Gut microbiota-mediated bile acid transformations alter the cellular response to multidrug resistant transporter substrates in vitro: focus on P-glycoprotein

dc.check.infoAccess to this article is restricted until 12 months after publication by request of the publisher.en
dc.contributor.authorEnright, Elaine F.
dc.contributor.authorGovindarajan, Kalaimathi
dc.contributor.authorDarrer, Rebecca
dc.contributor.authorMacSharry, John
dc.contributor.authorJoyce, Susan A.
dc.contributor.authorGahan, Cormac G.
dc.contributor.funderIrish Research Councilen
dc.contributor.funderScience Foundation Irelanden
dc.description.abstractPharmacokinetic research at the host-microbe interface has been primarily directed toward effects on drug metabolism, with fewer investigations considering the absorption process. We previously demonstrated that the transcriptional expression of genes encoding intestinal transporters involved in lipid translocation are altered in germ-free and conventionalized mice possessing distinct bile acid signatures. It was consequently hypothesized that microbial bile acid metabolism, which is the deconjugation and dehydroxylation of the bile acid steroid nucleus by gut bacteria, may impact upon drug transporter expression and/or activity and potentially alter drug disposition. Using a panel of three human intestinal cell lines (Caco-2, T84, and HT-29) that differ in basal transporter expression level, bile acid conjugation-, and hydroxylation-status was shown to influence the transcription of genes encoding several major influx and efflux transporter proteins. We further investigated if these effects on transporter mRNA would translate to altered drug disposition and activity. The results demonstrated that the conjugation and hydroxylation status of the bile acid steroid nucleus can influence the cellular response to multidrug resistance (MDR) substrates, a finding that did not directly correlate with directionality of gene or protein expression. In particular, we noted that the cytotoxicity of cyclosporine A was significantly augmented in the presence of the unconjugated bile acids deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) in P-gp positive cell lines, as compared to their taurine/glycine-conjugated counterparts, implicating P-gp in the molecular response. Overall this work identifies a novel mechanism by which gut microbial metabolites may influence drug accumulation and suggests a potential role for the microbial bile acid-deconjugating enzyme bile salt hydrolase (BSH) in ameliorating multidrug resistance through the generation of bile acid species with the capacity to access and inhibit P-gp ATPase. The physicochemical property of nonionization is suggested to underpin the preferential ability of unconjugated bile acids to attenuate the efflux of P-gp substrates and to sensitize tumorigenic cells to cytotoxic therapeutics in vitro. This work provides new impetus to investigate whether perturbation of the gut microbiota, and thereby the bile acid component of the intestinal metabolome, could alter drug pharmacokinetics in vivo. These findings may additionally contribute to the development of less toxic P-gp modulators, which could overcome MDR.en
dc.description.sponsorshipIrish Research Council (Government of Ireland Postgraduate Scholarship (grant number GOIPG/2015/3261)); Science Foundation of Ireland (APC Microbiome Ireland, Centres for Science, Engineering and Technology (CSET) programme (Grant Number SFI/12/RC/2273))en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.identifier.citationEnright, E. F., Govindarajan, K., Darrer, R., MacSharry, J., Joyce, S. A. and Gahan, C. G. M. (2018) 'Gut Microbiota-Mediated Bile Acid Transformations Alter the Cellular Response to Multidrug Resistant Transporter Substrates in Vitro: Focus on P-glycoprotein', Molecular Pharmaceutics, 15(12), pp. 5711-5727. doi: 10.1021/acs.molpharmaceut.8b00875en
dc.identifier.journaltitleMolecular Pharmaceuticsen
dc.publisherAmerican Chemical Society, ACSen
dc.rights© 2018 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see
dc.subjectBile acid metabolismen
dc.subjectDrug absorptionen
dc.subjectDrug transporteren
dc.subjectMultidrug resistanceen
dc.titleGut microbiota-mediated bile acid transformations alter the cellular response to multidrug resistant transporter substrates in vitro: focus on P-glycoproteinen
dc.typeArticle (peer-reviewed)en
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