title: Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility.
abstract: In recent years, the gut microbiome has gained increasing appreciation as a determinant of the health status of the human host. Bile salts that are secreted into the intestine may be biotransformed by enzymes produced by the gut bacteria. To date, bile acid research at the host-microbe interface has primarily been directed toward effects on host metabolism. The aim of this work was to investigate the effect of changes in gut microbial bile acid metabolism on the solubilization capacity of bile salt micelles and consequently intraluminal drug solubility. First, the impact of bile acid metabolism, mediated in vivo by the microbial enzymes bile salt hydrolase (BSH) and 7α-dehydroxylase, on drug solubility was assessed by comparing the solubilization capacity of (a) conjugated vs deconjugated and (b) primary vs secondary bile salts. A series of poorly water-soluble drugs (PWSDs) were selected as model solutes on the basis of an increased tendency to associate with bile micelles. Subsequently, PWSD solubility and dissolution was evaluated in conventional biorelevant simulated intestinal fluid containing host-derived bile acids, as well as in media modified to contain microbial bile acid metabolites. The findings suggest that deconjugation of the bile acid steroidal core, as dictated by BSH activity, influences micellar solubilization capacity for some PWSDs; however, these differences appear to be relatively minor. In contrast, the extent of bile acid hydroxylation, regulated by microbial 7α-dehydroxylase, was found to significantly affect the solubilization capacity of bile salt micelles for all nine drugs studied (p < 0.05). Subsequent investigations in biorelevant media containing either the trihydroxy bile salt sodium taurocholate (TCA) or the dihydroxy bile salt sodium taurodeoxycholate (TDCA) revealed altered drug solubility and dissolution. Observed differences in biorelevant media appeared to be both drug- and amphiphile (bile salt/lecithin) concentration-dependent. Our studies herein indicate that bile acid modifications occurring at the host-microbe interface could lead to alterations in the capacity of intestinal bile salt micelles to solubilize drugs, providing impetus to consider the gut microbiota in the drug absorption process. In the clinical setting, disruption of the gut microbial ecosystem, through disease or antibiotic treatment, could transform the bile acid pool with potential implications for drug absorption and bioavailability.
authors.affiliation: School of Pharmacy, ‡APC Microbiome Institute, §School of Biochemistry & Cell Biology, and ∥School of Microbiology, University College Cork , Cork, Ireland.
authors.forename: Elaine F
authors.identifier: 0000-0002-9253-3861
authors.initials: EF
authors.lastname: Enright
authors.affiliation: School of Pharmacy, ‡APC Microbiome Institute, §School of Biochemistry & Cell Biology, and ∥School of Microbiology, University College Cork , Cork, Ireland.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Joyce
authors.affiliation: School of Pharmacy, ‡APC Microbiome Institute, §School of Biochemistry & Cell Biology, and ∥School of Microbiology, University College Cork , Cork, Ireland.
authors.forename: Cormac G M
authors.initials: CG
authors.lastname: Gahan
authors.affiliation: School of Pharmacy, ‡APC Microbiome Institute, §School of Biochemistry & Cell Biology, and ∥School of Microbiology, University College Cork , Cork, Ireland.
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
mesh_terms: D001646:Bile / Q000737:chemistry*; D001647:Bile Acids and Salts / Q000737:chemistry*; D001682:Biological Availability; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D006801:Humans; D008823:Micelles; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D013256:Steroids / Q000737:chemistry; D013656:Taurocholic Acid / Q000737:chemistry; D013657:Taurodeoxycholic Acid / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D001647:Bile Acids and Salts; D008823:Micelles; D004364:Pharmaceutical Preparations; D013256:Steroids; D014867:Water; D013657:Taurodeoxycholic Acid; D013656:Taurocholic Acid
keywords: bile acid metabolism; bile micelle; biorelevant media; microbiota; pharmacokinetics; poorly water-soluble drug; solubility; solubilization capacity