DOI: https://doi.org/10.18524/2307-4663.2020.2(49).211285

БІОТРАНСФОРМАЦІЯ КСЕНОБІОТИКІВ МІКРОБІОТОЮ ШЛУНКОВО- КИШКОВОГО ТРАКТУ ТА ЇЇ НАСЛІДКИ ДЛЯ ЛЮДИНИ

Б. М. Галкін, Т. О. Філіпова

Анотація


В огляді представлені дані сучасних джерел літератури про біотрансформацію ксенобітиків мікробіотою шлунково-кишкового тракту людини. Приведені основні ензими, які беруть участь у біотрансформації. Показана роль біотрансформації ензимів мікробіоти у активації та пригнічення лікарських засобів, детоксикації та токсикації чужорідних сполук та важких металів.

Ключові слова


кишкова мікробіота; біотрансформація ксенобіотиків; ензими; барвники; важкі метали; лікарські препарати

Повний текст:

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Посилання


Koppel N, Rekdal V-M, Balskus EP Chemical transformation of xenobiotics by the human gut microbiota // Science. 2017; 356(6344): 1–11.

Sender R, Fuchs S, Milo R Revised estimates for the number of human and bacteria cells in the body // PLOS Biology. 2016; 14(8): e1002533.

Aron-Wisnewsky J, Doré J, Clement . The importance of the gut microbiota after bariatric surgery // Nat. Rev. Gastroenterol. Hepatol. 2012; 9(10): 590– 598.

Eckburg PB Diversity of the human intestinal microbial flora // Science. 2005; 308(572):1635–1638.

Wang B, Hu L, Siahaan T Drug Delivery: Principles and Applications, Wiley, 2016:757p.

Sousa T, Paterson R, Moore V et al. The gastrointestinal microbiota as a site for the biotransformation of drugs // Int. J. Pharmac. 2008; 363(1–2): P. 1–25.

Galkin BM, Ivanytia VO, Filipova TO Mechanisms of biodegradation of xenobiotics, Odessa, II Mechnikov ONU, 2017: 148 p (in Ukraine).

Linhardt RJ, Galliher PM, Cooney CL Polysaccharide lyases // Appl. Biochem. Biotechnol. 1987; 12 (2): 135–176.

Ryan A, Kaplan E, Nebel J-C et al. Identification of NAD(P)H quinone oxidoreductase activity in azoreductases from P. aeruginosa: Azoreductases and NAD(P)H quinone oxidoreductases belong to the same FMN-dependent superfamily of enzymes // PLoS. 2014; 9(6): e98551.

Martínez-del Campo A, Bodea S, Hamer H A et al Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria // mBio. 2015; 6 (2): e00042.

Kaoutari AE, Armougom F, Gordon J I et al The abundance and variety of carbohydrate-active enzymes in the human gut microbiota // Nat. Rev. Microbiol. 2013; 11 (7):497–504.

Levin BJ, Huang YY, Peck SC et al A prominent glycyl radical enzyme in human gut microbiomes metabolizes trans-4-hydroxy-l-proline // Science. 2017 ; 355(6325): eaai8386.

Jancova P, Anzenbacher P, Anzenbacherova E Phase II drug metabolizing enzymes // Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2019; 154(1): 103–116.

Wang J, Yadav V, Smart A L et al Stability of peptide drugs in the colon // Eur. J. Pharmac. Sci. 2015; 78(1): 31–36.

Tozaki H, Emi Y, Horisaka E, Fujita T et al Degradation of insulin and calcitonin and their protection by various protease inhibitors in rat caecal contents: Implications in peptide delivery to the colon // J. Pharmacy Pharm. 1997; 49(2): 164–168.

Wallace BD, Roberts AB, Pollet RM et al Structure and inhibition of microbiome β-glucuronidases essential to the alleviation of cancer drug toxicity // Chem. Biol. 2015; 22(9): 1238–1249.

