Gut Microbiome Alters the Activity of Liver Cytochromes P450 in Mice With Sex-Dependent Differences.

Lenka Jourová,Nina Zemanova,Tomas Hudcovic,Petra Hermanova,Pavel Anzenbacher,Katerina Langova,Marketa Vavreckova,Eva Anzenbacherova

doi:10.3389/fphar.2020.01303

Abstract

Sexual differences and the composition/function of the gut microbiome are not considered the most important players in the drug metabolism field; however, from the recent data it is obvious that they may significantly affect the response of the patient to therapy. Here, we evaluated the effect of microbial colonization and sex differences on mRNA expression and the enzymatic activity of hepatic cytochromes P450 (CYPs) in germ-free (GF) mice, lacking the intestinal flora, and control specific-pathogen-free (SPF) mice. We observed a significant increase in the expression of Cyp3a11 in female SPF mice compared to the male group. However, the sex differences were erased in GF mice, and the expression of Cyp3a11 was about the same in both sexes. We have also found higher Cyp2c38 gene expression in female mice compared to male mice in both the SPF and GF groups. Moreover, these changes were confirmed at the level of enzymatic activity, where the female mice exhibit higher levels of functional CYP2C than males in both groups. Interestingly, we observed the same trend as with CYP3A enzymes: a diminished difference between the sexes in GF mice. The presented data indicate that the mouse gut microbiome plays an important role in sustaining sexual dimorphism in terms of hepatic gene expression and metabolism.

Highlights

The gut microbiome, an aggregate genome of trillions of microorganisms, provides a wide range of beneficial functions for the host and has an immense effect on the host’s health status and predisposition to disease (Kinross et al, 2011)
We investigated the role of sex and presence/absence of the gut microbiome on the gene expression and enzymatic activity of CYPs in the liver using germ-free (GF) mice, lacking the intestinal flora and specific-pathogen-free (SPF) mice
The Cyp3a11 mRNA was significantly increased (21 times) in female SPF mice compared to their male counterparts

Summary

Introduction

The gut microbiome, an aggregate genome of trillions of microorganisms, provides a wide range of beneficial functions for the host and has an immense effect on the host’s health status and predisposition to disease (Kinross et al, 2011). This ecosystem of bacteria, archaea, viruses, and unicellular eukaryotes is mostly stable in the long run, but transiently they may be affected by many factors (Schlomann and Parthasarathy, 2019). Among the wide range of factors that influence the composition of the gut microbiota, diet seems to be the most potent (Wilson et al, 2020).

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Conclusion