Combinatorial, additive and dose-dependent drug–microbiome associations
Artikel i vetenskaplig tidskrift, 2021
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.
Författare
Sofia K. Forslund
European Molecular Biology Laboratory
Rima Chakaroun
Universität Leipzig
Maria Zimmermann-Kogadeeva
European Molecular Biology Laboratory
Lajos Markó
Max Delbrueck Centrum Fuer Molekulare Medizin
Judith Aron-Wisnewsky
Université Pierre et Marie Curie (UPMC)
Trine Nielsen
Köpenhamns universitet
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
Université Pierre et Marie Curie (UPMC)
Renato Alves
European Molecular Biology Laboratory
Karen Assmann
Université Pierre et Marie Curie (UPMC)
Jean-Phillippe Bastard
Assistance publique – Hôpitaux de Paris (AP-HP)
Till Birkner
Max Delbrueck Centrum Fuer Molekulare Medizin
Robert Caesar
Wallenberg Lab.
J. Chilloux
Imperial College London
Luis P. Coelho
European Molecular Biology Laboratory
Leopold Fezeu
Université Paris Nord
Nathalie Galleron
Université Paris-Saclay
Gerard Helft
Assistance publique – Hôpitaux de Paris (AP-HP)
Richard Isnard
Assistance publique – Hôpitaux de Paris (AP-HP)
Boyang Ji
Chalmers, Biologi och bioteknik, Systembiologi
Michael Kuhn
European Molecular Biology Laboratory
Emmanuelle Le Chatelier
Université Paris-Saclay
Antonis Myridakis
Imperial College London
Lisa M. Olsson
Wallenberg Lab.
Nicolas Pons
Université Paris-Saclay
Edi Prifti
Université Pierre et Marie Curie (UPMC)
Benoit Quinquis
Université Paris-Saclay
Hugo Roume
Université Paris-Saclay
Joe-Elie Salem
Université Pierre et Marie Curie (UPMC)
Nataliya Sokolovska
Université Pierre et Marie Curie (UPMC)
Valentina Tremaroli
Wallenberg Lab.
Mireia Vallès-Colomer
KU Leuven
Christian Lewinter
Köpenhamns universitet
Nadja B. Søndertoft
Köpenhamns universitet
Helle K. Pedersen
Köpenhamns universitet
Tue H. Hansen
Köpenhamns universitet
Chloe Amouyal
Université Pierre et Marie Curie (UPMC)
Ehm Astrid Andersson Galijatovic
Köpenhamns universitet
Fabrizio Andreelli
Université Pierre et Marie Curie (UPMC)
Olivier Barthelemy
Assistance publique – Hôpitaux de Paris (AP-HP)
Jean-Paul Batisse
Assistance publique – Hôpitaux de Paris (AP-HP)
Eugeni Belda
Assistance publique – Hôpitaux de Paris (AP-HP)
Magalie Berland
Université Paris-Saclay
Randa Bittar
Assistance publique – Hôpitaux de Paris (AP-HP)
Hervé Blottière
Université Paris-Saclay
Frederic Bosquet
Biobyte Solutions
Rachid Boubrit
Assistance publique – Hôpitaux de Paris (AP-HP)
Olivier Bourron
Biobyte Solutions
Mickael Camus
Université Paris-Saclay
Dominique Cassuto
Assistance publique – Hôpitaux de Paris (AP-HP)
Cecile Ciangura
Assistance publique – Hôpitaux de Paris (AP-HP)
Jean-Philippe Collet
Assistance publique – Hôpitaux de Paris (AP-HP)
Maria-Carlota Dao
Université Pierre et Marie Curie (UPMC)
Morad Djebbar
Assistance publique – Hôpitaux de Paris (AP-HP)
Angélique Doré
Université Paris-Saclay
Line Engelbrechtsen
Université Pierre et Marie Curie (UPMC)
Soraya Fellahi
Assistance publique – Hôpitaux de Paris (AP-HP)
