Haiser, Henry JSeim, Kristen LBalskus, EmilyTurnbaugh, Peter J2015-04-012014Haiser, Henry J, Kristen L Seim, Emily P Balskus, and Peter J Turnbaugh. 2014. “Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics.” Gut Microbes 5 (2): 233-238. doi:10.4161/gmic.27915. http://dx.doi.org/10.4161/gmic.27915.1949-0976http://nrs.harvard.edu/urn-3:HUL.InstRepos:14351165The 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.en-USdigoxinEggerthella lentaRNA-seqgnotobioticsmetagenomicspharmacokineticshuman microbiomeJournal Article2015-04-0110.4161/gmic.27915