image: This is a high-resolution image of a microbiome drug target complexed with a selective chemical probe. view more
Credit: Samuel Pellock, University of North Carolina
The blame for some of chemotherapy's awful side effects may lie with our gut microbes, early evidence suggests. As chemotherapy drugs are eliminated from the body, bacteria in the gastrointestinal tract can latch onto them and transform them into toxic species that cause severe diarrhea. In a Chemistry & Biology article published online on September 10, researchers present ways to shut down the ability of GI microbes to convert chemotherapy drugs to a toxic species in mice as a first step to helping cancer patients.
"The GI microbiota are the great crowd-sourcers of chemistry, using a dizzying array of enzymes to process drugs and other chemicals, occasionally with terrible consequences," says senior study author Matthew Redinbo, of the University of North Carolina at Chapel Hill. "We show that the bacteria in the GI contain 'druggable targets,' ones that we can modulate with the same types of small molecule approaches that have transformed other aspects of human health."
Bacteria consume a sugar called glucuronic acid through the use of a bacterial enzyme termed Beta-glucuronidase. This enzyme scavenges the sugar from small chemicals that the body sends to the gastrointestinal track for elimination. The chemotherapy drug irinotecan is linked to glucuronic acid to mark it for elimination, and when the GI bacteria remove the sugar, they release a virulently toxic drug back into the intestines. This causes diarrhea in up to 90% of patients who take irinotecan.
Previous research by Redinbo and others revealed that inhibiting Beta-glucuronidase helps reduce the GI toxicity associated with irinotecan, suggesting that bacteria are responsible for the drug's side effects. This may be true for other drugs as well--for example, nonsteroidal anti-inflammatory drugs also cause GI problems and contain glucuronic acid.
Redinbo and his team now characterize various forms of Beta-glucuronidase produced by different strains of bacteria residing in the gut, and they show that inhibiting GI bacterial Beta-glucuronidases in mice does not affect irinotecan that is circulating in the blood and is needed to combat cancer. Their findings provide a better understanding of bacterial Beta-glucuronidases and a promising new set of targets for controlling drug-induced GI toxicity.
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The work was supported by the University Cancer Research Fund of North Carolina and the US National Institutes of Health.
Chemistry & Biology, Wallace and Roberts et al.: "Structure and Inhibition of Microbiome Beta-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity" http://dx.doi.org/10.1016/j.chembiol.2015.08.005
Chemistry & Biology, published by Cell Press, is a monthly journal that publishes reports of novel investigations in all areas at the interface of chemistry and biology. Each issue contains articles of relevant interest to chemists and biologists, such as studies of the underlying chemistry of biological processes or the application of chemical tools to provide unique insight into biological functions and mechanisms. For more information, please visit http://www.cell.com/chemistry-biology. To receive media alerts for Chemistry & Biology or other Cell Press journals, contact press@cell.com.