Irinotecan is a leading chemotherapy drug used to treat CRC. Patients receive the inactive form of the drug intravenously. Irinotecan is converted in the liver into its active, toxic form, which kills cancer cells. After being metabolised back to the inactive state, irinotecan passes into the intestine for excretion.
Previous research has found that certain types of the enzyme family known as beta-glucuronidases (BG) reactivate the drug to its toxic form in the gut. In people who guts contain an abundance of these types of BGs, this causes severe diarrhoea and can be life-threatening.
As BG enzyme types are produced by specific gut bacteria, microbiome composition will have an effect on an individual’s reaction to irinotecan.
This identification of variability in how individuals metabolise the inactive metabolite of irinotecan in the gut was a key finding of the research team from the Albert Einstein College of Medicine, New York.
Using metabolomics analysis on faecal samples, the scientists found that people were either ‘high-metabolisers’ or ‘low-metabolisers’. In high metabolisers, faecal samples contained much higher levels of three particular types of BGs related to particular types of gut bacteria.
"We've known for some time that people's genetic makeup can affect how they respond to a medication," commented study leader Dr. Libusha Kelly. "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 findings are significant as they may enable the use of microbiome analysis prior to chemotherapy treatment to identify those at higher risk of side effects.
"We hypothesise 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," suggested Dr. Kelly.
The study results also raises the possibility of using prebiotics as a therapeutic treatment to prevent diarrhoea.
"Another intriguing idea is to give patients prebiotics," said Dr. Kelly. "Beta-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."
The discovery may also have applications for managing gut bacteria-related interactions with other drugs that undergo glucuronidation as the phase-II detoxification step in the liver. The researchers quote paracetamol, codeine, chloramphenicol and tamoxifen as examples.
“In these cases, the issue for patients may not be diarrhoea," says Dr. Kelly. "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."
Bacteria types linked to reactivation
In this study, the BGs responsible for irinotecan reactivation appear to be linked to three previously unreported bacteria species. The BG enzymes identified bore similarities to those derived from a predicted uncultured Clostridium species, Faecalibacterium prausnitzii and a species of Bacteroides.
“All were identified based on sequence homology to known or predicted glycosyl hydrolyases or BGs from genera that have experimentally confirmed BG activity,” reported the researchers.
The scientists suggested that pairing biochemical assessment of the diverse BGs (derived from different gut bacteria) with different metabotypes would be a critical future step in designing microbial BG inhibitors.
“Our findings suggest that a diverse set of BGs may need to be targeted for inhibition to be successful in the context of the human gut,” they concluded.
Source: npj Biofilms and Microbiomes
Volume 3, article 27 DOI: 10.1038/s41522-017-0034-1
“Human microbiome signatures of differential colorectal cancer drug metabolism”
Authors: Leah Guthrie, Sanchit Gupta, Johanna Daily and Libusha Kelly