Ulmer JE, Vilén EM, Namburi RB et al. Characterization of glycosaminoglycan (GAG) sulfatases from the human gut symbiont bacteroides the taiotaomicron reveals the first GAG-specific bacterial endosulfatase // J. Biol. Chem. 2014; 289(35): 24289–24303.

Lukatela G, Krauss N, Theis K, et al. Crystal structure of human arylsulfatase A: The aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis // Biochem.1998; 37(11):3654–3664.

Donohoe DR, Garge N, Zhang X et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon // Cell Metab. 2011; 13(5): P. 517–526.

Cooper AJL, Krasnikov BF, Niatsetskaya ZV et al. Cysteine S-conjugate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents // Amino Acids. 2010; 4(1): P. 7–27.

Claus SP, Guillou H, Ellero-Simatos S The gut microbiota: a major player in the toxicity of environmental pollutants? // Npj Biofilms and Microbiomes. 2016; 2(1):1-11.

Rossol I, Pühler A The Corynebacterium glutamicum aecD gene encodes a C-S lyase with alpha, beta-elimination activity that degrades aminoethylcysteine // J. Bacteriol. 1992; 174(9): 2968–2977.

Rafii F, Hall JD, Cerniglia CE Mutagenicity of azo dyes used in foods, drugs and cosmetics before and after reduction by Clostridium species from the human intestinal tract // Food Chem. Toxicol. 1997; 35(9): 897–901.

Lee SC, Renwick AG Sulphoxide reduction by rat intestinal flora and by Escherichia coli in vitro // Biochem. Pharm. 1995; 49(11): 1567–1576.

Laue H, Friedrich M, Ruff J, Cook AM Dissimilatory sulfite reductase (Desulfoviridin) of the taurine-degrading, non-sulfate-reducing bacterium bilophila wadsworthia RZATAU contains a fused DsrB-DsrD subunit // J. Bacteriol. 2001;183(5):1727–1733.

Haiser HJ, Gootenberg DB, Chatman K et al Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta // Science.2013; 341(6143); 295–298.

Peppercorn MA, Goldman P The role of intestinal bacteria in the metabolism of salicylazosulfapyridine // J. Pharm. Exp. Therap. 1972; 181 (3): 555-562.

Lavrijsen K, van Dyck D, van Houdt J et al. Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans // Drug Metab. Dispos. 1995; 23(3): 354–362.

Kumano T, Fujiki E, Hashimoto Y, Kobayashi M Discovery of a sesaminmetabolizing microorganism and a new enzyme // Proc. Nat. Acad. Sci.2016; 113(32): 9087–9092.

Ticak T, Kountz DJ, Girosky KE et al. A nonpyrrolysine member of the widely distributed trimethylamine methyltransferase family is a glycine betaine methyltransferase // Proc. Nat. Acad. Sci. 2014;111 (43): E4668–E4676.

Delomenie C, Fouix S, Longuemaux S et al. Identification and functional characterization of arylamine N-Acetyltransferases in eubacteria: Evidence for highly selective acetylation of 5-aminosalicylic acid // J. Bacteriol. 2001;183.(11): 3417–3427.

Sutton D, Butler AM, Nadin L, Murray M Role of CYP3A4 in Human Hepatic Diltiazem N-Demethylation: Inhibition of CYP3A4 Activity by Oxidized Diltiazem Metabolites // J. Pharmacol. Exp. Ther . 1997; 282 (1): 294-300.

Buckel W, Golding B T Radical enzymes in anaerobes // Ann. Rev. Microbiol. 2006; 60 (1): 27–49.

Bodea S, Funk MA, Balskus EP, Drennan CL Molecular basis of C–N bond cleavage by the glycyl radical enzyme choline trimethylamine-lyase // Cell Chem. Biol. 2016; 23(10): 1206–1216.

Selmer T, Andrei PI p-Hydroxyphenylacetate decarboxylase from Clostridium difficile // Euro. J. Biochem 2001: 268(5):1363–1372.

Clayton TA, Baker D, Lindon J C Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism // Proc. Nat. Acad. Sci. 2009; 106(34): 14728–14733.

