title: Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta.
abstract: Despite numerous examples of the effects of the human gastrointestinal microbiome on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the cardiac drug digoxin by the gut Actinobacterium Eggerthella lenta. Transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, inhibited by arginine, absent in nonmetabolizing E. lenta strains, and predictive of digoxin inactivation by the human gut microbiome. Pharmacokinetic studies using gnotobiotic mice revealed that dietary protein reduces the in vivo microbial metabolism of digoxin, with significant changes to drug concentration in the serum and urine. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes.
authors.affiliation: Faculty of Arts and Sciences Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Haiser
authors.forename: David B
authors.initials: DB
authors.lastname: Gootenberg
authors.forename: Kelly
authors.initials: K
authors.lastname: Chatman
authors.forename: Gopal
authors.initials: G
authors.lastname: Sirasani
authors.forename: Emily P
authors.initials: EP
authors.lastname: Balskus
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Turnbaugh
mesh_terms: D039903:Actinobacteria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D003580:Cytochromes / Q000235:genetics; D004044:Dietary Proteins / Q000494:pharmacology; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000382:microbiology*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D005856:Germ-Free Life; D006801:Humans; D054892:Metagenome; D051379:Mice; D008815:Mice, Inbred Strains; D009876:Operon / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects
chemical_list: D003580:Cytochromes; D004044:Dietary Proteins; D004077:Digoxin; D001120:Arginine