Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide
Artikel i vetenskaplig tidskrift, 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.
Författare
Petros Andrikopoulos
Imperial College London
National Heart and Lung Institute
Judith Aron-Wisnewsky
Assistance publique – Hôpitaux de Paris (AP-HP)
Université Pierre et Marie Curie (UPMC)
Rima Chakaroun
Wallenberg Lab.
Universität Leipzig
Antonis Myridakis
Imperial College London
Sofia K. Forslund
Max Delbrueck Centrum Fuer Molekulare Medizin
European Molecular Biology Laboratory
Charité Universitätsmedizin Berlin
Deutsches Zentrum für Herz-Kreislauf-Forshung (DZHK)
Trine Nielsen
Novo Nordisk Fonden
Solia Adriouch
Université Pierre et Marie Curie (UPMC)
Bridget Holmes
Danone Research
J. Chilloux
Imperial College London
Sara Vieira-Silva
University Medical Center Mainz
KU Leuven
Flanders Interuniversity Institute for Biotechnology
Johannes Gutenberg-Universität Mainz
Gwen Falony
KU Leuven
University Medical Center Mainz
Flanders Interuniversity Institute for Biotechnology
Johannes Gutenberg-Universität Mainz
Joe-Elie Salem
Assistance publique – Hôpitaux de Paris (AP-HP)
Fabrizio Andreelli
Assistance publique – Hôpitaux de Paris (AP-HP)
Université Pierre et Marie Curie (UPMC)
Eugeni Belda
Université Pierre et Marie Curie (UPMC)
Julius Kieswich
The Royal London Hospital
Barts Cancer Institute
Kanta Chechi
National Heart and Lung Institute
Imperial College London
Francesc Puig-Castellvi
Lille University Hospital
Mickael Chevalier
Lille University Hospital
Emmanuelle Le Chatelier
Université Paris-Saclay
Michael Olanipekun
Imperial College London
L. Hoyles
Nottingham Trent University
Renato Alves
European Molecular Biology Laboratory
Gerard Helft
Inserm Transfert
Assistance publique – Hôpitaux de Paris (AP-HP)
Richard Isnard
Université Pierre et Marie Curie (UPMC)
Assistance publique – Hôpitaux de Paris (AP-HP)
Lars Køber
Rigshospitalet
Luis P. Coelho
European Molecular Biology Laboratory
Christine Rouault
Université Pierre et Marie Curie (UPMC)
Dominique Gauguier
McGill University
Sorbonne Université
Jens P. Gøtze
Rigshospitalet
Edi Prifti
Université Pierre et Marie Curie (UPMC)
Philippe Froguel
Imperial College London
Lille University Hospital
Rohia Alili
Université Pierre et Marie Curie (UPMC)
Ehm Astrid Andersson Galijatovic
Novo Nordisk Fonden
Olivier Barthelemy
Assistance publique – Hôpitaux de Paris (AP-HP)
Jean-Phillippe Bastard
Université Pierre et Marie Curie (UPMC)
Jean-Paul Batisse
Assistance publique – Hôpitaux de Paris (AP-HP)
Pierre Bel-Lassen
Université Pierre et Marie Curie (UPMC)
Magalie Berland
Université Paris-Saclay
Randa Bittar
Assistance publique – Hôpitaux de Paris (AP-HP)
Hervé Blottière
Université 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
Université Pierre et Marie Curie (UPMC)
Cecile Ciangura
Assistance publique – Hôpitaux de Paris (AP-HP)
Jean-Philippe Collet
Assistance publique – Hôpitaux de Paris (AP-HP)
Arne Dietrich
Universität Leipzig
Morad Djebbar
Assistance publique – Hôpitaux de Paris (AP-HP)
Angélique Doré
Université Paris-Saclay
Line Engelbrechtsen
Novo Nordisk Fonden
Leopold Fezeu
Conservatoire National des Arts et Metiers
Sebastien Fromentin
Université Paris-Saclay
Nicolas Pons
Université Paris-Saclay
Marianne Graine
Université Pierre et Marie Curie (UPMC)
Caroline Grünemann
Universität Leipzig
Agnes Hartemann
Assistance publique – Hôpitaux de Paris (AP-HP)
Bolette Hartmann
Novo Nordisk Fonden
Malene Hornbak
Novo Nordisk Fonden
Sophie Jaqueminet
Assistance publique – Hôpitaux de Paris (AP-HP)
Niklas Rye Jørgensen
Rigshospitalet
Hanna Julienne
Université Paris-Saclay
Johanne Justesen
Novo Nordisk Fonden
Judith Kammer
Universität Leipzig
Nikolaj Karup
Novo Nordisk Fonden
Ruby Kozlowski
Imperial College London
Michael Kuhn
European Molecular Biology Laboratory
Véronique Lejard
Université Paris-Saclay
Ivica Letunic
European Molecular Biology Laboratory
Florence Levenez
Université Paris-Saclay
Lajos Markó
Max Delbrueck Centrum Fuer Molekulare Medizin
Laura Martinez-Gili
Imperial College London
Robin Massey
Université Paris-Saclay
Nicolas Maziers
Université 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
Université 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
Universität Leipzig
Lucas Silva
European Molecular Biology Laboratory
Johanne Silvain
Assistance publique – Hôpitaux de Paris (AP-HP)
Mathilde Svendstrup
Novo Nordisk Fonden
Timothy Swartz
Université Pierre et Marie Curie (UPMC)
Thierry Vanduyvenboden
Université Paris-Saclay
Eric Verger
Université de Montpellier
Stefanie Walther
Universität Leipzig
Jean-Daniel Zucker
Université Pierre et Marie Curie (UPMC)
Fredrik Bäckhed
Novo Nordisk Fonden
Wallenberg Lab.
H. Vestergaard
Bornholms Hospital
Novo Nordisk Fonden
Torben Hansen
Novo Nordisk Fonden
Jean-Michel Oppert
Assistance publique – Hôpitaux de Paris (AP-HP)
M. Bluher
Universität Leipzig
Jens B Nielsen
Chalmers, Life sciences, Systembiologi
Jeroen Raes
KU Leuven
Flanders Interuniversity Institute for Biotechnology
Peer Bork
Max Delbrueck Centrum Fuer Molekulare Medizin
European Molecular Biology Laboratory
Yonsei University
Julius-Maximilians Universität Würzburg
Muhammad Magdi Yaqoob
Barts Cancer Institute
The Royal London Hospital
M. Stumvoll
Universität Leipzig
O. B. Pedersen
Novo Nordisk Fonden
Gentofte Hospital
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 14 1 5843Ämneskategorier (SSIF 2011)
Urologi och njurmedicin
Kardiologi
DOI
10.1038/s41467-023-39824-4
PubMed
37730687