Kluenemann, Martina, Andrejev, Sergej ORCID: 0000-0002-7875-0261, Blasche, Sonja, Mateus, Andre ORCID: 0000-0001-6870-0677, Phapale, Prasad, Devendran, Saravanan, Vappiani, Johanna, Simon, Bernd ORCID: 0000-0003-0164-5516, Scott, Timothy A., Kafkia, Eleni ORCID: 0000-0001-9550-4487, Konstantinidis, Dimitrios ORCID: 0000-0002-2134-6823, Zirngibl, Katharina, Mastrorilli, Eleonora ORCID: 0000-0003-2127-4150, Banzhaf, Manuel, Mackmull, Marie-Therese, Hoevelmann, Felix, Nesme, Leo, Brochado, Ana Rita, Maier, Lisa ORCID: 0000-0002-6473-4762, Bock, Thomas, Periwal, Vinita, Kumar, Manjeet, Kim, Yongkyu, Tramontano, Melanie, Schultz, Carsten, Beck, Martin ORCID: 0000-0002-7397-1321, Hennig, Janosch ORCID: 0000-0001-5214-7002, Zimmermann, Michael, Sevin, Daniel C., Cabreiro, Filipe, Savitski, Mikhail M., Bork, Peer ORCID: 0000-0002-2627-833X, Typas, Athanasios ORCID: 0000-0002-0797-9018 and Patil, Kiran R. (2021). Bioaccumulation of therapeutic drugs by human gut bacteria. Nature, 597 (7877). S. 533 - 556. BERLIN: NATURE PORTFOLIO. ISSN 1476-4687

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Abstract

Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping ofthe interactions between drugs and bacteria has only started recently' 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 ofthe 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 bindsto 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 elegansto 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kluenemann, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrejev, SergejUNSPECIFIEDorcid.org/0000-0002-7875-0261UNSPECIFIED
Blasche, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mateus, AndreUNSPECIFIEDorcid.org/0000-0001-6870-0677UNSPECIFIED
Phapale, PrasadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devendran, SaravananUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vappiani, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, BerndUNSPECIFIEDorcid.org/0000-0003-0164-5516UNSPECIFIED
Scott, Timothy A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kafkia, EleniUNSPECIFIEDorcid.org/0000-0001-9550-4487UNSPECIFIED
Konstantinidis, DimitriosUNSPECIFIEDorcid.org/0000-0002-2134-6823UNSPECIFIED
Zirngibl, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mastrorilli, EleonoraUNSPECIFIEDorcid.org/0000-0003-2127-4150UNSPECIFIED
Banzhaf, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mackmull, Marie-ThereseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoevelmann, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nesme, LeoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brochado, Ana RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maier, LisaUNSPECIFIEDorcid.org/0000-0002-6473-4762UNSPECIFIED
Bock, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Periwal, VinitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumar, ManjeetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, YongkyuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tramontano, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schultz, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, MartinUNSPECIFIEDorcid.org/0000-0002-7397-1321UNSPECIFIED
Hennig, JanoschUNSPECIFIEDorcid.org/0000-0001-5214-7002UNSPECIFIED
Zimmermann, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sevin, Daniel C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cabreiro, FilipeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savitski, Mikhail M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bork, PeerUNSPECIFIEDorcid.org/0000-0002-2627-833XUNSPECIFIED
Typas, AthanasiosUNSPECIFIEDorcid.org/0000-0002-0797-9018UNSPECIFIED
Patil, Kiran R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-605359
DOI: 10.1038/s41586-021-03891-8
Journal or Publication Title: Nature
Volume: 597
Number: 7877
Page Range: S. 533 - 556
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 1476-4687
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CANCER DRUG; MICROBIOTA; METABOLISM; IDENTIFICATION; METABOLOMICS; INFORMATION; SEARCH; ALTERS; IMPACT; TARGETMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60535

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