Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium <i>Eggerthella lenta</i>

TLDR

The human gut microbiome can alter drug efficacy and toxicity, yet the mechanisms are often unclear. The study investigates how the gut bacterium *Eggerthella lenta* inactivates the cardiac drug digoxin. Transcriptional profiling, comparative genomics, and culture assays uncovered a digoxin‑induced cytochrome operon that is arginine‑inhibited and absent in non‑metabolizing strains, predicting digoxin inactivation; gnotobiotic mouse pharmacokinetics showed dietary protein reduces microbial digoxin metabolism, altering serum and urine concentrations, underscoring the importance of integrating human and microbial genomes in drug pharmacology.

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.