Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics.

TitleMechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics.
Publication TypeJournal Article
Year of Publication2014
AuthorsHaiser, HJ, Seim, KL, Balskus, EP, Turnbaugh, PJ
JournalGut Microbes
Volume5
Issue2
Pagination233-8
Date Published2014 Mar-Apr
ISSN1949-0984
KeywordsActinobacteria, Animals, Digoxin, Gastrointestinal Tract, Germ-Free Life, Humans, Mice
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.

DOI10.4161/gmic.27915
Alternate JournalGut Microbes
PubMed ID24637603
PubMed Central IDPMC4063850
Grant List2P30DK034854-26 / DK / NIDDK NIH HHS / United States
MFE-112991 / / Canadian Institutes of Health Research / Canada
P30 DK034854 / DK / NIDDK NIH HHS / United States
P50GM068763 / GM / NIGMS NIH HHS / United States