Medicilon Logo
search icon search icon language icon contact icon menu icon
Medicilon Logo
search icon close search icon language icon contact icon menu icon
Contact Us
Close Button
Back To Top
Online Message×
Click switch
Close Button
Medicilon's News information
News information

Microbiome Link with Colorectal Cancer Drug Toxicity Points to Predictive Tests and Prevention

Page View:

Albert Einstein College of Medicine researchers 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 treating metastatic colorectal cancer.

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.”

Relevant newsRelevant news
Genomic Makeup of Colorectal Cancers Predicts Immune System Ability to Fight Tumors
Colorectal cancers heavily bedecked with tumor-related proteins called neoantigens are likely to be permeated with disease-fighting white blood cells, researchers at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard report in a new study. Because such an influx of white blood cells often signifies an immune system attack on cancer, the discovery will sharpen research into therapies that make tumors more vulnerable to such an attack.
Role of STING Protein in Development of Colorectal Cancer
    A new study published by researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine (Sylvester) reports on a key finding about the immune system's response to tumor development following studies on colorectal cancer. This is the first detailed examination of how the stimulator of interferon genes (STING) signaling pathway,Read more
Discovery and synthesis of a new class of selective TNIK inhibitors and evaluation of their anti-colorectal cancer effects, the pharmacokinetic properties was carried out by Medicilon
The Traf2- and Nck-interacting protein kinase (TNIK) is a downstream signal protein of the Wnt/β-catenin pathway and has been thought of as a potential target for the treatment of colorectal cancer. SAR analysis leads to the identification of a number of potent TNIK inhibitors with Compound 21k being the most active one. Preliminary assessment for the pharmacokinetic properties of Compound 21k was carried out through services provided by Medicilon.