Borzelleca JF, Depukat K, Hallagan JB Lifetime toxicity/carcinogenicity studies of FD & C blue No. 1 (Brilliant blue FCF) in rats and mice // Food Chem. Toxicol. 1990; 28(4): 221–234.

Singh Z, Chadha P Textile industry and occupational cancer// J. Occup. Med. Toxicol. 2016; 11(1): 1-6.

Ingelfinger JR Melamine and the global implications of food contamination // New Eng. J. Med. 2008; 359(26): 2745–2748.

Zheng X, Zhao A, Xie G Melamine-induced renal toxicity is mediated by the gut microbiota // Sci. Trans. Med. 2013; 5 (172): 172ra22 (1-10).

Rowland IR, Davies M J Grasso P Metabolism of methylmercuric chloride by the gastro-intestinal flora of the rat// Xenobiotica 1978;8(1): 37–43.

Rowland IR, Davies M J, Evans J G The effect of the gastrointestinal flora on tissue content of mercury and organomercurial neurotoxicity in rats given methylmercuric chloride // Dev. Toxicol. Environ. Sci.1980; 8(1): 79–82.

Liebert CA, Wireman J, Smith T, Summers AO Phylogeny of mercury resistance (mer) operons of gramnegative bacteria isolated from the fecal flora of primates // Appl. Environ. Microbiol. 1997; 63(3): 1066–1076.

Diaz-Bone RA, van de Wiele TR Biovolatilization of metal(loid)s by intestinal microorganisms in the simulator of the human intestinal microbial ecosystem // Environ. Sci. Tech. 2009;43 (14): 5249–5256.

Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism // Nat. Rev. Microbiol. 2016; 14(5): 273–287.

Takeno S Comparative developmental toxicity and metabolism of nitrazepam in rats and mice // Toxicol. Appl. Pharmacol. 1993; 121(2): 233–238.

Okuda H, Nishiyama A, Ogura K et al. Lethal drug interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs // Drug Metab. Dispos.1997; 25(2): 270–273.

Vetizou M, Pitt J-M, Daillere R et al. Anticancer immunotherapy by CTLA4 blockade relies on the gut microbiota // Science. 2015; 350 (6264): 1079– 1084.

Shin N-R, Lee J-C, Lee H-Y et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice // Gut. 2013; 63(5):727–735.

Strong HA, Renwick AG, George CF et al. The reduction of sulphinpyrazone and sulindac by intestinal bacteria // Xenobiotica. 1987; 17(6): 685–696.

Lehouritis P, Cummins J, Stanton M, et al. Local bacteria affect the efficacy of chemotherapeutic drugs // Sci. Rep. 2015; 5(1):1-12.

Calne DB, Reid JL, Vakil SD et al. Idiopathic parkinsonismt treated with an extracerebral decarboxylase inhibitor in combination with levodopa // BMJ. 1971; 3 (5777): 729–732.

Bergmark J, Carlsson A, Granerus A-K et al. Decarboxylation of orally administered l-dopa in the human digestive tract// Naunyn-Schmiedeberg’s Arch. Pharm.1972; 272(4):437–440.

Goldin BR, Peppercorn MA, Goldman P Contributions of host and intestinal microflora in the metabolism of L-dopa by the rat // J. Pharmacol. Exp. Ther.1973; 186(1):160–166.

Sharon G, Sampson TR, Geschwind DH, Mazmanian S K The central nervous system and the gut microbiome // Cell. 2016; 167 (4): 915–932.

Lindenbaum J, Rund DG, Butler VP Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy // New Eng. J. Med.1981;305(14):789–794.

Saha RI, Butler V, Neu H, Lindenbaum J Digoxin-inactivating bacteria: identification in human gut flora // Science 1983; 220 (4594): 325–327.


Пристатейна бібліографія ГОСТ


Koppel N., Rekdal V-M., Balskus E.P. Chemical transformation of xenobiotics by the human gut microbiota // Science. – 2017. – V. 356(6344). – P. 1–11.

