Gut Microbial Metabolites and Hepatic Xenobiotic Metabolism: A High Throughput Screening Approach

Idiosyncratic drug responses leading to drug induced liver injury (DILI) occur in 15% of patients receiving drug treatments. These idiosyncratic drug reactions cannot be explained or predicted. The gut microbiome is highly host specific and is known to influence the host metabolic system including xenobiotic metabolism. Here, the potential for gut microbial-associated metabolites to impact on host drug metabolism and toxicity was explored using a novel exploratory pipeline. Candidate microbial metabolites were identified using two antibiotic-treated rodent models and a 1H NMR spectroscopy-based metabonomic approach. The modulatory potential of each metabolite was then evaluated using a high throughput in vitro screening approach following co-administration with paracetamol. Hepatic SV40 large T-antigen immortalized human liver epithelial (THLE) cell lines were used including a subline transfected with CYP2E1, a major drug metabolising enzyme. Twelve microbial metabolites were screened and one microbial metabolite, 4-cresyl, was found to increase toxicity when dosed to THLE-CYP2E1 cells. Co-administration of paracetamol with 4-cresyl resulted in a greater toxic effect compared to an equivalent dose of paracetamol or 4-cresyl alone. Through this novel screening approach microbial-associated metabolites have been identified and their potential to modulate host xenobiotic metabolism, and therefore contribute to idiosyncratic drug responses, has been evaluated.