Combinatorial, additive and dose-dependent drug–microbiome associations

Sofia K. Forslund, Rima Chakaroun, Maria Zimmermann-Kogadeeva, Lajos Markó, Judith Aron-Wisnewsky, Trine Nielsen, Lucas Moitinho-Silva, Thomas S. B. Schmidt, Gwen Falony, Sara Vieira-Silva, Solia Adriouch, Renato J. Alves, Karen Assmann, Jean-Philippe Bastard, Till Birkner, Robert Caesar, Julien Chilloux, Luis Pedro Coelho, Leopold Fezeu, Nathalie Galleron, Gerard Helft, Richard Isnard, Boyang Ji, Michael Kuhn, Emmanuelle Le Chatelier, Antonis Myridakis, Lisa Olsson, Nicolas Pons, Edi Prifti, Benoit Quinquis, Hugo Roume, Joe-Elie Salem, Nataliya Sokolovska, Valentina Tremaroli, Mireia Valles-Colomer, Christian Lewinter, Nadja B. Søndertoft, Helle Krogh Pedersen, Tue H. Hansen, Jens Peter Gøtze, Lars Køber, Henrik Vestergaard, Torben Hansen, Jean-Daniel Zucker, Serge Hercberg, Jean-Michel Oppert, Ivica Letunic, Jens Nielsen, Fredrik Bäckhed, S. Dusko Ehrlich, Marc-Emmanuel Dumas, Jeroen Raes, Oluf Pedersen, Karine Clément (), Michael Stumvoll () and Peer Bork ()
Additional contact information
Sofia K. Forslund: European Molecular Biology Laboratory
Rima Chakaroun: University of Leipzig Medical Center
Maria Zimmermann-Kogadeeva: European Molecular Biology Laboratory
Lajos Markó: Max Delbrück Center for Molecular Medicine (MDC)
Judith Aron-Wisnewsky: Sorbonne Université, INSERM
Trine Nielsen: University of Copenhagen
Lucas Moitinho-Silva: European Molecular Biology Laboratory
Thomas S. B. Schmidt: European Molecular Biology Laboratory
Gwen Falony: KU Leuven
Sara Vieira-Silva: KU Leuven
Solia Adriouch: Sorbonne Université, INSERM
Renato J. Alves: European Molecular Biology Laboratory
Karen Assmann: Sorbonne Université, INSERM
Jean-Philippe Bastard: Tenon Hospital
Till Birkner: Max Delbrück Center for Molecular Medicine (MDC)
Robert Caesar: University of Gothenburg
Julien Chilloux: Imperial College London
Luis Pedro Coelho: European Molecular Biology Laboratory
Leopold Fezeu: Sorbonne Paris Cité Epidemiology and Statistics Research Centre (CRESS), U1153 INSERM, U1125, INRA, CNAM, University of Paris 13
Nathalie Galleron: Université Paris-Saclay
Gerard Helft: Assistance Publique Hôpitaux de Paris, Pitie-Salpêtrière Hospital
Richard Isnard: Assistance Publique Hôpitaux de Paris, Pitie-Salpêtrière Hospital
Boyang Ji: Chalmers University of Technology
Michael Kuhn: European Molecular Biology Laboratory
Emmanuelle Le Chatelier: Université Paris-Saclay
Antonis Myridakis: Imperial College London
Lisa Olsson: University of Gothenburg
Nicolas Pons: Université Paris-Saclay
Edi Prifti: Sorbonne Université, INSERM
Benoit Quinquis: Université Paris-Saclay
Hugo Roume: Université Paris-Saclay
Joe-Elie Salem: Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris
Nataliya Sokolovska: Sorbonne Université, INSERM
Valentina Tremaroli: University of Gothenburg
Mireia Valles-Colomer: KU Leuven
Christian Lewinter: Rigshopitalet, University of Copenhagen
Nadja B. Søndertoft: University of Copenhagen
Helle Krogh Pedersen: University of Copenhagen
Tue H. Hansen: University of Copenhagen
Jens Peter Gøtze: Rigshopitalet, University of Copenhagen
Lars Køber: Rigshopitalet, University of Copenhagen
Henrik Vestergaard: University of Copenhagen
Torben Hansen: University of Copenhagen
Jean-Daniel Zucker: Sorbonne Université, INSERM
Serge Hercberg: Sorbonne Paris Cité Epidemiology and Statistics Research Centre (CRESS), U1153 INSERM, U1125, INRA, CNAM, University of Paris 13
Jean-Michel Oppert: Assistance Publique Hôpitaux de Paris, Pitie-Salpêtrière Hospital
Ivica Letunic: European Molecular Biology Laboratory
Jens Nielsen: Chalmers University of Technology
Fredrik Bäckhed: University of Copenhagen
S. Dusko Ehrlich: Université Paris-Saclay
Marc-Emmanuel Dumas: Imperial College London
Jeroen Raes: KU Leuven
Oluf Pedersen: University of Copenhagen
Karine Clément: Sorbonne Université, INSERM
Michael Stumvoll: University of Leipzig Medical Center
Peer Bork: European Molecular Biology Laboratory

Nature, 2021, vol. 600, issue 7889, 500-505

Abstract: Abstract During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1–5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.

Date: 2021
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DOI: 10.1038/s41586-021-04177-9

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