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Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

Authors :
Petros Andrikopoulos
Judith Aron-Wisnewsky
Rima Chakaroun
Antonis Myridakis
Sofia K. Forslund
Trine Nielsen
Solia Adriouch
Bridget Holmes
Julien Chilloux
Sara Vieira-Silva
Gwen Falony
Joe-Elie Salem
Fabrizio Andreelli
Eugeni Belda
Julius Kieswich
Kanta Chechi
Francesc Puig-Castellvi
Mickael Chevalier
Emmanuelle Le Chatelier
Michael T. Olanipekun
Lesley Hoyles
Renato Alves
Gerard Helft
Richard Isnard
Lars Køber
Luis Pedro Coelho
Christine Rouault
Dominique Gauguier
Jens Peter Gøtze
Edi Prifti
Philippe Froguel
The MetaCardis Consortium
Jean-Daniel Zucker
Fredrik Bäckhed
Henrik Vestergaard
Torben Hansen
Jean-Michel Oppert
Matthias Blüher
Jens Nielsen
Jeroen Raes
Peer Bork
Muhammad M. Yaqoob
Michael Stumvoll
Oluf Pedersen
S. Dusko Ehrlich
Karine Clément
Marc-Emmanuel Dumas
Source :
Nature Communications, Vol 14, Iss 1, Pp 1-18 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

Abstract

Abstract 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.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723 and 48944513
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.12ff1d1de8474b4894451345fa26b4ed
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-023-39824-4