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Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta
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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References and Notes
1
Haiser H. J., Turnbaugh P. J., Is it time for a metagenomic basis of therapeutics? Science 336, 1253–1255 (2012).
2
Wallace B. D., Wang H., Lane K. T., Scott J. E., Orans J., Koo J. S., Venkatesh M., Jobin C., Yeh L. A., Mani S., Redinbo M. R., Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330, 831–835 (2010).
3
L. S. Goodman et al., Goodman & Gilman's the Pharmacological Basis of Therapeutics (McGraw-Hill, New York, ed. 12, 2011).
4
Lindenbaum J., Rund D. G., Butler V. P., Tse-Eng D., Saha J. R., Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy. N. Engl. J. Med. 305, 789–794 (1981).
5
Farr C. D., Burd C., Tabet M. R., Wang X., Welsh W. J., Ball W. J., Three-dimensional quantitative structure-activity relationship study of the inhibition of Na(+),K(+)-ATPase by cardiotonic steroids using comparative molecular field analysis. Biochemistry 41, 1137–1148 (2002).
6
Dobkin J. F., Saha J. R., Butler V. P., Neu H. C., Lindenbaum J., Digoxin-inactivating bacteria: Identification in human gut flora. Science 220, 325–327 (1983).
7
Materials and methods are available as supplementary materials on Science Online.
8
Sperry J. F., Wilkins T. D., Arginine, a growth-limiting factor for Eubacterium lentum. J. Bacteriol. 127, 780–784 (1976).
9
Saunders E., Pukall R., Abt B., Lapidus A., Glavina Del Rio T., Copeland A., Tice H., Cheng J. F., Lucas S., Chen F., Nolan M., Bruce D., Goodwin L., Pitluck S., Ivanova N., Mavromatis K., Ovchinnikova G., Pati A., Chen A., Palaniappan K., Land M., Hauser L., Chang Y. J., Jeffries C. D., Chain P., Meincke L., Sims D., Brettin T., Detter J. C., Göker M., Bristow J., Eisen J. A., Markowitz V., Hugenholtz P., Kyrpides N. C., Klenk H. P., Han C., Complete genome sequence of Eggerthella lenta type strain (IPP VPI 0255). Stand. Genomic Sci. 1, 174–182 (2009).
10
Nelson K. E., Weinstock G. M., Highlander S. K., Worley K. C., Creasy H. H., Wortman J. R., Rusch D. B., Mitreva M., Sodergren E., Chinwalla A. T., Feldgarden M., Gevers D., Haas B. J., Madupu R., Ward D. V., Birren B. W., Gibbs R. A., Methe B., Petrosino J. F., Strausberg R. L., Sutton G. G., White O. R., Wilson R. K., Durkin S., Giglio M. G., Gujja S., Howarth C., Kodira C. D., Kyrpides N., Mehta T., Muzny D. M., Pearson M., Pepin K., Pati A., Qin X., Yandava C., Zeng Q., Zhang L., Berlin A. M., Chen L., Hepburn T. A., Johnson J., McCorrison J., Miller J., Minx P., Nusbaum C., Russ C., Sykes S. M., Tomlinson C. M., Young S., Warren W. C., Badger J., Crabtree J., Markowitz V. M., Orvis J., Cree A., Ferriera S., Fulton L. L., Fulton R. S., Gillis M., Hemphill L. D., Joshi V., Kovar C., Torralba M., Wetterstrand K. A., Abouellleil A., Wollam A. M., Buhay C. J., Ding Y., Dugan S., FitzGerald M. G., Holder M., Hostetler J., Clifton S. W., Allen-Vercoe E., Earl A. M., Farmer C. N., Liolios K., Surette M. G., Xu Q., Pohl C., Wilczek-Boney K., Zhu D., A catalog of reference genomes from the human microbiome. Science 328, 994–999 (2010).
