Date:

November 1, 2017

Source:

Albert Einstein College
of Medicine

Summary:

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, new research has
discovered. The findings could help predict which patients will suffer side
effects and prevent complications in susceptible patients.

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, described
online in npj Biofilms and Microbiomes, a Nature research journal, could
help predict which patients will suffer 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
medication,” says study leader Libusha Kelly, Ph.D., assistant professor
of systems & computational biology and of microbiology & immunology at
Einstein. “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.”

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 percent
of patients who receive irinotecan experience severe diarrhea that requires hospitalization
and can lead to death. “As you can imagine, such patients are already
quite ill, so giving them a treatment that causes intestinal 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 that kills cancer cells. Later, other liver
enzymes convert the drug back into its inactive form, which enters the
intestine via bile for elimination. But some people harbor digestive-tract
bacteria that use part of inactivated irinotecan as a food source by digesting
the drug with enzymes called beta-glucuronidases. Unfortunately, this enzyme
action metabolizes and reactivates irinotecan into its toxic form, which causes
serious side effects by damaging the intestinal lining.

To minimize
irinotecan-related toxicity, doctors have tried using oral antibiotics to kill
bacteria that make the enzymes. But antibiotics kill protective gut microbes as
well, including those that counteract disease-causing bacteria. A 2010 study in
Science involving mice found that drugs that selectively target E. coli
beta-glucuronidases can reduce irinotecan’s toxicity.

In the current study, Dr.
Kelly and her colleagues investigated whether the composition of a person’s
microbiome influenced whether irinotecan would be reactivated or not. The
researchers collected fecal samples from 20 healthy individuals and treated the
samples with inactivated irinotecan. Then using metabolomics (the study of the
unique chemical fingerprints that cellular processes leave behind), 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 remaining 16 were “low
metabolizers.”

Fecal samples in 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 low metabolizers.

“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,” says Dr. Kelly.

The findings suggest that
analyzing the composition of patients’ microbiomes before giving irinotecan
might predict whether patients will suffer side effects from the drug. In
addition, as suggested by the 2010 mouse study, it might be possible to prevent
adverse reactions by using drugs that inhibit specific beta-glucuronidases.

“Another intriguing
idea is to give patients prebiotics,” says 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.”

Beta-glucuronidases in
the gut might also interact with commonly used drugs including ibuprofen and
other nonsteroidal anti-inflammatory drugs, morphine, and tamoxifen. “In
these cases, the issue for patients may not be diarrhea,” 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.”

Story Source:

Materials provided by Albert Einstein College of Medicine. Note: Content may
be edited for style and length.

Journal Reference:

1.    Leah Guthrie, Sanchit
Gupta, Johanna Daily, Libusha Kelly. Human microbiome signatures of
differential colorectal cancer drug metabolism. npj Biofilms and
Microbiomes, 2017; 3 (1) DOI: 10.1038/s41522-017-0034-1