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Gut Microbes. 2014 Mar-Apr;5(2):233-8. doi: 10.4161/gmic.27915. Epub 2014 Jan 23.

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

Author information

1
Faculty of Arts and Sciences (FAS) Center for Systems Biology; Harvard University; Cambridge, MA USA.
2
Department of Chemistry and Chemical Biology; Harvard University; Cambridge, MA USA.

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.

KEYWORDS:

Eggerthella lenta; RNA-seq; digoxin; gnotobiotics; human microbiome; metagenomics; pharmacokinetics

PMID:
24637603
PMCID:
PMC4063850
DOI:
10.4161/gmic.27915
[Indexed for MEDLINE]
Free PMC Article

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