signature=cdca6dcff644e950c88d4b899692a25a,Gut Microbiota-Mediated Bile Acid Transformations Alter t...

摘要：

Pharmacokinetic research at the host-microbe interface has beenprimarily directed toward effects on drug metabolism, with fewer investigationsconsidering the absorption process. We previously demonstrated thatthe transcriptional expression of genes encoding intestinal transportersinvolved in lipid translocation are altered in germ-free and conventionalizedmice possessing distinct bile acid signatures. It was consequentlyhypothesized that microbial bile acid metabolism, which is the deconjugationand dehydroxylation of the bile acid steroid nucleus by gut bacteria,may impact upon drug transporter expression and/or activity and potentiallyalter drug disposition. Using a panel of three human intestinal celllines (Caco-2, T84, and HT-29) that differ in basal transporter expressionlevel, bile acid conjugation-, and hydroxylation-status was shownto influence the transcription of genes encoding several major influxand efflux transporter proteins. We further investigated if theseeffects on transporter mRNA would translate to altered drug dispositionand activity. The results demonstrated that the conjugation and hydroxylationstatus of the bile acid steroid nucleus can influence the cellularresponse to multidrug resistance (MDR) substrates, a finding thatdid not directly correlate with directionality of gene or proteinexpression. In particular, we noted that the cytotoxicity of cyclosporineA was significantly augmented in the presence of the unconjugatedbile acids deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA)in P-gp positive cell lines, as compared to their taurine/glycine-conjugatedcounterparts, implicating P-gp in the molecular response. Overallthis work identifies a novel mechanism by which gut microbial metabolitesmay influence drug accumulation and suggests a potential role forthe microbial bile acid-deconjugating enzyme bile salt hydrolase (BSH)in ameliorating multidrug resistance through the generation of bileacid species with the capacity to access and inhibit P-gp ATPase.The physicochemical property of nonionization is suggested to underpinthe preferential ability of unconjugated bile acids to attenuate theefflux of P-gp substrates and to sensitize tumorigenic cells to cytotoxictherapeutics . These findings mayadditionally contribute to the development of less toxic P-gp modulators,which could overcome MDR.

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