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Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta
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Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta
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Journal Article
Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta
2013
Overview
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.
Publisher
American Association for the Advancement of Science,The American Association for the Advancement of Science
Subject
/ Actinobacteria - drug effects
/ Animals
/ arginine
/ Bacteria
/ diet
/ Dietary Proteins - pharmacology
/ Diets
/ digoxin
/ Drugs
/ feces
/ Gastrointestinal Tract - microbiology
/ Gene Expression Regulation, Bacterial - drug effects
/ heart
/ Human
/ Humans
/ Mice
/ operon
/ Operons
/ patients
/ people
/ Proteins
/ Rodents
/ Strain
/ T tests
/ Transcriptome - drug effects
/ Urine
