Gut microbiota and host cytochrome P450 characteristics in the pseudo germ-free model: co-contributors to a diverse metabolic landscape

Abstract

Background The pseudo germ-free (PGF) model has been widely used to research the role of intestinal microbiota in drug metabolism and efficacy, while the modelling methods and the utilization of the PGF model are still not standardized and unified. A comprehensive and systematic research of the PGF model on the composition and function of the intestinal microbiota, changes in host cytochrome P450 (CYP450) enzymes expression and intestinal mucosal permeability in four different modelling cycles of the PGF groups are provided in this paper. Results 16S rRNA gene amplicon sequencing was employed to compare and analyze the alpha and beta diversity, taxonomic composition, taxonomic indicators and predicted function of gut microbiota in the control and PGF groups. Bacterial richness and diversity decreased significantly in the PGF group beginning after the first week of establishment of the PGF model with antibiotic exposure. The PGF group exposed to antibiotics for 4-week-modelling possessed the fewest indicator genera. Moreover, increased intestinal mucosal permeability occurred in the second week of PGF model establishment, indicating that one week of antibiotic exposure is an appropriate time to establish the PGF model. The results of immunoblots revealed that CYP1A2, CYP2C19 and CYP2E1 expression was significantly upregulated in the PGF group compared with the control group, implying that the metabolic clearance of related drugs would change accordingly. The abundance of functional pathways predicted in the gut microbiota changed dramatically between the control and PGF groups. Conclusions This study provides information concerning the microbial and CYP450 enzyme expression profiles as a reference for evaluating drug metabolism differences co-affected by gut microbiota and host CYP450 enzymes in the PGF model.

The breath volatilome is shaped by the gut microbiota

“…methanethiol) (62), either in the epithelial cells or liver, prior to breath exhalation. Third, the presence of the gut microbiota could impact the expression of hormones or metabolic enzymes in the host, such as insulin (63) or the cytochrome p450 enzymes in the liver (64), which could, in turn, alter the VOC profile of exhaled breath (65)(66)(67)(68)(69). Fourth, many breath VOCs are thought to be of dietary origin, such as terpenes like eucalyptol and limonene (70)(71)(72).…”

Antibiotics affect the pharmacokinetics of n-butylphthalidein vivoby altering the intestinal microbiota

“…First, the intestinal flora secretes a variety of phase I and phase II metabolic enzymes, which can directly participate in the metabolism of oral drugs and affect the efficacy and toxicity of drugs [19][20][21] . Second, the alteration of the intestinal microbiota influences the expression of liver drug metabolism enzymes [22,23] . Secondary bile acids and short-chain fatty acids (SCFAs), the metabolites of intestinal flora, can enter the liver through the portal vein and alter mRNA expression of multiple drug enzymes [24][25][26][27] .Furthermore, the intestinal microbiota can also affect intestinal drug transporters [28,29] , maintain intestinal structure and mucosal integrity, and alter drug absorption [30] .…”

Antibiotics affect the pharmacokinetics of n-butylphthalide in vivo by altering the intestinal microbiota

“…First, the intestinal flora secretes a variety of phase I and phase II metabolic enzymes, which can directly participate in the metabolism of oral drugs and affect the efficacy and toxicity of drugs [28][29][30]. Second, the alteration of the intestinal microbiota influences the expression of liver drug metabolism enzymes [31,32]. Secondary bile acids and short-chain fatty acids (SCFAs), the metabolites of intestinal flora, can enter the liver through the portal vein and alter mRNA expression of multiple drug enzymes [33][34][35][36].…”