title: Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics.
abstract: The human gut microbiota plays a key role in pharmacology, yet the mechanisms responsible remain unclear, impeding efforts toward personalized medicine. We recently identified a cytochrome-encoding operon in the common gut Actinobacterium Eggerthella lenta that is transcriptionally activated by the cardiac drug digoxin. These genes represent a predictive microbial biomarker for the inactivation of digoxin. Gnotobiotic mouse experiments revealed that increased protein intake can limit microbial drug inactivation. Here, we present a biochemical rationale for how the proteins encoded by this operon might inactivate digoxin through substrate promiscuity. We discuss digoxin signaling in eukaryotic systems, and consider the possibility that endogenous digoxin-like molecules may have selected for microbial digoxin inactivation. Finally, we highlight the diverse contributions of gut microbes to drug metabolism, present a generalized approach to studying microbe-drug interactions, and argue that mechanistic studies will pave the way for the clinical application of this work.
authors.affiliation: Faculty of Arts and Sciences (FAS) Center for Systems Biology; Harvard University; Cambridge, MA USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Haiser
authors.affiliation: Department of Chemistry and Chemical Biology; Harvard University; Cambridge, MA USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Seim
authors.affiliation: Department of Chemistry and Chemical Biology; Harvard University; Cambridge, MA USA.
authors.forename: Emily P
authors.initials: EP
authors.lastname: Balskus
authors.affiliation: Faculty of Arts and Sciences (FAS) Center for Systems Biology; Harvard University; Cambridge, MA USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Turnbaugh
mesh_terms: D039903:Actinobacteria / Q000378:metabolism*; D000818:Animals; D004077:Digoxin / Q000378:metabolism* / Q000493:pharmacokinetics; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000382:microbiology*; D005856:Germ-Free Life / Q000502:physiology; D006801:Humans; D051379:Mice
chemical_list: D004077:Digoxin
keywords: Eggerthella lenta; RNA-seq; digoxin; gnotobiotics; human microbiome; metagenomics; pharmacokinetics