Gut microbiome may make chemotherapy toxic for patients

Researchers at the Albert Einstein College of Medicine report that the composition of people’s gut bacteria may explain why some of them suffer life-threatening reactions after taking a key drug for the treatment of metastatic colorectal cancer. The results, described online in npj Biofilms and Microbiomesa Nature research journal, could help predict which patients will suffer from side effects and prevent complications in susceptible patients.

“We’ve known for some time that people’s genetic makeup can affect how they respond to a drug,” says Libusha Kelly, Ph.D., assistant professor of systems and computational biology and microbiology and immunology at Einstein. “Now it’s becoming clear that variations in the gut microbiome – the population of bacteria and other microbes that live in the digestive tract – can also influence the effects of treatment.”

Irinotecan is one of three first-line chemotherapy drugs used to treat colorectal cancer that has spread or metastasized to other parts of the body. However, up to 40% of patients who receive irinotecan experience severe diarrhea that requires hospitalization and can lead to death. “As you can imagine, these patients are already very sick, so giving them a treatment that causes bowel problems can be very dangerous,” says Dr Kelly. “At the same time, irinotecan is an important weapon against this type of cancer.”

Irinotecan is administered intravenously in an inactive form. Liver enzymes metabolize the drug into its active, toxic form which kills cancer cells. Later, other liver enzymes convert the drug back to its inactive form, which enters the intestine via bile for elimination. But some people harbor bacteria in the digestive tract that use some of the inactivated irinotecan as a food source by digesting the drug with enzymes called beta-glucuronidases. Unfortunately, this enzymatic action metabolizes and reactivates irinotecan in its toxic form, which causes serious side effects by damaging the intestinal mucosa.

To minimize irinotecan toxicity, doctors have tried using oral antibiotics to kill the bacteria that make the enzymes. But antibiotics also kill protective microbes in the gut, including those that neutralize disease-causing bacteria. A 2010 study in Science involving mice found that drugs that selectively target beta-glucuronidases from E. coli may reduce the toxicity of irinotecan.

In the current study, Dr. Kelly and his colleagues investigated whether the composition of a person’s microbiome influences whether or not irinotecan reactivates. The researchers took fecal samples from 20 healthy people and treated the samples with inactivated irinotecan. Then, using metabolomics (the study of the unique chemical fingerprints left by cellular processes), the researchers grouped the fecal samples according to whether they could metabolize or reactivate the drug. Four of the 20 individuals were found to be “high metabolizers” and the other 16 were “poor metabolizers.”

Fecal samples from the two groups were then analyzed for differences in the composition of their microbiomes, with a focus on the presence of beta-glucuronidases. The researchers found that the microbiomes of high metabolizers contained significantly higher levels of three previously unreported types of beta-glucuronidases compared to poor metabolizers.

“We hypothesize that people who are high metabolizers would be at increased risk of side effects if given irinotecan, but this will require examining the microbiomes of cancer patients – which is what we are currently doing,” explains Dr Kelly.

The results suggest that analyzing the composition of patients’ microbiomes before giving irinotecan could predict whether patients will suffer side effects from the drug. Additionally, as the 2010 mouse study suggests, it may be possible to prevent adverse effects by using drugs that inhibit specific beta-glucuronidases.

“Another intriguing idea is to give prebiotics to patients,” says Dr. Kelly. “Beta-glucuronidases crave the carbohydrates present in the inactive form of irinotecan. If we give patients another carbohydrate source when we give irinotecan, we might be able to block these enzymes from metabolizing the drug. .”

Beta-glucuronidases in the gut can also interact with commonly used medications including ibuprofen and other nonsteroidal anti-inflammatory drugs, morphine, and tamoxifen. “In these cases, the problem for patients may not be diarrhea,” says Dr. Kelly. “Instead, if gut bacteria reactivate these drugs, patients could be exposed to higher than expected doses. Our study provides a general framework for understanding these drug-microbiome interactions.”

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