Microbiota-Host-Irinotecan Axis: A New Insight Toward Irinotecan Chemotherapy

Abstract

Irinotecan (CPT11) and its active metabolite ethyl-10-hydroxy-camptothecin (SN38) are broad-spectrum cytotoxic anticancer agents. Both cause cell death in rapidly dividing cells (e.g., cancer cells, epithelial cells, hematopoietic cells) and commensal bacteria. Therefore, CPT11 can induce a series of toxic side-effects, of which the most conspicuous is gastrointestinal toxicity (nausea, vomiting, diarrhea). Studies have shown that the gut microbiota modulates the host response to chemotherapeutic drugs. Targeting the gut microbiota influences the efficacy and toxicity of CPT11 chemotherapy through three key mechanisms: microbial ecocline, catalysis of microbial enzymes, and immunoregulation. This review summarizes and explores how the gut microbiota participates in CPT11 metabolism and mediates host immune dynamics to affect the toxicity and efficacy of CPT11 chemotherapy, thus introducing a new concept that is called “microbiota-host-irinotecan axis”. Also, we emphasize the utilization of bacterial β-glucuronidase-specific inhibitor, dietary interventions, probiotics and strain-engineered interventions as emergent microbiota-targeting strategies for the purpose of improving CPT11 chemotherapy efficiency and alleviating toxicity.

Bacterial Interactions Affecting Chemotherapy Effectiveness

“…Although antibiotics are useful for treating some cases of bacterialmediated resistance such as with gemcitabine 23 , these drugs are notorious for causing gut dysbiosis and biome imbalance 25,34 , so caution must be taken when prescribing these to immunocompromised chemotherapy patients. An emphasis on complementary treatments such as probiotics and faecal microbiota transplants can be a supplementary way to support the immune system as well as the natural balance of the gut, particularly where platinum drugs such as oxaliplatin and irinotecan are being used 28,34,35,36,38 .…”

The Debate between the Human Microbiota and Immune System in Treating Aerodigestive and Digestive Tract Cancers: A Review

“…Irinotecan (also known as CPT11) is a topoisomerase I inhibitor that blocks DNA replication preferentially in rapidly dividing cells [ 126 ]. Irinotecan is administered intravenously to treat a variety of solid tumors, particularly advanced CRC [ 127 ].…”

“…Irinotecan is biotransformed into its active metabolite ethyl-10-hydroxy-camptothecin (SN/38) at the hepatic level and small intestine tissue carboxylesterase, being cleared in the liver by host UDP-glucuronosyltransferases into inactive SN-38-G and secreted into the gut. Once in the gut, SN-38-G can be reconverted into active SN-38 by the β-glucuronidases, inducing gastrointestinal toxicity (nausea, vomiting, diarrhea) [ 2 , 126 ]. The action and toxic mechanisms of irinotecan have been described to be influenced by the microbiota, namely through: microbial ecocline, catalysis of microbial enzymes, and immunoregulation, which is essential for the maintenance of intestinal homeostasis [ 126 ].…”

“…Once in the gut, SN-38-G can be reconverted into active SN-38 by the β-glucuronidases, inducing gastrointestinal toxicity (nausea, vomiting, diarrhea) [ 2 , 126 ]. The action and toxic mechanisms of irinotecan have been described to be influenced by the microbiota, namely through: microbial ecocline, catalysis of microbial enzymes, and immunoregulation, which is essential for the maintenance of intestinal homeostasis [ 126 ].…”

The semi-synthetic flavonoid 2′,3′,4′-trihydroxyflavone (2-D08) inhibits both SN-38- and cytokine-evoked increases in epithelial barrier permeability in anin vitrointestinal mucositis model

“…75,76 Altered intestinal microbiota has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and plays an important role in the development of irinotecan-induced GIM. [77][78][79][80][81] Dietary polyphenols such as flavonoids play an important role in maintaining intestinal homeostasis and possess the ability to modulate the gut microbiome in a variety of ways, such as influencing the abundance of various pathogenic bacteria, and may play a role in the amelioration of IBD-associated dysbiosis. 82,83 In this light, future studies focusing on novel flavonoids such as 2-D08, transilitin and myricetin and their effects on intestinal pathologies linked to dysbiosis are warranted.…”