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 500-505

Ämneskategorier

Farmaceutisk vetenskap

Samhällsfarmaci och klinisk farmaci

Neurologi

DOI

10.1038/s41586-021-04177-9

PubMed

34880489

Mer information

Senast uppdaterat

2022-04-05