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

Abstract

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. microbiome | chemotherapy | cancer | gastrointestinal toxicity I rinotecan (CPT-11) is essential for treating colorectal and pancreatic cancers and is frequently administered as a mixture with 5-fluorouracil and/or oxaliplatin. Ongoing clinical trials seek to extend irinotecan to other forms of cancer. However, irinotecan causes both myelosuppression and gastrointestinal (GI) side effects, including mucositis and late-onset diarrhea, which are often dose limiting: 88% of irinotecan patients develop diarrhea, with 30% experiencing acute grade 3 to 4 diarrhea (1-3). This toxicity is frequently refractory to antimotility drugs. Thus, treating irinotecaninduced diarrhea is a significant clinical need (4, 5).The irinotecan prodrug is activated in vivo to SN38, a potent topoisomerase I inhibitor (6) that retards the growth of rapidly proliferating cells in tumors and the intestinal epithelium, which renews every 5 d. SN38 is detoxified through the addition of glucuronic acid (GlcA) to form SN38-G, a compound marked for elimination via the GI tract. Gut commensal bacterial β-glucuronidase (GUS) proteins remove GlcA from SN38-G. Reactivated SN38 inflicts epithelial damage, resulting in bleeding diarrhea and acute weight loss in animal models (7). We reduced irinotecan-induced gut toxicity using inhibitors that selectively, nonlethally, and potently block the actions of gut bacterial GUS enzymes (8,9). The utility of GUS inhibition also extends to drugs be...

Nutritional Value and Biological Activity of Gluten-Free Bread Enriched with Cricket Powder

“…The use of food additives that inhibit β-Glu activity may also be of key importance in the treatment of certain diseases. As β-Glu plays a key role in reducing the effectiveness of anticancer drugs [ 63 ], its inhibition with food ingredients may aid the treatment of certain diseases in a non-pharmacological manner. It therefore seems that CP has the potential to be used as a new β-Glu inhibitor, and further studies of the biological activity of CP may deepen our understanding of the mechanisms underlying the beneficial effects observed in the current experiments.…”

Drug–Microbiota Interaction in Colon Cancer Therapy: Impact of Antibiotics

“…Some drugs have little contact with the small intestinal/colonic microbiota because they are rapidly and completely absorbed in the upper gastrointestinal tract. Some other drugs are transformed to active, inactive, or toxic metabolite(s) by the microbiota [ 46 , 50 , 51 , 52 ]. Chemotherapy-induced diarrhea (CID) and mucositis are among the most common dose-limiting side effects.…”

The Multifaceted Roles of Diet, Microbes, and Metabolites in Cancer

“…A diet high in fats or meats has also been shown to increase the abundance of select opportunistic microbe species responsible for the production of enzymes such as B-glucuronidase, which plays a key role in xenobiotic-induced toxicity within the intestine [ 61 , 62 ]. B-glucuronidase has been previously associated with increased risk of select breast cancers [ 63 ], pancreatic cancer [ 64 ], and colorectal cancer [ 65 ], and recent evidence supports the use of inhibitor compounds targeting B-glucuronidase for improved anticancer efficacy [ 66 ].…”