Gut Microbiota and Host CYP450s Characteristics in the Pseudo Germ-free Model: Co-shaping Individual Metabolic Landscapes

Abstract

Abstract Background Pseudo germ-free (PGF) model has been widely used to research the role of intestinal microbiota in drug metabolism and efficacy, while the modeling methods and the utilization of PGF model are still not standardized and unified. A comprehensive and systematic research of PGF model on the composition and function of intestinal microbiota, the changes of CYP450s enzyme expression in host and intestinal mucosal permeability in 4 different modeling cycles of the PGF groups were provided in this paper. Results 16S rRNA sequencing was employed to compare and analyze the alpha and beta diversity, species composition, indicator species and predicted function of gut microbiota in control and PGF groups. The results showed that bacterial species richness and diversity decreased significantly in the PGF group from the first week of PGF model establishment with the antibiotic cocktail. PGF group at the fourth week of modeling possessed the least indicator genera. Moreover, the increase of intestinal mucosal permeability occurred in the second week of PGF model establishment, indicating that 1 week was appropriate time for PGF modeling with antibiotic treatment. The results of western blot displayed that the expression level of CYP1A2, CYP2C19 and CYP2E1 in PGF group was significantly upregulated compared with the control group,, implying that the metabolic clearance of related drugs will change accordingly. The abundance of functional pathways predicted in gut microbiota changed dramatically between the control group and the PGF groups. Conclusions These results manifested the microbial profile and the expression characteristic of CYP450s enzymes and provides model reference for the study on individual drug metabolism differences co-affected by gut microbiota and host CYP450s enzymes.