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000170558 041__ $$aEnglish
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000170558 1001_ $$00000-0002-1602-5371$$aKlünemann, Martina$$b0
000170558 245__ $$aBioaccumulation of therapeutic drugs by human gut bacteria.
000170558 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2021
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000170558 500__ $$a#EA:B400# /2021 Sep;597(7877):533-538
000170558 520__ $$aBacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.
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000170558 7001_ $$0P:(DE-He78)0f0276d7e9af07e98339a060db121ab2$$aAndrejev, Sergej$$b1$$eFirst author$$udkfz
000170558 7001_ $$aBlasche, Sonja$$b2
000170558 7001_ $$00000-0001-6870-0677$$aMateus, Andre$$b3
000170558 7001_ $$00000-0002-9487-597X$$aPhapale, Prasad$$b4
000170558 7001_ $$aDevendran, Saravanan$$b5
000170558 7001_ $$aVappiani, Johanna$$b6
000170558 7001_ $$aSimon, Bernd$$b7
000170558 7001_ $$aScott, Timothy A$$b8
000170558 7001_ $$00000-0001-9550-4487$$aKafkia, Eleni$$b9
000170558 7001_ $$aKonstantinidis, Dimitrios$$b10
000170558 7001_ $$aZirngibl, Katharina$$b11
000170558 7001_ $$00000-0003-2127-4150$$aMastrorilli, Eleonora$$b12
000170558 7001_ $$aBanzhaf, Manuel$$b13
000170558 7001_ $$00000-0003-2928-1144$$aMackmull, Marie-Therese$$b14
000170558 7001_ $$aHövelmann, Felix$$b15
000170558 7001_ $$aNesme, Leo$$b16
000170558 7001_ $$aBrochado, Ana Rita$$b17
000170558 7001_ $$00000-0002-6473-4762$$aMaier, Lisa$$b18
000170558 7001_ $$00000-0002-9314-5318$$aBock, Thomas$$b19
000170558 7001_ $$aPeriwal, Vinita$$b20
000170558 7001_ $$aKumar, Manjeet$$b21
000170558 7001_ $$00000-0002-3336-6741$$aKim, Yongkyu$$b22
000170558 7001_ $$aTramontano, Melanie$$b23
000170558 7001_ $$aSchultz, Carsten$$b24
000170558 7001_ $$00000-0002-7397-1321$$aBeck, Martin$$b25
000170558 7001_ $$00000-0001-5214-7002$$aHennig, Janosch$$b26
000170558 7001_ $$00000-0002-5797-3589$$aZimmermann, Michael$$b27
000170558 7001_ $$aSévin, Daniel C$$b28
000170558 7001_ $$00000-0002-3696-4843$$aCabreiro, Filipe$$b29
000170558 7001_ $$00000-0003-2011-9247$$aSavitski, Mikhail M$$b30
000170558 7001_ $$00000-0002-2627-833X$$aBork, Peer$$b31
000170558 7001_ $$00000-0002-0797-9018$$aTypas, Athanasios$$b32
000170558 7001_ $$00000-0002-6166-8640$$aPatil, Kiran R$$b33
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