Multi-omics analysis of the molecular mechanisms underlying the influence of gut microbiota on pharmacokinetics of cyclosporine A via P- glycoprotein

In our previous study, we demonstrated that gut microbiota significantly influenced the expression of P-glycoprotein (P-gp), thereby modulating the pharmacokinetics of cyclosporine A (CSA). Building upon this, the current study aimed to further elucidate the molecular mechanisms through which gut microbiota regulates host pharmacokinetics using a multi-omics approach. untargeted metabolomics with database identification and transcriptomic analyses revealed that gut microbiota intervention notably altered several host metabolic pathways, including glycerophospholipid metabolism, triglyceride metabolism, and cysteine and methionine metabolism. KEGG pathway enrichment analysis of differentially expressed metabolites and GO pathway enrichment analysis of differentially expressed genes revealed a significant enrichment in the synthesis and modification of bile acids. In the ABT group, levels of lithocholic acid (LCA), deoxycholic acid (DCA), and hyodeoxycholic acid (HDCA) decreased by 86.88%, 98.82%, and 98.28%, respectively, compared to the CON group, and by 87.36%, 98.68%, and 98.24%, respectively, compared to the FMT group. Moreover, in the ABT group, hepatic P-gp and caveolin-1 (Cav-1) expression decreased by 44% and 54%, respectively, while intestinal P-gp and Cav-1 expression reduced by 47% and 80.2% compared to the CON group. FMT administration largely reversed these trends. Overall, our findings suggest that gut microbiota influences lipid and bile acid metabolism, which in turn affects the expression of P-gp and regulates CSA pharmacokinetics.