In vitro investigation of gut microbiota-mediated SN38G conversion and modulation by candidate inhibitory compounds
In this study human fecal microbiota samples were incubated in vitro to investigate microbial conversion of the irinotecan metabolite SN38G into the active metabolite SN38. Initial experiments evaluated the extent and kinetics of SN38G conversion and the effects of antibiotic treatment on this process. Subsequently, candidate inhibitory compounds were selected using the MicrobeFDT platform and tested in a high-throughput i-screen fecal incubation model to identify compounds capable of reducing microbial SN38G conversion. Experimental conditions included untreated controls, vehicle controls, SN38G-treated samples, antibiotic-treated samples, and treatment with multiple natural compounds and plant extracts, including berberine, Murraya koenigii extract, and Ruta graveolens extract. Based on the conversion experiments, selected conditions were further analyzed using metagenomic whole-genome shotgun sequencing on the Illumina NextSeq platform to investigate treatment-associated shifts in gut microbiota composition and relative abundance of microbial ß-glucuronidase-associated genes. The experiments showed rapid microbiota-mediated conversion of SN38G, while several tested compounds and extracts were associated with reduced conversion in vitro. The dataset was generated to support further investigation of microbiota-dependent SN38G metabolism and potential microbiota-targeted strategies to reduce irinotecan-associated intestinal toxicity.
In this study human fecal microbiota samples were incubated in vitro to investigate microbial conversion of the irinotecan metabolite SN38G into the active metabolite SN38. Initial experiments evaluated the extent and kinetics of SN38G conversion and the effects of antibiotic treatment on this process. Subsequently, candidate inhibitory compounds were selected using the MicrobeFDT platform and tested in a high-throughput i-screen fecal incubation model to identify compounds capable of reducing microbial SN38G conversion. Experimental conditions included untreated controls, vehicle controls, SN38G-treated samples, antibiotic-treated samples, and treatment with multiple natural compounds and plant extracts, including berberine, Murraya koenigii extract, and Ruta graveolens extract. Based on the conversion experiments, selected conditions were further analyzed using metagenomic whole-genome shotgun sequencing on the Illumina NextSeq platform to investigate treatment-associated shifts in gut microbiota composition and relative abundance of microbial ß-glucuronidase-associated genes. The experiments showed rapid microbiota-mediated conversion of SN38G, while several tested compounds and extracts were associated with reduced conversion in vitro. The dataset was generated to support further investigation of microbiota-dependent SN38G metabolism and potential microbiota-targeted strategies to reduce irinotecan-associated intestinal toxicity.
Netherlands Organisation for Applied Scientific Research