11
Mathan V. I., Wiederman J., Dobkin J. F., Lindenbaum J., Geographic differences in digoxin inactivation, a metabolic activity of the human anaerobic gut flora. Gut 30, 971–977 (1989).
12
Maymó-Gatell X., Chien Y., Gossett J. M., Zinder S. H., Isolation of a bacterium that reductively dechlorinates tetrachloroethene to ethene. Science 276, 1568–1571 (1997).
13
Maurice C. F., Haiser H. J., Turnbaugh P. J., Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell 152, 39–50 (2013).
14
Ning Z., Cox A. J., Mullikin J. C., SSAHA: A fast search method for large DNA databases. Genome Res. 11, 1725–1729 (2001).
15
Breitling R., Armengaud P., Amtmann A., Herzyk P., Rank products: A simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments. FEBS Lett. 573, 83–92 (2004).
16
Untergasser A., Cutcutache I., Koressaar T., Ye J., Faircloth B. C., Remm M., Rozen S. G., Primer3—new capabilities and interfaces. Nucleic Acids Res. 40, e115 (2012).
17
Kurtz S., Phillippy A., Delcher A. L., Smoot M., Shumway M., Antonescu C., Salzberg S. L., Versatile and open software for comparing large genomes. Genome Biol. 5, R12 (2004).
18
Thiele B., Füllner K., Stein N., Oldiges M., Kuhn A. J., Hofmann D., Analysis of amino acids without derivatization in barley extracts by LC-MS-MS. Anal. Bioanal. Chem. 391, 2663–2672 (2008).
19
Okarma T. B., Tramell P., Kalman S. M., The surface interaction between digoxin and cultured heart cells. J. Pharmacol. Exp. Ther. 183, 559–576 (1972).
20
Gabel L. P., Bihler I., Dresel P. E., Induction of failure in gas-perfused hearts by intermittent administration of Krebs solution. The effect of digitalis glycosides. Circ. Res. 21, 263–270 (1967).
21
Jacobs W. A., Hoffmann A., The relationship between the structure and the biological action of the cardiac glucosides. J. Biol. Chem. 74, 482–486 (1927).
22
Brown B. T., Wright S. E., Hydrogenation of digitalis genins and anhydrogenins. J. Pharm. Pharmacol. 13, 262–267 (1961).
23
Qazzaz H. M. A. M., El-Masri M. A., Valdes R., Secretion of a lactone-hydrogenated ouabain-like effector of sodium, potassium-adenosine triphosphatase activity by adrenal cells. Endocrinology 141, 3200–3209 (2000).
24
Belz G. G., Breithaupt-Grögler K., Osowski U., Treatment of congestive heart failure—current status of use of digitoxin. Eur. J. Clin. Invest. 31, (Suppl 2), 10–17 (2001).
25
Fürstenwerth H., Ouabain - the insulin of the heart. Int. J. Clin. Pract. 64, 1591–1594 (2010).
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Published In
Science
Volume 341 | Issue 6143
19 July 2013
19 July 2013
Copyright
Copyright © 2013, American Association for the Advancement of Science.
Submission history
Received: 30 January 2013
Accepted: 14 June 2013
Published in print: 19 July 2013
Acknowledgments
B. Budnik and S. Trauger for liquid chromatography–mass spectrometry (LC-MS) analyses; V. Yeliseyev, A. Liou, and R. Carmody for mouse studies; C. Reardon and C. Daly for sequencing support; C. Maurice, L. David, R. Dutton, B. Wolfe, J. Button, M. Elliot, Y. Falanga, R. Losick, A. Murray, and B. Stern for helpful discussions. Mouse experiments were done with the generous support of the Harvard Digestive Diseases Center and the University of North Carolina gnotobiotic cores. This work was supported by grants from the NIH (P50 GM068763) and the Harvard Digestive Diseases Center (2P30DK034854-26). H.J.H. is supported by the Canadian Institutes of Health Research (MFE-112991). RNA-Seq data are deposited in the Gene Expression Omnibus (GEO) database (accession GSE43919).
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