Sebastien Fromentin
Université Paris-Saclay
Pilar Galan
Imperial College London
Dominique Gauguier
McGill University
Philippe Giral
Assistance publique – Hôpitaux de Paris (AP-HP)
Agnes Hartemann
Biobyte Solutions
Bolette Hartmann
Köpenhamns universitet
Jens Juul Holst
Köpenhamns universitet
Malene Hornbak
Köpenhamns universitet
L. Hoyles
Nottingham Trent University
Jean-Sébastien Hulot
Université Pierre et Marie Curie (UPMC)
Sophie Jaqueminet
Université Paris-Saclay
Niklas Rye Jørgensen
Biobyte Solutions
Hanna Julienne
Université Paris-Saclay
Johanne Justesen
Köpenhamns universitet
Judith Kammer
Universität Leipzig
Nikolaj Krarup
Köpenhamns universitet
Mathieu Kerneis
Assistance publique – Hôpitaux de Paris (AP-HP)
Jean Khemis
Assistance publique – Hôpitaux de Paris (AP-HP)
Ruby Kozlowski
Imperial College London
Véronique Lejard
Assistance publique – Hôpitaux de Paris (AP-HP)
Florence Levenez
Assistance publique – Hôpitaux de Paris (AP-HP)
Lea Lucas-Martini
Assistance publique – Hôpitaux de Paris (AP-HP)
Robin Massey
Assistance publique – Hôpitaux de Paris (AP-HP)
Laura Martinez-Gili
Wallenberg Lab.
Nicolas Maziers
Université Paris-Saclay
Jonathan Medina-Stamminger
Assistance publique – Hôpitaux de Paris (AP-HP)
Gilles Montalescot
Assistance publique – Hôpitaux de Paris (AP-HP)
Sandrine Moute
Université Pierre et Marie Curie (UPMC)
Ana Luisa Neves
Imperial College London
Michael Olanipekun
Imperial College London
Laetitia Pasero Le Pavin
Université Paris-Saclay
Christine Poitou
Université Pierre et Marie Curie (UPMC)
Francoise Pousset
Assistance publique – Hôpitaux de Paris (AP-HP)
Laurence Pouzoulet
Assistance publique – Hôpitaux de Paris (AP-HP)
Andrea Rodriguez-Martinez
Imperial College London
Christine Rouault
Université Pierre et Marie Curie (UPMC)
Johanne Silvain
Assistance publique – Hôpitaux de Paris (AP-HP)
Mathilde Svendstrup
Köpenhamns universitet
Timothy Swartz
Université Pierre et Marie Curie (UPMC)
Thierry Vanduyvenboden
Université Paris-Saclay
Camille Vatier
Assistance publique – Hôpitaux de Paris (AP-HP)
Stefanie Walther
Universität Leipzig
Jens P. Gøtze
Köpenhamns universitet
Lars Køber
Köpenhamns universitet
H. Vestergaard
Köpenhamns universitet
Torben Hansen
Köpenhamns universitet
Jean-Daniel Zucker
Université Pierre et Marie Curie (UPMC)
Serge Hercberg
Université Paris Nord
Jean-Michel Oppert
Assistance publique – Hôpitaux de Paris (AP-HP)
Ivica Letunic
European Molecular Biology Laboratory
Jens B Nielsen
Chalmers, Biologi och bioteknik, Systembiologi
Fredrik Bäckhed
Köpenhamns universitet
Stanislav Dusko Ehrlich
Université Paris-Saclay
Marc-Emmanuel Dumas
Imperial College London
Jeroen Raes
KU Leuven
O. B. Pedersen
Köpenhamns universitet
K. Clement
Université Pierre et Marie Curie (UPMC)
M. Stumvoll
Universität Leipzig
Peer Bork
European Molecular Biology Laboratory
Nature
0028-0836 (ISSN) 1476-4687 (eISSN)
Vol. 600 7889 500-505Ämneskategorier
Farmaceutisk vetenskap
Samhällsfarmaci och klinisk farmaci
Neurologi
DOI
10.1038/s41586-021-04177-9
PubMed
34880489