Gut microbiome-mediated modulation of hepatic cytochrome P450 and P-glycoprotein: impact of butyrate and fructo-oligosaccharide-inulin
Walsh, Jacinta; Gheorghe, Cassandra E.; Lyte, Joshua M.; van de Wouw, Marcel; Boehme, Marcus; Dinan, Timothy G.; Cryan, John F.; Griffin, Brendan T.; Clarke, Gerard; Hyland, Niall P.
Date:
2020-04-26
Copyright:
© 2020 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology. This is the peer reviewed version of the following article: (2020), Gut microbiome‐mediated modulation of hepatic cytochrome P450 and P‐glycoprotein: impact of butyrate and fructo‐oligosaccharide‐inulin. J Pharm Pharmacol., which has been published in final form at https://doi.org/10.1111/jphp.13276 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
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Access to this article is restricted until 12 months after publication by request of the publisher.
Restriction lift date:
2021-04-26
Citation:
Walsh, J., Gheorghe, C.E., Lyte, J.M., van de Wouw, M., Boehme, M., Dinan, T.G., Cryan, J.F., Griffin, B.T., Clarke, G. and Hyland, N.P. (2020) 'Gut microbiome‐mediated modulation of hepatic cytochrome P450 and P‐glycoprotein: impact of butyrate and fructo‐oligosaccharide‐inulin', Journal of Pharmacy and Pharmacology, doi: 10.1111/jphp.13276
Abstract:
Objectives: Our objective was to demonstrate microbial regulation of hepatic genes implicated in drug metabolism and transport using germ‐free (GF) mice and to explore the impact of a microbial metabolite, butyrate, and a prebiotic dietary intervention on hepatic gene expression in mice. Methods: Using reverse‐transcriptase PCR, we investigated cytochrome P450 (CYP) and multidrug‐resistance protein 1 (MDR1) expression in conventional, GF and colonised GF mice. To investigate the effects of butyrate, sodium butyrate (3 g/l) was administered for 21 days to conventional or GF mice. In the prebiotic study, young adult and middle‐aged mice received diet enriched with 10% fructo‐oligosaccharide (FOS)‐inulin for 14 weeks. Key findings: Colonisation of GF animals normalised expression of Cyp3a11 and Mdr1b to conventional levels. Butyrate upregulated Cyp2b10 in conventional mice (P < 0.05) but overall did not induce widespread changes in hepatic genes. FOS‐inulin increased Cyp3a13 expression and had the opposite effect on Mdr1a expression in young adult mice (P < 0.05). Age, on the other hand, influenced the prebiotic effect on Cyp2a4 expression (P < 0.01). Conclusion: The expression of hepatic genes implicated in drug metabolism and transport displays sensitivity to the microbiome, microbiome‐derived metabolites and a microbial‐targeted intervention. Our study may provide the impetus to explore microbiota‐targeted interventions in normalising host metabolic activity and reducing inter‐individual variability in drug pharmacokinetics.
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