Gut bacteria influence response to the anti-cancer drug irinotecan


Irinotecan, a first-line chemotherapy agent for colon cancer, can cause a wide spectrum of side effects, ranging from mild to severe. Irinotecan has been studied extensively in clinical trials, and it's estimated that 40% of the treated patients develop severe diarrhea associated with an increased risk of death.

It's well established that the differences in genetic/inherited makeup among individuals influence how the body responds to a drug. Now, a study demonstrates that the differences in the composition of gut bacteria among individuals also affect the efficacy of irinotecan. This work was carried out by four researchers, Leah Guthrie, Sanchit Gupta, Johanna Daily and Libusha Kelly, from the Albert Einstein College of Medicine (AECOM).

The study "Human microbiome signatures of differential colorectal cancer drug metabolism" is published online 1 Nov. 2017 in npj Biofilms and Microbiomes.

Irinotecan is a derivative of a cytotoxic compound isolated from the Asian tree, Camptotheca acuminata. The potent anti-tumor activity of irinotecan is mainly due to its active metabolite, SN-38. In the human body, irinotecan is first converted to its active form, SN-38, which is further converted to an inactive form, SN-38G. If SN-38G is reactivated by a class of enzymes produced by gut microbes known as beta-glucuronidases, it will seriously damage the intestinal epithelial cells and trigger severe diarrhea.

So far, the relationship between the composition of a person's gut bacteria and reactivation of SN-38G has not been fully understood. To solve this problem, AECOM researchers conducted this study. They analyzed fecal samples from 20 healthy people, and found differences in the capacity to metabolize SN-38G among samples. Based on the results, the fecal samples were divided into two groups: the high metabotype group and the low metabotype group. Next, the researchers compared the composition of bacteria in the two groups. They showed that a high turnover microbiota metabotype is associated with an increased risk of irinotecan-associated side effects. In addition, they discovered that the high metabotype group had larger amounts of previously unknown microbial beta-glucuronidases.

In conclusion, the study suggests a link between the composition of gut bacteria and people's response to the anti-cancer drug irinotecan. Further, the study offers an approach to identify biomarkers of treatment outcomes in colon cancer.
 
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