Gut Microbiota-Mediated Bile Acid Transformations
Alter the Cellular Response to Multidrug Resistant Transporter Substrates in Vitro: Focus on P‑glycoprotein
Version 2 2018-11-16, 17:49
Version 1 2018-11-16, 17:48
Posted on 2018-11-16 - 17:49
Pharmacokinetic 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.
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Enright, Elaine
F.; Govindarajan, Kalaimathi; Darrer, Rebecca; MacSharry, John; A. Joyce, Susan; G. M. Gahan, Cormac (2018). Gut Microbiota-Mediated Bile Acid Transformations
Alter the Cellular Response to Multidrug Resistant Transporter Substrates in Vitro: Focus on P‑glycoprotein. ACS Publications. Collection. https://doi.org/10.1021/acs.molpharmaceut.8b00875
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AUTHORS (6)
EE
Elaine
F. Enright
KG
Kalaimathi Govindarajan
RD
Rebecca Darrer
JM
John MacSharry
SA
Susan A. Joyce
CG
Cormac G. M. Gahan
KEYWORDS
bile acid componentGut Microbiota-Mediated BileDCAbile acid speciesbasal transporter expression leveldrug transporter expressionbile acid-deconjugating enzyme bile salt hydrolasecell linesHTbile acid signaturesdrug dispositionameliorating multidrug resistancebile acid metabolismBSHMDRunconjugated bile acidsefflux transporter proteinsP-gpCDCAbile acidMultidrug Resistant Transporter Substratesunconjugated bile acids deoxycholic acidgenes encoding