Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta
By Henry J. Haiser, David B. Gootenberg, K. Chatman, G. Sirasani, E. Balskus, Peter J. Turnbaugh. Science, 2013
663 citations recorded by the source corpus.
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. The heart drug digoxin can be inactivated by a strain of gut microbe bearing a cardiac glycoside reductase operon. 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.
Subfields: Infectious Diseases, Molecular Biology, Pharmacology
View Paper: https://www.semanticscholar.org/paper/7a402c5be9321f2000e886b00529d3aaf9ab2e39
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In Infectious Diseases
In Molecular Biology
- Jeroen Raes
- Eric G. Pamer
- Rachel N. Carmody
- J. Luévano
- Peer Bork
- Y. Taur
- Peter J. Turnbaugh
- Thomas S. B. Schmidt
In Pharmacology
Citations in the corpus
- Antibiotic-Induced Changes in the Intestinal Microbiota and Disease. (2016, background): “This activity is enhanced in the presence of other commensals, but is repressed by arginine, which can be supplemented through a high-protein diet [72].”
- Diet dominates host genotype in shaping the murine gut microbiota (2014, background): “Diet-induced changes in the gut microbiota could also alter key metabolic activities, as shown recently for the interaction between dietary protein and the bacterial inactivation of cardiac drugs (Haiser et al., 2013).”
- Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism (2019, background): “lentaalso inactivates the cardiac drug digoxin, our finding suggests awider role for this gut organism in drug metabolism (44, 45).”
- The Human Gut Microbiome: From Association to Modulation. (2018, background): “For example, specific strains of Eggerthella lenta have been shown to metabolize the cardiac drug digoxin, rendering it inefficient in some patients (Haiser et al., 2013).”