Pharmacomicrobiomics of Hepatic Drug Processing Genes During Pregnancy

Abstract

At present, little is known about how gut microbiome and pregnancy interplay to regulate expression or the activities of drug processing genes (DPGs). The objective of this study was to investigate the effects of gut microbiome on host hepatic DPGs during pregnancy using conventional (CV) and germ‐free (GF) mice. Four groups of C57BL/6 female mice were used: CV non‐pregnant (CVNP, n=6), GF non‐pregnant (GFNP, n=6), CV pregnant (CVP, n=5), and GF pregnant (GFP, n=5) mice. Hepatic transcriptome and proteome for DPGs were profiled using multi‐omics approach. Plasma bile acids and steroid hormone levels were determined using LC‐MS/MS. Cyp activities were measured using hepatic microsome incubations. Overall, RNA‐seq analysis revealed a similar trend of gene regulation by pregnancy, but different magnitudes of change in hepatic DPGs, in CV and GF mice. Of note, the Cyp3a11 mRNA levels were decreased 1.7‐fold and 3.2‐fold by pregnancy in CV and GF mice, respectively. On the contrary, the Cyp3a11 protein abundance was increased 1.2‐fold and 1.6‐fold by pregnancy in CV and GF mice, respectively. The Cyp3a activity was also significantly induced by pregnancy in CV and GF mice; however, the magnitude of induction in CV mice was >5‐fold greater than that in GF mice. Plasma bile acid and steroid hormone levels were significantly impacted by microbiome and pregnancy‐status, respectively, which may contribute to the differential effects of pregnancy in CV and GF mice. This is the first study to demonstrate that the gut microbiome may play a role in altering hepatic drug disposition in pregnancy.Support or Funding InformationThis project was supported by the University of Washington Drug Metabolism, Transport and Pharmacogenomics Research Program (DMTPR)