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. 2009 Sep 9;4(9):e6958.
doi: 10.1371/journal.pone.0006958.

Intestinal microbiota regulate xenobiotic metabolism in the liver

Britta Björkholm  1 , Chek Mei Bok, Annelie Lundin, Joseph Rafter, Martin Lloyd Hibberd, Sven Pettersson
Affiliations

Intestinal microbiota regulate xenobiotic metabolism in the liver

Britta Björkholm et al. PLoS One. .

Abstract

Background: The 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 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.

Conclusion: Our data demonstrate that gut microbiota modulates hepatic gene expression and function by altering its xenobiotic response to drugs without direct contact with the liver.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Canonical Pathways Analysis.
Shown are the top fifteen significant canonical pathways as determined by using the Ingenuity Pathway Analysis software (Ingenuity® Systems). The strength of the statistical association is indicated by the length of the bars. The ration value reflects the proportion of gene elements in the differentially abundant gene list that corresponded to genes in each pathway. The vertical line represents the threshold of the significance.
Figure 2
Figure 2. Pathway analysis based on the Ingenuity Pathway Knowledge Base (IPKB).
The two highest scoring networks (A) Network 1 and (B) Network 2 created from the 112 differentially expressed genes list are shown. (C) showed the merged network of Network 1 and Network 2. Nodes that are not colored are added by IPKB. Colored nodes are shaded by their relative expression, green when lower in GF than SPF and red when higher expressed in GF compared to SPF, intensity is relative to expression. The shape of the node indicates the major function of the protein. A line denotes binding of the products of the two genes while a line with an arrow denotes ‘acts on’. A dotted line denotes an indirect interaction. Yellow lines in (C) denotes connection between Network 1 and Network 2.
Figure 3
Figure 3. Selected differentially expressed genes in SPF compared to GF NMRI mice (n = 7 animals/group).
Fold changes of genes in the categories (A) Xenobiotic Metabolism and (B) Circadian rhythm, are shown.
Figure 4
Figure 4. (A) Average time between loosing and regaining the righting reflex after i.p. injection (45 mg/kg body weight) of Pentobarbital and (B) Liver/Body weight ratio (%) in GF, Conv-D and SPF NMRI mice.
GF: germ-free; Conv-D: conventionalized 1, 3 or 6 weeks; SPF: conventionally-raised specific pathogen free.
See this image and copyright information in PMC

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