Combinatorial, additive and dose-dependent drug–microbiome associations
Journal article, 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.
Author
Sofia K. Forslund
European Molecular Biology Laboratory
Rima Chakaroun
Leipzig University
Maria Zimmermann-Kogadeeva
European Molecular Biology Laboratory
Lajos Markó
The Max Delbrück Center for Molecular Medicine
Judith Aron-Wisnewsky
Pierre and Marie Curie University (UPMC)
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
Pierre and Marie Curie University (UPMC)
Renato Alves
European Molecular Biology Laboratory
Karen Assmann
Pierre and Marie Curie University (UPMC)
Jean-Phillippe Bastard
Assistance publique – Hôpitaux de Paris (AP-HP)
Till Birkner
The Max Delbrück Center for Molecular Medicine
Robert Caesar
Wallenberg Lab.
J. Chilloux
Imperial College London
Luis P. Coelho
European Molecular Biology Laboratory
Leopold Fezeu
University of Paris North
Nathalie Galleron
University Paris-Saclay
Gerard Helft
Assistance publique – Hôpitaux de Paris (AP-HP)
Richard Isnard
Assistance publique – Hôpitaux de Paris (AP-HP)
Boyang Ji
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Michael Kuhn
European Molecular Biology Laboratory
Emmanuelle Le Chatelier
University Paris-Saclay
Antonis Myridakis
Imperial College London
Lisa M. Olsson
Wallenberg Lab.
Nicolas Pons
University Paris-Saclay
Edi Prifti
Pierre and Marie Curie University (UPMC)
Benoit Quinquis
University Paris-Saclay
Hugo Roume
University Paris-Saclay
Joe-Elie Salem
Pierre and Marie Curie University (UPMC)
Nataliya Sokolovska
Pierre and Marie Curie University (UPMC)
Valentina Tremaroli
Wallenberg Lab.
Mireia Vallès-Colomer
KU Leuven
Christian Lewinter
University of Copenhagen
Nadja B. Søndertoft
University of Copenhagen
Helle K. Pedersen
University of Copenhagen
Tue H. Hansen
University of Copenhagen
Chloe Amouyal
Pierre and Marie Curie University (UPMC)
Ehm Astrid Andersson Galijatovic
University of Copenhagen
Fabrizio Andreelli
Pierre and Marie Curie University (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
University Paris-Saclay
Randa Bittar
Assistance publique – Hôpitaux de Paris (AP-HP)
Hervé Blottière
University Paris-Saclay
Frederic Bosquet
Biobyte Solutions
Rachid Boubrit
Assistance publique – Hôpitaux de Paris (AP-HP)
Olivier Bourron
Biobyte Solutions
Mickael Camus
University 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
Pierre and Marie Curie University (UPMC)
Morad Djebbar
Assistance publique – Hôpitaux de Paris (AP-HP)
Angélique Doré
University Paris-Saclay
Line Engelbrechtsen
Pierre and Marie Curie University (UPMC)
Soraya Fellahi
Assistance publique – Hôpitaux de Paris (AP-HP)
Sebastien Fromentin
University 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
University of Copenhagen
Jens Juul Holst
University of Copenhagen
Malene Hornbak
University of Copenhagen
L. Hoyles
Nottingham Trent University
Jean-Sébastien Hulot
Pierre and Marie Curie University (UPMC)
Sophie Jaqueminet
University Paris-Saclay
Niklas Rye Jørgensen
Biobyte Solutions
Hanna Julienne
University Paris-Saclay
Johanne Justesen
University of Copenhagen
Judith Kammer
Leipzig University
Nikolaj Krarup
University of Copenhagen
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
University Paris-Saclay
Jonathan Medina-Stamminger
Assistance publique – Hôpitaux de Paris (AP-HP)
Gilles Montalescot
Assistance publique – Hôpitaux de Paris (AP-HP)
Sandrine Moute
Pierre and Marie Curie University (UPMC)
Ana Luisa Neves
Imperial College London
Michael Olanipekun
Imperial College London
Laetitia Pasero Le Pavin
University Paris-Saclay
Christine Poitou
Pierre and Marie Curie University (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
Pierre and Marie Curie University (UPMC)
Johanne Silvain
Assistance publique – Hôpitaux de Paris (AP-HP)
Mathilde Svendstrup
University of Copenhagen
Timothy Swartz
Pierre and Marie Curie University (UPMC)
Thierry Vanduyvenboden
University Paris-Saclay
Camille Vatier
Assistance publique – Hôpitaux de Paris (AP-HP)
Stefanie Walther
Leipzig University
Jens P. Gøtze
University of Copenhagen
Lars Køber
University of Copenhagen
H. Vestergaard
University of Copenhagen
Torben Hansen
University of Copenhagen
Jean-Daniel Zucker
Pierre and Marie Curie University (UPMC)
Serge Hercberg
University of Paris North
Jean-Michel Oppert
Assistance publique – Hôpitaux de Paris (AP-HP)
Ivica Letunic
European Molecular Biology Laboratory
Jens B Nielsen
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Fredrik Bäckhed
University of Copenhagen
Stanislav Dusko Ehrlich
University Paris-Saclay
Marc-Emmanuel Dumas
Imperial College London
Jeroen Raes
KU Leuven
O. B. Pedersen
University of Copenhagen
K. Clement
Pierre and Marie Curie University (UPMC)
M. Stumvoll
Leipzig University
Peer Bork
European Molecular Biology Laboratory
Nature
0028-0836 (ISSN) 1476-4687 (eISSN)
Vol. 600 7889 500-505Subject Categories
Pharmaceutical Sciences
Social and Clinical Pharmacy
Neurology
DOI
10.1038/s41586-021-04177-9
PubMed
34880489