Intestinal Microbiota Regulate Xenobiotic Metabolism in the Liver

Britta Björkholm,Martin Lloyd Hibberd,Chek Mei Bok,Sven Pettersson,Annelie Lundin,Joseph Rafter,Stefan Bereswill

doi:10.1371/journal.pone.0006958

Britta Björkholm, Martin Lloyd Hibberd + Show 5 more

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https://doi.org/10.1371/journal.pone.0006958

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Abstract

BackgroundThe liver is the central organ for xenobiotic metabolism (XM) and is regulated by nuclear receptors such as CAR and PXR, which control the metabolism of drugs. Here we report that gut microbiota influences liver gene expression and alters xenobiotic metabolism in animals exposed to barbiturates.Principal findingsBy comparing hepatic gene expression on microarrays from germfree (GF) and conventionally-raised mice (SPF), we identified a cluster of 112 differentially expressed target genes predominantly connected to xenobiotic metabolism and pathways inhibiting RXR function. These findings were functionally validated by exposing GF and SPF mice to pentobarbital which confirmed that xenobiotic metabolism in GF mice is significantly more efficient (shorter time of anesthesia) when compared to the SPF group.ConclusionOur data demonstrate that gut microbiota modulates hepatic gene expression and function by altering its xenobiotic response to drugs without direct contact with the liver.

Highlights

Data accumulated over the last decade strongly support that the commensal intestinal flora has profound effects on the physiology of the host
Effect of intestinal microbiota on gene expression in liver Gene expression in the liver was initially assessed on 60-mer oligo microarrays on RNA from GF and specific pathogen-free (SPF) male NRMI mice (n = 4/group; NCBI GEO platform accession GSE14689, according to MIAME guidelines)
The genes that were significantly differentially expressed were selected for quantitative PCRverification based on the following criteria: q,5%, fold change (FC) of 2#FC$22 and the presence of a human orthologue resulting in 380 genes

Summary

Introduction

Data accumulated over the last decade strongly support that the commensal intestinal flora has profound effects on the physiology of the host. We report that gut microbiota influences liver gene expression and alters xenobiotic metabolism in animals exposed to barbiturates. Principal findings: By comparing hepatic gene expression on microarrays from germfree (GF) and conventionally-raised mice (SPF), we identified a cluster of 112 differentially expressed target genes predominantly connected to xenobiotic metabolism and pathways inhibiting RXR function. These findings were functionally validated by exposing GF and SPF mice to pentobarbital which confirmed that xenobiotic metabolism in GF mice is significantly more efficient (shorter time of anesthesia) when compared to the SPF group

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