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

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 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, 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 () and Marc-Emmanuel Dumas ()
Additional contact information
Petros Andrikopoulos: Imperial College London
Judith Aron-Wisnewsky: Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
Rima Chakaroun: University of Leipzig Medical Center
Antonis Myridakis: Imperial College London
Sofia K. Forslund: European Molecular Biology Laboratory
Trine Nielsen: University of Copenhagen
Solia Adriouch: Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
Bridget Holmes: Danone Research
Julien Chilloux: Imperial College London
Sara Vieira-Silva: KU Leuven
Gwen Falony: KU Leuven
Joe-Elie Salem: Assistance Publique Hôpitaux de Paris, Pitie-Salpêtrière Hospital
Fabrizio Andreelli: Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
Eugeni Belda: Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
Julius Kieswich: The Royal London Hospital
Kanta Chechi: Imperial College London
Francesc Puig-Castellvi: European Genomics Institute for Diabetes, EGENODIA, INSERM U1283, CNRS UMR8199, Institut Pasteur de Lille, Lille University Hospital, University of Lille
Mickael Chevalier: European Genomics Institute for Diabetes, EGENODIA, INSERM U1283, CNRS UMR8199, Institut Pasteur de Lille, Lille University Hospital, University of Lille
Emmanuelle Chatelier: Metagenopolis, INRA, AgroParisTech, Université Paris-Saclay
Michael T. Olanipekun: Imperial College London
Lesley Hoyles: Nottingham Trent University
Renato Alves: European Molecular Biology Laboratory
Gerard Helft: Assistance Publique Hôpitaux de Paris, Pitie-Salpêtrière Hospital
Richard Isnard: Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
Lars Køber: University of Copenhagen
Luis Pedro Coelho: European Molecular Biology Laboratory
Christine Rouault: Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
Dominique Gauguier: INSERM UMR 1124, Université de Paris
Jens Peter Gøtze: University of Copenhagen
Edi Prifti: Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
Philippe Froguel: European Genomics Institute for Diabetes, EGENODIA, INSERM U1283, CNRS UMR8199, Institut Pasteur de Lille, Lille University Hospital, University of Lille
Jean-Daniel Zucker: Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
Fredrik Bäckhed: University of Gothenburg
Henrik Vestergaard: University of Copenhagen
Torben Hansen: University of Copenhagen
Jean-Michel Oppert: Assistance Publique Hôpitaux de Paris, Pitie-Salpêtrière Hospital
Matthias Blüher: University of Leipzig Medical Center
Jens Nielsen: Chalmers University of Technology
Jeroen Raes: KU Leuven
Peer Bork: European Molecular Biology Laboratory
Muhammad M. Yaqoob: The Royal London Hospital
Michael Stumvoll: University of Leipzig Medical Center
Oluf Pedersen: University of Copenhagen
S. Dusko Ehrlich: University College London
Karine Clément: Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
Marc-Emmanuel Dumas: Imperial College London

Nature Communications, 2023, vol. 14, issue 1, 1-18

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.

Date: 2023
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DOI: 10.1038/s41467-023-39824-4

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