Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta.

TitlePredicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta.
Publication TypeJournal Article
Year of Publication2013
AuthorsHaiser, HJ, Gootenberg, DB, Chatman, K, Sirasani, G, Balskus, EP, Turnbaugh, PJ
JournalScience
Volume341
Issue6143
Pagination295-8
Date Published2013 Jul 19
ISSN1095-9203
KeywordsActinobacteria, Animals, Arginine, Cytochromes, Dietary Proteins, Digoxin, Feces, Gastrointestinal Tract, Gene Expression Regulation, Bacterial, Germ-Free Life, Humans, Metagenome, Mice, Mice, Inbred Strains, Operon, Transcriptome
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.

DOI10.1126/science.1235872
Alternate JournalScience
PubMed ID23869020
PubMed Central IDPMC3736355
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
P50 GM068763 / GM / NIGMS NIH HHS / United States
P50 GM068763 / GM / NIGMS NIH HHS / United States