 metabolism and how to intelligently manipulate microbial ecology," Dr. Cohen concluded, "it may be possible to attenuate CPT-11 toxicity or modulate chemotherapeutic response by changing cohorts of bacteria present in the gut."

SOURCE: http://go.nature.com/2Ac3DKG

NPJ Biofilms Microbiomes 2017.