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Published on: August 23, 2019
Intestinal microbiota regulate xenobiotic metabolism in the liver
Britta Björkholm1, Chek Mei Bok, Annelie Lundin
1Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden.
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.
Insights
Gut microbiota significantly impacts liver function and drug metabolism. Germ-free mice exhibit more efficient xenobiotic metabolism compared to conventionally-raised mice, demonstrating microbiota
Area of Science:
- Hepatology
- Microbiology
- Pharmacology
Background:
- The liver is a primary site for xenobiotic metabolism (XM), with nuclear receptors like CAR and PXR regulating drug metabolism.
- Gut microbiota's influence on liver gene expression and xenobiotic metabolism, particularly in response to barbiturates, is under investigation.
Purpose of the Study:
- To investigate how gut microbiota influences hepatic gene expression and xenobiotic metabolism.
- To determine the effect of gut microbiota on the metabolism of drugs like barbiturates.
Main Methods:
- Comparative analysis of hepatic gene expression using microarrays in germ-free (GF) and specific-pathogen-free (SPF) mice.
- Functional validation through exposure of GF and SPF mice to pentobarbital to assess xenobiotic metabolism efficiency.
Main Results:
- Identified 112 differentially expressed genes in the liver, primarily related to xenobiotic metabolism and RXR function inhibition.
- Germ-free mice demonstrated significantly more efficient xenobiotic metabolism, indicated by a shorter anesthesia duration with pentobarbital, compared to SPF mice.
Conclusions:
- Gut microbiota plays a crucial role in modulating hepatic gene expression and xenobiotic metabolism.
- Microbiota influences the liver's response to drugs even without direct hepatic contact.
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