Sender R., Fuchs S., Milo R. Revised estimates for the number of human and bacteria cells in the body // PLOS Biology. – 2016. – V. 14(8). – e1002533.

Aron-Wisnewsky J., Doré J., Clement K. The importance of the gut microbiota after bariatric surgery // Nat. Rev. Gastroenterol. Hepatol. –2012. – V. 9. – No.10. – P. 590–598.

Eckburg P. B. Diversity of the human intestinal microbial flora // Science. – 2005. – V.308(572). – P. 1635–1638

Wang, B. Hu, L., Siahaan, T. Drug Delivery: Principles and Applications. Wiley: 2016. – 757p.

Sousa T., Paterson R., Moore V. et al. The gastrointestinal microbiota as a site for the biotransformation of drugs // Int. J. Pharmac. – 2008. – V. 363. – №1–2. – P. 1–25.

Галкін Б. М., Іваниця В. О., Філіпова Т.О. Механізми біодеградації ксенобіотиків. – Одеса : ОНУ імені І. І. Мечникова, 2017. – 148 с.

Linhardt R. J., Galliher P. M., Cooney C. L. Polysaccharide lyases // Appl. Biochem. Biotechnol. – 1987. – V. 12 (2). – P. 135–176.

Ryan A., Kaplan E., Nebel J.-C. et al. Identification of NAD(P)H quinone oxidoreductase activity in azoreductases from P. aeruginosa: Azoreductases and NAD(P)H quinone oxidoreductases belong to the same FMN-dependent superfamily of enzymes // PLoS. – 2014. – V. 9(6). – e98551.

Martínez-del Campo A., Bodea S., Hamer H. A. et al. Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria // mBio. – 2015. – V. 6 (2). – e00042.

Kaoutari A. E., Armougom F., Gordon J. I. et al. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota // Nat. Rev. Microbiol. – 2013. – V. 11 (7). – P. 497–504.

Levin B. J., Huang Y. Y., Peck S. C. et al. A prominent glycyl radical enzyme in human gut microbiomes metabolizes trans-4-hydroxy-l-proline // Science. – 2017. – V. 355(6325). – eaai8386.

Jancova P., Anzenbacher P., Anzenbacherova E. Phase II drug metabolizing enzymes // Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. – 2019. – V.154(1). – P. 103–116.

Wang J., Yadav V., Smart A. L. et al. Stability of peptide drugs in the colon // Eur. J. Pharmac. Sci. – 2015. – V. 78(1). – P. 31–36.

Tozaki H., Emi Y., Horisaka E., Fujita T. et al. Degradation of insulin and calcitonin and their protection by various protease inhibitors in rat caecal contents: Implications in peptide delivery to the colon // J. Pharmacy Pharm. – 1997. – V. 49(2). – P. 164–168.

Wallace B. D., Roberts A. B., Pollet R. M. et al. Structure and inhibition of microbiome β-glucuronidases essential to the alleviation of cancer drug toxicity // Chem. Biol. – 2015. – V. 22(9). – P. 1238–1249.

Ulmer J. E., Vilén E. M., Namburi R. B. et al. Characterization of glycosaminoglycan (GAG) sulfatases from the human gut symbiont bacteroides the taiotaomicron reveals the first GAG-specific bacterial endosulfatase // J. Biol. Chem. – 2014. – V. 289(35). – P. 24289–24303.

Lukatela G., Krauss N., Theis K., et al. Crystal structure of human arylsulfatase A: The aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis // Biochem. – 1998. – V. 37(11). – P. 3654–3664.

Donohoe D. R., Garge N., Zhang X. et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon // Cell Metab. – 2011. – 13(5). – P. 517–526.

Cooper A. J. L., Krasnikov B. F., Niatsetskaya Z. V. et al. Cysteine S-conju-gate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents // Amino Acids. – 2010. – V. 4. – No.1. – P. 7–27.

Claus S. P., Guillou H., Ellero-Simatos S. The gut microbiota: a major player in the toxicity of environmental pollutants? // Npj Biofilms and Microbiomes. – 2016. – V. 2,(1). – P.1–11.

