Journal Article

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Creekmore, Benjamin C., Wilson, Ian D., Azcarate-Peril, M. Andrea, Bhatt, Aadra P., Darr, David B., Swann, Jonathan R., Bultman, Scott J., Biernat, Kristen A., Wallace, Bret D., Montgomery, Stephanie A., Redinbo, Matthew R., Pellock, Samuel J., Letertre, Marine M., Walton, William G., Roques, Jose R., Sartor, R. Balfour, Roach, Jeffrey M., Bailey, Sean T., Gharaibeh, Raad Z.

2020

Overview

Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models.We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immunedeficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan’s effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.

• Publisher: National Academy of Sciences
• Subject: 60 APPLIED LIFE SCIENCES / Animals / antineoplastic agents / Antineoplastic Agents, Phytogenic - pharmacology / Bacteria - drug effects / Biological Sciences / cancer / cell proliferation / chemotherapy / diarrhea / digestive tract / Disease Models, Animal / drug therapy / dysbiosis / Dysbiosis - drug therapy / Enterobacteriaceae / Enzyme Inhibitors - pharmacology / epithelial cells / Female / Gastrointestinal Microbiome - drug effects / gastrointestinal toxicity / genetic engineering / Glucuronidase - antagonists & inhibitors / Glucuronidase - drug effects / Glucuronidase - metabolism / Humans / intestinal microorganisms / Irinotecan - pharmacology / Life Sciences / Mice / Mice, Nude / Microbiology / microbiome / neoplasms / Neoplasms - drug therapy / toxicity / xenotransplantation