Gut Microbiota-Mediated SN-38G Metabolism In Vitro: Effects of Murraya koenigii and Ruta graveolens

The influence of the human microbiome on health and disease has been extensively studied over the past two decades. More recently, the microbiota has also been implicated in modulating the efficacy and toxicity of various drugs, including cancer therapies. This study focuses on irinotecan, a chemotherapeutic prodrug used in colorectal cancer treatment. Irinotecan is converted to the active metabolite SN-38, which is then glucuronidated in the liver to form the inactive metabolite SN-38G. Following biliary secretion into the intestine, microbial enzymes can cleave the glucuronide group and release SN-38, a process that may contribute to gastrointestinal toxicity. Human fecal microbiota converted SN-38G to SN-38 in vitro. Antibiotic treatment markedly reduced conversion, indicating that microbial activity accounted for most of the conversion under these conditions. In an exploratory screen, extracts from Murraya koenigii and Ruta graveolens reduced SN-38G conversion. Differences in community composition and beta-glucuronidase gene abundance were observed after extract exposure. These results show microbiota-dependent SN-38G conversion in vitro and identify compounds and plant extracts that delay or inhibit this conversion. Whether this effect is caused by direct inhibition of microbial beta-glucuronidase or by more generic microbiota effects is open for future research.