Rossol I., Pühler A. The Corynebacterium glutamicum aecD gene encodes a C-S lyase with alpha, beta-elimination activity that degrades aminoethylcysteine // J. Bacteriol. – 1992. – V. 174. – № 9. – P. 2968 –2977.

Rafii F., Hall J. D., Cerniglia C. E. Mutagenicity of azo dyes used in foods, drugs and cosmetics before and after reduction by Clostridium species from the human intestinal tract // Food Chem. Toxicol. – 1997. – V. 35(9). – P. 897–901.

Lee S. C., Renwick A. G. Sulphoxide reduction by rat intestinal flora and by Escherichia coli in vitro // Biochem. Pharm. – 1995. – V. 49. – №11. – P. –1567–1576.

 Laue H., Friedrich M., Ruff J., Cook A. M. Dissimilatory sulfite reductase (Desulfoviridin) of the taurine-degrading, non-sulfate-reducing bacterium bilophila wadsworthia RZATAU contains a fused DsrB-DsrD subunit // J. Bacteriol. – 2001. – V.183. – № 5. – P. 1727–1733.

Haiser H. J., Gootenberg D. B., Chatman K. et al. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta // Science. – 2013. – V. 341(6143). – P. 295–298.

 Peppercorn M. A., Goldman P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine // J. Pharm. Exp. Therap. – 1972 . – V.181 (3). – P. 555–562.

Lavrijsen K., van Dyck D., van Houdt J. et al. Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans // Drug Metab. Dispos. –1995. – V. 23(3). – P. 354–362.

Kumano T., Fujiki E., Hashimoto Y., Kobayashi M. Discovery of a sesamin-metabolizing microorganism and a new enzyme // Proc. Nat. Acad. Sci. – 2016. –V. 113(32). – P. 9087–9092.

 Ticak T., Kountz D. J., Girosky K. E. et al. A nonpyrrolysine member of the widely distributed trimethylamine methyltransferase family is a glycine betaine methyltransferase // Proc. Nat. Acad. Sci. – 2014. – V. 111 (43). – P. E4668–E4676.

Delomenie C., Fouix S., Longuemaux S. et al. Identification and functional characterization of arylamine N-Acetyltransferases in eubacteria: Evidence for highly selective acetylation of 5-aminosalicylic acid // J. Bacteriol. – 2001. – V. 183. – No.11. – P. 3417–3427.

Sutton D., Butler A. M., Nadin L., Murray M. Role of CYP3A4 in Human Hepatic Diltiazem N-Demethylation: Inhibition of CYP3A4 Activity by Oxidized Diltiazem Metabolites // J. Pharmacol. Exp. Ther . – 1997. – V.282 (1). – P.294-300.

 Buckel W., Golding B. T. Radical enzymes in anaerobes // Ann. Rev. Microbiol. – 2006. – V.60 (1). – P. 27–49.

Bodea S., Funk M. A., Balskus E. P., Drennan C. L. Molecular basis of C–N bond cleavage by the glycyl radical enzyme choline trimethylamine-lyase // Cell Chem. Biol. – 2016. – V. 23(10). – P. 1206–1216.

 Selmer T., Andrei P. I. p-Hydroxyphenylacetate decarboxylase from Clostridium difficile // Euro. J. Biochem. – 2001. – V. 268(5). – P. 1363–1372.

Clayton T. A., Baker D., Lindon J. C. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism // Proc. Nat. Acad. Sci. – 2009. – V.106. – No.34. – P. 14728– 14733.

Borzelleca J. F., Depukat K., Hallagan J. B. Lifetime toxicity/carcinogenicity studies of FD & C blue No. 1 (Brilliant blue FCF) in rats and mice // Food Chem. Toxicol. – 1990. – V.28. – No.4.- P. 221–234.

Singh Z., Chadha P. Textile industry and occupational cancer// J. Occup. Med. Toxicol. – 2016. – V. 11(1). – P.1-6.

