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Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta

Science  19 Jul 2013:
Vol. 341, Issue 6143, pp. 295-298
DOI: 10.1126/science.1235872

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Digoxin Dangers

A proportion of patients treated with digoxin, a cardiac glycoside used to treat heart function abnormalities, generate the inactive metabolite, dihydrodigoxin, resulting in poor efficacy. Haiser et al. (p. 295) examined a potential culprit responsible for this transformation—the actinobacterium, Eggerthella lenta—to probe the microbiota-digoxin interaction. Microbe growth was promoted by arginine, and differential expression analysis revealed a two-gene cardiac glycoside reductase (cgr) operon that was induced by digoxin in low arginine conditions. Not all strains of E. lenta could reduce digoxin and, when fecal samples from healthy people were tested, a spectrum of digoxin inactivation was detected. When the digoxin-reducing strain of E. lenta was given to germ-free mice that were fed a high-protein (that is, high-arginine) diet, digoxin levels stayed high in serum, and drug inactivation was suppressed.

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.

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