Nature Communications (Sep 2023)
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 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
Affiliations
- Petros Andrikopoulos
- Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London
- Judith Aron-Wisnewsky
- Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
- Rima Chakaroun
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center
- Antonis Myridakis
- Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London
- Sofia K. Forslund
- Structural and Computational Biology, European Molecular Biology Laboratory
- Trine Nielsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Solia Adriouch
- Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
- Bridget Holmes
- Danone Research
- Julien Chilloux
- Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London
- Sara Vieira-Silva
- Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, KU Leuven
- Gwen Falony
- Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, 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
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital
- Kanta Chechi
- Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, 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 Le Chatelier
- Metagenopolis, INRA, AgroParisTech, Université Paris-Saclay
- Michael T. Olanipekun
- Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London
- Lesley Hoyles
- Department of Biosciences, School of Science and Technology, Nottingham Trent University
- Renato Alves
- Structural and Computational Biology, 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
- Department of Cardiology, Rigshospitalet, University of Copenhagen
- Luis Pedro Coelho
- Structural and Computational Biology, 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
- Department of Clinical Biochemistry, Rigshospitalet, 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
- The MetaCardis Consortium
- Jean-Daniel Zucker
- Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
- Fredrik Bäckhed
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
- Henrik Vestergaard
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Jean-Michel Oppert
- Assistance Publique Hôpitaux de Paris, Pitie-Salpêtrière Hospital
- Matthias Blüher
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center
- Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology
- Jeroen Raes
- Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, KU Leuven
- Peer Bork
- Structural and Computational Biology, European Molecular Biology Laboratory
- Muhammad M. Yaqoob
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital
- Michael Stumvoll
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center
- Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- S. Dusko Ehrlich
- Department of Clinical and Movement Neurosciences, University College London
- Karine Clément
- Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics)
- Marc-Emmanuel Dumas
- Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London
- DOI
- https://doi.org/10.1038/s41467-023-39824-4
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