Ingelfinger J. R. Melamine and the global implications of food contamination // New Eng. J. Med. – 2008. – V. 359(26). – P. 2745–2748.

 Zheng X., Zhao A., Xie G. Melamine-induced renal toxicity is mediated by the gut microbiota // Sci. Trans. Med. – 2013. – V.5 (172). – P. 172ra22 (1–10).

Rowland I. R., Davies M. J. Grasso P. Metabolism of methylmercuric chloride by the gastro-intestinal flora of the rat// Xenobiotica. –1978. – V. 8. – №1. – P. 37–43.

Rowland I. R., Davies M. J., Evans J. G. The effect of the gastrointestinal flora on tissue content of mercury and organomercurial neurotoxicity in rats given methylmercuric chloride // Dev. Toxicol. Environ. Sci. – 1980. – V. 8(1). – P. 79–82.

 Liebert C. A., Wireman J., Smith T., Summers A. O. Phylogeny of mercury resistance (mer) operons of gramnegative bacteria isolated from the fecal flora of primates // Appl. Environ. Microbiol. – 1997. – V. 63(3). –P.1066–1076.

Diaz-Bone R. A., van de Wiele T. R. Biovolatilization of metal(loid)s by intestinal microorganisms in the simulator of the human intestinal microbial ecosystem // Environ. Sci. Tech. – 2009. – V.43. –No.14. – P. 5249–5256.

Spanogiannopoulos P., Bess E. N., Carmody R. N., Turnbaugh P. J. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism // Nat. Rev. Microbiol. – 2016. – V.14 (5). – P. 273–287.

Takeno S. Comparative developmental toxicity and metabolism of nitrazepam in rats and mice // Toxicol. Appl. Pharmacol. – 1993. – V.121. No.2. – P. 233–238.

Okuda H., Nishiyama A., Ogura K. et al. Lethal drug interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs // Drug Metab. Dispos. – 1997. – V. 25(2). – P. 270–273.

 Vetizou M., Pitt J. M., Daillere R. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota // Science. – 2015. – V. 350 (6264). – P. 1079–1084.

 Shin N.-R., Lee J.-C., Lee H.-Y. et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice // Gut. – 2013. – V. 63(5). – P.727–735.

Strong H. A., Renwick A. G., George C. F. et al. The reduction of sulphinpyrazone and sulindac by intestinal bacteria // Xenobiotica. –1987. –V. 17. – No. 6. – P. 685–696.

Lehouritis P., Cummins J., Stanton M., et al. Local bacteria affect the efficacy of chemotherapeutic drugs // Sci. Rep. – 2015. – V. 5(1) – P. 1–12.

Calne D. B., Reid J. L., Vakil S. D. et al. Idiopathic parkinsonismt treated with an extracerebral decarboxylase inhibitor in combination with levodopa // BMJ. –1971. – V. 3 (5777). – P. 729–732.

Bergmark J., Carlsson A., Granerus A.-K. et al. Decarboxylation of orally administered l-dopa in the human digestive tract// Naunyn-Schmiedeberg’s Arch. Pharm. – 1972. – V.272 . –No. 4. – P. 437–440.

Goldin B. R., Peppercorn M. A., Goldman P. Contributions of host and intestinal microflora in the metabolism of L-dopa by the rat. // J. Pharmacol. Exp. Ther. – 1973. – V. 186. – No. 1. – P. 160–166.

Sharon G., Sampson T. R., Geschwind D. H., Mazmanian S. K. The central nervous system and the gut microbiome // Cell. – 2016. – V. 167 (4). – P. 915–932.

Lindenbaum. J., Rund D. G., Butler V. P. Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy // New Eng. J. Med. – 1981. – V. 305 . – No.14. – P. 789–794.

Saha R. I., Butler V., Neu H., Lindenbaum J. Digoxin-inactivating bacteria: identification in human gut flora // Science. –1983. –V. 220 (4594). – P. 325–327.





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ISSN 2076-0558 (Print); 2307-4663 (Online)

DOI 10.18524/2307-4663