Regulation of hepatic drug-metabolizing enzymes in germ-free mice by conventionalization and probiotics
Open accessAbstract
Little is known regarding the effect of intestinal microbiota modifiers, such as probiotics and conventionalization with exogenous bacteria, on host hepatic drug metabolism. Therefore, the goal of this study was to determine the effect of these modifiers on the expression of various drug-metabolizing enzymes of the host liver. VSL3 is a probiotic that contains eight live strains of bacteria. Five groups of mice were used: 1) conventional mice (CV), 2) conventional mice treated with VSL3 in drinking water, 3) germ-free (GF) mice, 4) GF mice treated with VSL3, and 5) GF mice exposed to the conventional environment for 2 months. All mice were 3 months old at tissue collection. GF conditions markedly downregulated the cytochrome P450 (P450) 3a gene cluster, but upregulated the Cyp4a cluster, whereas conventionalization normalized their expression to conventional levels [reverse-transcription quantitative polymerase chain reaction (qPCR) and western blot]. Changes in the Cyp3a and 4a gene expression correlated with alterations in the pregnane X receptor and peroxisome proliferator-activated receptor α-DNA binding, respectively (chromatin immunoprecipitation-qPCR). VSL3 increased each bacterial component in the large intestinal content of the CV mice, and increased these bacteria even more in GF mice, likely due to less competition for growth in the GF environment. VSL3 given to conventional mice increased the mRNAs of Cyp4v3, alcohol dehydrogenase 1, and carboxyesterase 2a, but decreased the mRNAs of multiple phase II glutathione-S-transferases. VSL3 given to germ-free mice decreased the mRNAs of UDP-glucuronosyltransferases 1a9 and 2a3. In conclusion, conventionalization and VSL3 alter the expression of many drug-metabolizing enzyme s in the liver, suggesting the importance of considering "bacteria-drug" interactions for various adverse drug reactions in patients.
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Microbial colonization of germ-free animals normalized the expression of Cyp3a and Cyp4a gene clusters to those observed in conventional animals.
“Microbial colonization of germ-free animals normalized the expression of Cyp3a and Cyp4a gene clusters to those observed in conventional animals (Selwyn et al., 2016).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
In germ-free mice, Cyp3a mRNA and protein are decreased.
“| Cyp3a (mice) | Decreased mRNA and protein | Upregulated following colonization, but VSL3 probiotic | Selwyn et al., 2016 |”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
VSL3 moderately decreases mRNAs of Cyp3a44 and Cyp3a11 in conventional mice.
“VSL3 moderately decreased mRNAs of Cyp3a44 and”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
Colonization upregulates Cyp3a.
“Upregulated following colonization, but VSL3 probiotic”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
Host hepatic enzyme expression and activity are altered in animals reared in a germ-free environment.
“For example, host hepatic enzyme expression and activity are altered in animals reared in a germ-free environment (Selwyn et al., 2016).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
The VSL3 probiotic cocktail does not normalize Cyp3a expression.
“cocktail was not able to normalize their expression;”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
In germ-free mice, Cyp4a mRNA and protein are increased.
“| Cyp4a (mice) | Increased mRNA and protein | Downregulated following colonization, but VSL3 | Selwyn et al., 2016 |”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
Cyp4a is similar to the human CYP4A cluster.
“similar to the human CYP4A cluster”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
Colonization downregulates Cyp4a.
“Downregulated following colonization, but VSL3”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
The VSL3 probiotic cocktail does not normalize Cyp4a expression.
“probiotic cocktail was not able to normalize their”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Selwyn et al., 2016
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- Authors
- Selwyn, F. P., Cheng, S. L., Klaassen, C. D., & Cui, J. Y.
- Affiliations
- University of Washington (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 44
- Issue
- 2
- Pages
- 262-274
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC4746487
- OpenAlex
- W2183144597
- Cited by
- 138
- References
- 41
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 13 · 2023: 7 · 2022: 15 · 2021: 31 · 2020: 18 · 2019: 15 · 2018: 7 · 2017: 10 · 2016: 4 · 2014: 1
- FWCI
- 15.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM111381, GM111381)
- National Institute of Environmental Health Sciences (ES-019487, P30 ES0007033, R01ES019487, P30ES007033)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- hepatic drug-metabolizing enzymes, germ-free mice, conventionalization, probiotics, gut microbiota, CYP3A, CYP4A, pregnane X receptor, PPARα, UDP-glucuronosyltransferase, glutathione S-transferase, ADH1, adverse drug reactions
- MeSH terms
- Pregnane X Receptor, UDP-Glucuronosyltransferase 1A9, Animals, Cytochrome P-450 Enzyme System, Glutathione Transferase, Liver, Male, Mice, Inbred C57BL, Receptors, Steroid, RNA, Messenger, Glucuronosyltransferase, Down-Regulation, Up-Regulation, Probiotics, PPAR alpha, Mice
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