Speaker at Global Conference on Pharmaceutics and Drug Delivery Systems 2018 - Elaine Frances Enright
University College Cork, Israel
Title : The influence of gut microbiota-mediated bile acid metabolism on the cellular response to therapeutics at the intestinal barrier

Abstract:

Once regarded obscure, the cohabitation of man and microbe has gained increasing recognition as a determinant of the health status of the host. To date, pharmacokinetic research at the host-microbe interface has been primarily directed towards effects on metabolism. Microbial bile acid metabolism, deconjugation and dehydroxylation of the steroidal nucleus by the gut bacteria, may constitute a source of pharmacokinetic variability, and has been shown to impact bile acid solubilization capacity for poorly water-soluble drugs. Previous work within our research group involving germ-free and conventionalized mice (each group possessing distinct bile acid signatures) identified altered transcriptional expression of genes encoding intestinal transporters involved in lipid translocation. The purpose of this work was to investigate if microbial bile acid metabolism could similarly influence intestinal drug transporter expression and thereby drug uptake.

The impact of microbial bile acid metabolism on the transcriptional expression of genes encoding common influx and efflux transporters (including ABCB1, encoding P-glycoprotein) in Caco-2 cells was assessed. The ability of host (conjugated) and microbial (deconjugated/dehydroxylated) bile acids to differentially affect drug uptake and activity was investigated using the P-glycoprotein substrates, cyclosporine A (CsA) and rhodamine 6G (Rho 6G). Cell viability was used as a preliminary marker of altered CsA uptake/activity. Potential mechanisms by which bile acids could affect P-glycoprotein functioning was evaluated using ATPase and bidirectional transport assays.

Unconjugated bile acids significantly augmented CsA toxicity and reduced Rho 6G efflux, compared to tauro-conjugates (P < 0.05). These effects could not be explained by changes to ABCB1 mRNA transcripts. Bile acids were determined to inhibit, rather than stimulate, basal P-gp ATPase suggesting a non-competitive interaction with the transporter.

Overall, microbial bile metabolism was demonstrated to affect the uptake and activity of efflux transporter substrates. The physicochemical properties of unconjugated bile acids, including their capacity for passive membrane diffusion, is speculated to underpin their preferential attenuation of P-glycoprotein-mediated efflux.

Audience take away:
• To differentiate between host- and microbe- derived bile acids and to gain an appreciation of their altered physicochemical properties.
• To identify the key physicochemical descriptors influencing the differential effect of bile acids on the transcriptional expression and functionality of clinically relevant intestinal drug transporter proteins.
• To discuss the potential significance of altered bile acid “signatures” in the context of multidrug resistance and clinical pharmacokinetic variability.
• The aim of the outlined oral presentation is to provide an insight into the possible mechanisms by which the gut microbiota may affect the uptake and efficacy of multidrug resistant transporter substrates. It is envisaged that this topical subject matter will stimulate discussions on the need to consider both the human host and the gut microbiota in individualized dosage regimen design (PharmacoMicrobiomics).

Biography:

Elaine Enright is a registered pharmacist, having graduated from University College Cork, Ireland, in 2014 as “Highest Achieving Student” in the BPharm degree. Elaine subsequently obtained a Masters in Pharmacy from the Royal College of Surgeons in Ireland in 2015. During her studies, Elaine gained experience in the pharmaceutical and regulatory sectors at Servier Laboratories Ireland and at the Health Products Regulatory Authority. Elaine is presently pursuing a PhD in Pharmaceutics (year 3), funded by an Irish Research Council Government of Ireland Postgraduate Scholarship. Elaine’s PhD research, which is a collaboration between the APC Microbiome Institute and the School of Pharmacy, UCC, is supervised by Dr Cormac Gahan and Dr Susan Joyce. This four year trans-disciplinary work programme seeks to explore the effect of the gut microbiota on altering drug uptake from the gastrointestinal tract and, in particular, the potential clinical implications of this interplay. It is expected that this research will uncover new mechanisms by which the microbiota can influence individual patient responses to medicines.

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