Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide
Journal article, 2023
The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.
Author
Petros Andrikopoulos
National Heart and Lung Institute
Imperial College London
Judith Aron-Wisnewsky
Pierre and Marie Curie University (UPMC)
Assistance publique – Hôpitaux de Paris (AP-HP)
Rima Chakaroun
Leipzig University
Wallenberg Lab.
Antonis Myridakis
Imperial College London
MRC Centre for Environment and Health
Sofia K. Forslund
Charité University Medicine Berlin
The Max Delbrück Center for Molecular Medicine
Deutsches Zentrum für Herz-Kreislauf-Forschung e. V.
European Molecular Biology Laboratory
Trine Nielsen
Novo Nordisk Foundation
Solia Adriouch
Pierre and Marie Curie University (UPMC)
Bridget Holmes
Danone Research
J. Chilloux
Imperial College London
Sara Vieira-Silva
KU Leuven
Flanders Interuniversity Institute for Biotechnology
Johannes Gutenberg University Mainz
University Medical Center Mainz
Gwen Falony
University Medical Center Mainz
Flanders Interuniversity Institute for Biotechnology
KU Leuven
Johannes Gutenberg University Mainz
Joe-Elie Salem
Assistance publique – Hôpitaux de Paris (AP-HP)
Fabrizio Andreelli
Assistance publique – Hôpitaux de Paris (AP-HP)
Pierre and Marie Curie University (UPMC)
Eugeni Belda
Pierre and Marie Curie University (UPMC)
Julius Kieswich
Barts Cancer Institute
The Royal London Hospital
Kanta Chechi
Imperial College London
National Heart and Lung Institute
Francesc Puig-Castellvi
CHU Lille
Mickael Chevalier
CHU Lille
Emmanuelle Le Chatelier
University Paris-Saclay
Michael Olanipekun
Imperial College London
L. Hoyles
Nottingham Trent University
Renato Alves
European Molecular Biology Laboratory
Gerard Helft
Assistance publique – Hôpitaux de Paris (AP-HP)
Inserm Transfert
Richard Isnard
Assistance publique – Hôpitaux de Paris (AP-HP)
Pierre and Marie Curie University (UPMC)
Lars Køber
Rigshospitalet
Luis P. Coelho
European Molecular Biology Laboratory
Christine Rouault
Pierre and Marie Curie University (UPMC)
Dominique Gauguier
McGill University
Universite de la Sorbonne Nouvelle Paris III
Jens P. Gøtze
Rigshospitalet
Edi Prifti
Pierre and Marie Curie University (UPMC)
Philippe Froguel
Imperial College London
CHU Lille
Rohia Alili
Pierre and Marie Curie University (UPMC)
Ehm Astrid Andersson Galijatovic
Novo Nordisk Foundation
Olivier Barthelemy
Assistance publique – Hôpitaux de Paris (AP-HP)
Jean-Phillippe Bastard
Pierre and Marie Curie University (UPMC)
Jean-Paul Batisse
Assistance publique – Hôpitaux de Paris (AP-HP)
Pierre Bel-Lassen
Pierre and Marie Curie University (UPMC)
Magalie Berland
University Paris-Saclay
Randa Bittar
Assistance publique – Hôpitaux de Paris (AP-HP)
Hervé Blottière
University Paris-Saclay
Frederic Bosquet
Assistance publique – Hôpitaux de Paris (AP-HP)
Rachid Boubrit
Assistance publique – Hôpitaux de Paris (AP-HP)
Olivier Bourron
Assistance publique – Hôpitaux de Paris (AP-HP)
Mickael Camus
Pierre and Marie Curie University (UPMC)
Cecile Ciangura
Assistance publique – Hôpitaux de Paris (AP-HP)
Jean-Philippe Collet
Assistance publique – Hôpitaux de Paris (AP-HP)
Arne Dietrich
Leipzig University
Morad Djebbar
Assistance publique – Hôpitaux de Paris (AP-HP)
Angélique Doré
University Paris-Saclay
Line Engelbrechtsen
Novo Nordisk Foundation
Leopold Fezeu
Conservatoire National des Arts et Metiers
Sebastien Fromentin
University Paris-Saclay
Nicolas Pons
University Paris-Saclay
Marianne Graine
Pierre and Marie Curie University (UPMC)
Caroline Grünemann
Leipzig University
Agnes Hartemann
Assistance publique – Hôpitaux de Paris (AP-HP)
Bolette Hartmann
Novo Nordisk Foundation
Malene Hornbak
Novo Nordisk Foundation
Sophie Jaqueminet
Assistance publique – Hôpitaux de Paris (AP-HP)
Niklas Rye Jørgensen
Rigshospitalet
Hanna Julienne
University Paris-Saclay
Johanne Justesen
Novo Nordisk Foundation
Judith Kammer
Leipzig University
Nikolaj Karup
Novo Nordisk Foundation
Ruby Kozlowski
Imperial College London
Michael Kuhn
European Molecular Biology Laboratory
Véronique Lejard
University Paris-Saclay
Ivica Letunic
European Molecular Biology Laboratory
Florence Levenez
University Paris-Saclay
Lajos Markó
The Max Delbrück Center for Molecular Medicine
Laura Martinez-Gili
Imperial College London
Robin Massey
University Paris-Saclay
Nicolas Maziers
University Paris-Saclay
Lucas Moitinho-Silva
European Molecular Biology Laboratory
Gilles Montalescot
Assistance publique – Hôpitaux de Paris (AP-HP)
Ana Luisa Neves
Imperial College London
Laetitia Pasero Le Pavin
University Paris-Saclay
Francoise Pousset
Assistance publique – Hôpitaux de Paris (AP-HP)
Andrea Rodriguez-Martinez
Imperial College London
Sebastian Schmidt
European Molecular Biology Laboratory
Tatjana Schütz
Leipzig University
Lucas Silva
European Molecular Biology Laboratory
Johanne Silvain
Assistance publique – Hôpitaux de Paris (AP-HP)
Mathilde Svendstrup
Novo Nordisk Foundation
Timothy Swartz
Pierre and Marie Curie University (UPMC)
Thierry Vanduyvenboden
University Paris-Saclay
Eric Verger
University of Montpellier
Stefanie Walther
Leipzig University
Jean-Daniel Zucker
Pierre and Marie Curie University (UPMC)
Fredrik Bäckhed
Novo Nordisk Foundation
Wallenberg Lab.
H. Vestergaard
Novo Nordisk Foundation
Bornholms Hospital
Torben Hansen
Novo Nordisk Foundation
Jean-Michel Oppert
Assistance publique – Hôpitaux de Paris (AP-HP)
M. Bluher
Leipzig University
Jens B Nielsen
Chalmers, Life Sciences, Systems and Synthetic Biology
Jeroen Raes
KU Leuven
Flanders Interuniversity Institute for Biotechnology
Peer Bork
European Molecular Biology Laboratory
The Max Delbrück Center for Molecular Medicine
Yonsei University
University of Würzburg
Muhammad Magdi Yaqoob
Barts Cancer Institute
The Royal London Hospital
M. Stumvoll
Leipzig University
O. B. Pedersen
Novo Nordisk Foundation
Amtssygehuset i Gentofte
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 14 1 5843Subject Categories
Urology and Nephrology
Cardiac and Cardiovascular Systems
DOI
10.1038/s41467-023-39824-4
PubMed
37730687