Chemotherapy can come with a range of side effects, including severe diarrhoea. Oral antibiotics can be used to reduce toxicity by protecting against infection and increasing the capacity to metabolize dietary substrates, but the indiscriminate depletion of gut microbes can directly impact the effectiveness of the chemotherapy. Libusha Kelly, Assistant Professor in the departments of Systems & Computational Biology, and Microbiology and Immunology at the Albert Einstein College of Medicine in New York, has been studying how the microbiome can influence the likelihood of chemotherapy side effects. Kelly and coworkers focused on irinotecan (CPT-11), which, in combination with fluorouracil and leucovorin, is one of three first-line treatments for metastatic colorectal cancer. Severe diarrhoea only seems to affect a subset of individuals taking the drugs: 30-40 percent when administered as a single agent, and 11-37 percent when used along with other therapeutics.
“In light of a study demonstrating that CPT-11’s toxicity could be alleviated by inhibiting the E. Coli version of a beta-glucuronidase (BG) enzyme in mice (1), we hypothesized that the gut microbiome metabolism would vary between people, and that it might be possible to identify who was likely to be a high versus low metabolizer of the drug based on the expression of certain genes – including BG genes – present in the gut microbiome,” explains Kelly. Using high throughput genomics in combination with metabolomics, the researchers identified gut microbiome-derived metagenomic signatures linked to an individual’s ability to convert the inactive form of CPT-11, SN-38G, to the active form, SN-38 (2).
According to Kelly, analyzing the composition of patients’ microbiomes before giving CPT-11 might predict whether patients will suffer side effects from the drug. “High throughput sequencing technologies have started to give us a glimpse into the incredible diversity of microbes that live in and on our bodies,” says Kelly. “Our work with CPT-11 has implications for the many additional drugs that are glucuronidated via Phase II drug metabolism and excreted to the gut. We anticipate that gut microbes may metabolize many additional glucuronidated drugs, with unknown consequences for patients.” The researchers are now collecting samples from colorectal cancer patients who are on treatment regimens that include CPT-11. “We will track these patients over time to find out whether we can predict, based on a fecal sample, which patients are likely to suffer an adverse response to CPT-11,” says Kelly.
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References
- BD Wallace, et al., “Alleviating cancer drug toxicity by inhibiting a bacterial enzyme”, Science, 330, 831-5 (2010). PMID: 21051639. L Guthere et al., “Human microbiome signatures of differential colorectal cancer drug metabolism”, Biofilms Microbiomes, 27 (2017). PMID: 29104759.
