Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 5843 |
| Tidsskrift | Nature Communications |
| Vol/bind | 14 |
| Antal sider | 18 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This work was supported by European Union’s Seventh Framework Program for research, technological development, and demonstration under grant agreement HEALTH-F4-2012-305312 (METACARDIS). Assistance Publique-Hôpitaux de Paris (AP-HP) is the promoter of clinical investigation (MetaCardis). Partial funding supports to K.C. and J.A.-W. were also obtained from Leducq Foundation (TransAtlantic grant), SFN (Société Française de Nutrition), F-CRIN-FORCE network for support, INSERM via ITMO and JPI-Microdiet study and Novo Nordisk foundation (Jacobaus prize). S.K.F. received support from Deutsche Forschungsgesellschaft SFB1365 (“RENOPROTECTION”) and SFB1470: “HFpEF”. P.A. and K.Ch. are recipients of a Wellcome ISSF Fellowship (ISSF204834/Z/16/Z). M.-E.D. is supported by the NIHR Imperial Biomedical Research Centre, GutsUK, Diabetes UK and by grants from the French National Research Agency (ANR-10-LABX-46, European Genomics Institute for Diabetes), from the National Center for Diabetes Precision Medicine—PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council (Agreement 20001891/NP0025517) and by the European Metropolis of Lille (MEL, Agreement 2019_ESR_11) and by Isite ULNE (R-002-20-TALENT-DUMAS), also jointly funded by ANR (ANR16-IDEX-0004-ULNE), the Hauts-de-France Regional Council (20002845) and by the European Metropolis of Lille (MEL). This research was conducted within the context of the CNRS–Imperial International Research Project METABO-LIC. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research institution at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation. We thank the subjects for their participation in the MetaCardis study and particularly patient associations (Alliance du Coeur and CNAO) for their input and interface, as well as Dr Dominique Bonnefont-Rousselot (Department of Metabolic Biochemistry, Pitié-Salpêtrière hospital) for the analysis of plasma lipid profiles. We thank the nurses, technicians, clinical research assistants and data managers from the Clinical investigation platform at the Institute of Cardiometabolism and Nutrition for patient investigations, at the CRNH (Centre de recherche en Nutrition Humaine CRNH-Ile de France) and, the Clinical Investigation Center (CIC) from Pitié-Salpêtrière Hospital for investigation of healthy controls. Quanta Medical provided regulatory oversight of the clinical study and contributed to the processing and management of electronic data.
Funding Information:
This work was supported by European Union’s Seventh Framework Program for research, technological development, and demonstration under grant agreement HEALTH-F4-2012-305312 (METACARDIS). Assistance Publique-Hôpitaux de Paris (AP-HP) is the promoter of clinical investigation (MetaCardis). Partial funding supports to K.C. and J.A.-W. were also obtained from Leducq Foundation (TransAtlantic grant), SFN (Société Française de Nutrition), F-CRIN-FORCE network for support, INSERM via ITMO and JPI-Microdiet study and Novo Nordisk foundation (Jacobaus prize). S.K.F. received support from Deutsche Forschungsgesellschaft SFB1365 (“RENOPROTECTION”) and SFB1470: “HFpEF”. P.A. and K.Ch. are recipients of a Wellcome ISSF Fellowship (ISSF204834/Z/16/Z). M.-E.D. is supported by the NIHR Imperial Biomedical Research Centre, GutsUK, Diabetes UK and by grants from the French National Research Agency (ANR-10-LABX-46, European Genomics Institute for Diabetes), from the National Center for Diabetes Precision Medicine—PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council (Agreement 20001891/NP0025517) and by the European Metropolis of Lille (MEL, Agreement 2019_ESR_11) and by Isite ULNE (R-002-20-TALENT-DUMAS), also jointly funded by ANR (ANR16-IDEX-0004-ULNE), the Hauts-de-France Regional Council (20002845) and by the European Metropolis of Lille (MEL). This research was conducted within the context of the CNRS–Imperial International Research Project METABO-LIC. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research institution at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation. We thank the subjects for their participation in the MetaCardis study and particularly patient associations (Alliance du Coeur and CNAO) for their input and interface, as well as Dr Dominique Bonnefont-Rousselot (Department of Metabolic Biochemistry, Pitié-Salpêtrière hospital) for the analysis of plasma lipid profiles. We thank the nurses, technicians, clinical research assistants and data managers from the Clinical investigation platform at the Institute of Cardiometabolism and Nutrition for patient investigations, at the CRNH (Centre de recherche en Nutrition Humaine CRNH-Ile de France) and, the Clinical Investigation Center (CIC) from Pitié-Salpêtrière Hospital for investigation of healthy controls. Quanta Medical provided regulatory oversight of the clinical study and contributed to the processing and management of electronic data.
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© 2023, Springer Nature Limited.
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