|WALSH, JACINTA - University College Cork|
|GHEORGHE, CASSANDRA - University College Cork|
|Lyte, Joshua - Josh|
|VAN DE WOUW, MARCEL - University College Cork|
|BOEHME, MARCUS - University College Cork|
|DINAN, TIMOTHY - University College Cork|
|CRYAN, JOHN - University College Cork|
|GRIFFIN, BRENDAN - University College Cork|
|CLARKE, GERARD - University College Cork|
|HYLAND, NAILL - University College Cork|
Submitted to: Journal of Pharmacy and Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/21/2020
Publication Date: 4/27/2020
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., 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. https://doi.org/10.1111/jphp.13276.
Interpretive Summary: Many drugs given to animals, and taken by people are taken through the mouth such as swallowing pills or adding to food. When drugs are taken this way, they often enter the body through the intestine, then through the liver, and finally into the bloodstream to reach the target they intend to treat. When the drug enters the liver, however, the liver can cause changes in the drug. Understanding how drug-relevant genes in the liver work are very important to make sure oral drugs are effective. In addition to this, the microbiota, which is the collection of bacteria and other microorganisms that live in the gut, are known to interact with the liver. However, little is known how the microbiota influence drug-relevant genes in the liver which is an important consideration to host health. We sought to investigate whether the microbiota affects liver drug-relevant genes. To accomplish this we used normal, germ-free, and colonized germ-free mice. Germ free means mice that have no bacteria at all, and colonized are mice that were germ free but later obtained a normal microbiota. This system allowed us to meaningfully identify a role for the microbiota in influencing drug-relevant genes found in the liver. We found that the microbiota can have substantial impact on several important drug-relevant genes in the liver. These results will inform future strategies to improve animal and human health.
Technical Abstract: Objectives: We aimed to confirm the microbial regulation of hepatic genes implicated in drug metabolism and transport, to explore the mechanistic basis for this host-microbe interaction and to examine if a more clinically relevant microbiota-directed intervention alters hepatic gene expression. Methods: Using reverse-transcriptase PCR, we investigated cytochrome P450 (CYP) and multidrug-resistance protein 1 (MDR1) expression in conventional, germ-free (GF), and colonised GF mice. Sodium butyrate (3 g/L), or sodium chloride for sodium-matched controls, was administered via the drinking water for 21 days to conventional or GF C57BL/6 mice (n=13-15/group). Young adult (approx. 2 months at start of treatment) and middle-aged (approx. 10 months at start of treatment) conventional C57BL/6 mice received diet-enriched with 10% Oligofructose-inulin or standard diet for 14 weeks. Key findings: The colonisation of GF animals normalised the altered expression of Cyp3a11 and Mdr1b to conventional levels but did not exert the same effect on Cyp2b10. Butyrate upregulated Cyp2b10 in conventional mice (p<0.05) and normalised Mdr1b expression in GF mice. FOS-inulin increased Cyp3a13 expression but had the opposite effect on Mdr1a expression in young-adult mice (p<0.05) while age influenced the prebiotic effect on Cyp2a4 expression (p<0.01). Conclusion: Manipulation of the gut microbiome alters the expression of hepatic genes implicated in drug metabolism and transport. The overall effect of butyrate and FOS-inulin on CYP and MDR expression is gene-specific, and FOS-inulin alters CYP and MDR1 expression in an age-dependent manner.