Studies by scientists at the Albert Einstein College of Medicine in New York offer new insights into how gut microbiome composition and enzyme activity impact on the likelihood that cancer patients will suffer potentially life-threatening diarrhea following treatment with the chemotherapy agent irinotecan. The findings indicate that it may be possible to use simple gut microbiome sampling tests to predict drug response, but also suggest that specific enzyme-inhibiting drugs could be developed to reduce the adverse effects of irinotecan and other drugs.
It may also be feasible that serious irinotecan-related side effects could be prevented by giving patients prebiotics prior to their treatment, suggests lead Albert Einstein researcher Libusha Kelly, Ph.D., assistant professor of systems & computational biology, and of microbiology & immunology. “We’ve known for some time that individual genetic makeup can affect how a patient responds to a medication,” Dr. Kelly notes. “Now it’s becoming clear that variations in one’s gut microbiome—the population of bacteria and other microbes that live in the digestive tract—can also influence the effects of treatment.”
The team’s findings are published in npj Biofilms and Microbiomes, in a paper entitled “Human Microbiome Signatures of Differential Colorectal Cancer Drug Metabolism.”
Irinotecan combined with fluouracil and leucovorin is one of three first-line treatments for metastatic colorectal cancer. The prodrug is administered intravenously and is converted to its active form (SN-38) by enzymes in the liver. SN-38 is later metabolized by different liver enzymes into an inactive, glucuronidated form (SN-38G), which can safely enter the intestinal tract. However, intestinal damage and severe diarrhea can result when gut microbial β-glucuronidase enzymes recognize SN-38G as a carbon source and metabolize the compound back into its active, toxic form.
In fact, irinotecan is one of the few therapeutic drugs for which we have a mechanistic understanding of how the gut microbiome specifically influences its metabolism. Oral antibiotics have been used to reduce irinotecan toxicity, but these can also indiscriminately kill good gut bacteria that are important for food digestion, or that help to protect against infection. Studies by the Albert Einstein team have now characterized interindividual variations in the capacity of human gut microbiota to covert inactive irinotecan into its active form. The researchers treated fecal samples from 20 healthy individuals using inactivated irinotecan and grouped the samples as either “high metabolizers” or “low metabolizers,” dependent upon how much of the inactivated form of irinotecan was converted back into its active, toxic form.
Analysis of the fecal samples showed that compared with the low metabolizers, the high-metabolizer microbiomes contained elevated levels of three previously unreported β-glucuronidases. Bacteria that metabolize SN-38G have to take the compound up into their cells, and the study results also identified carbohydrate uptake transporters that were more abundant in the high metabolizers. “…inhibiting these enzymes may decrease irinotecan-dependent adverse drug responses in targeted subsets of patients,” the researchers write. “We hypothesize that people who are high metabolizers would be at increased risk for side effects if given irinotecan, but that will require examining the microbiomes of cancer patients—something we are now doing,” Dr. Kelly added.
Studies back in 2010 identified targeted inhibitors of Escherichia coli β-glucuronidase enzymes that significantly reduced irinotecan-induced toxicity in mice. The latest data by the Albert Einstein team suggest that it might be feasible to develop β-glucuronidase enzyme inhibitors that can prevent adverse reactions to irinotecan in humans.
“Another intriguing idea is to give patients prebiotics,” Dr. Kelly suggests. “β-Glucuronidases have an appetite for the carbohydrates found in the inactive form of irinotecan. If we feed patients another source of carbohydrates when we administer irinotecan, perhaps we could prevent those enzymes from metabolizing the drug.”
It’s also possible that gut microbiome β-glucuronidases interact with other drugs, such as ibuprofen, other nonsteroidal anti-inflammatory drugs, morphine, or tamoxifen. “In these cases, the issue for patients may not be diarrhea,” Dr. Kelly continued. “Instead, if gut bacteria reactivate those drugs, then patients might be exposed to higher-than-intended doses. Our study provides a broad framework for understanding such drug–microbiome interactions.”