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; 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; MetaCardis Consortium; Line Engelbrechtsen

doi:10.1038/s41467-023-39824-4

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 OlanipekunLesley 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^*, Marc-Emmanuel Dumas^*, MetaCardis Consortium, Line Engelbrechtsen (Member of author group)

^*Corresponding author for this work

62 Citations (Scopus)

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.

Original language	English
Article number	5843
Journal	Nature Communications
Volume	14
Issue number	1
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-023-39824-4
Publication status	Published - 20 Sept 2023

Keywords

Adult
Humans
Causality
Methylamines
Endocrinology
Kidney

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Andrikopoulos, P., Aron-Wisnewsky, J., Chakaroun, R., Myridakis, A., Forslund, S. K., Nielsen, T., Adriouch, S., Holmes, B., Chilloux, J., Vieira-Silva, S., Falony, G., Salem, J.-E., Andreelli, F., Belda, E., Kieswich, J., Chechi, K., Puig-Castellvi, F., Chevalier, M., Le Chatelier, E., ... Engelbrechtsen, L. (2023). Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide. Nature Communications, 14(1), Article 5843. https://doi.org/10.1038/s41467-023-39824-4

Andrikopoulos, P, Aron-Wisnewsky, J, Chakaroun, R, Myridakis, A, Forslund, SK, Nielsen, T, Adriouch, S, Holmes, B, Chilloux, J, Vieira-Silva, S, Falony, G, Salem, J-E, Andreelli, F, Belda, E, Kieswich, J, Chechi, K, Puig-Castellvi, F, Chevalier, M, Le Chatelier, E, Olanipekun, MT, Hoyles, L, Alves, R, Helft, G, Isnard, R, Køber, L, Coelho, LP, Rouault, C, Gauguier, D, Gøtze, JP, Prifti, E, Froguel, P, Zucker, J-D, Bäckhed, F, Vestergaard, H, Hansen, T, Oppert, J-M, Blüher, M, Nielsen, J, Raes, J, Bork, P, Yaqoob, MM, Stumvoll, M, Pedersen, O, Ehrlich, SD, Clément, K, Dumas, M-E, MetaCardis Consortium & Engelbrechtsen, L 2023, 'Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide', Nature Communications, vol. 14, no. 1, 5843. https://doi.org/10.1038/s41467-023-39824-4

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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.",

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AU - Myridakis, Antonis

AU - Forslund, Sofia K

AU - Nielsen, Trine

AU - Adriouch, Solia

AU - Holmes, Bridget

AU - Chilloux, Julien

AU - Vieira-Silva, Sara

AU - Falony, Gwen

AU - Salem, Joe-Elie

AU - Andreelli, Fabrizio

AU - Belda, Eugeni

AU - Kieswich, Julius

AU - Chechi, Kanta

AU - Puig-Castellvi, Francesc

AU - Chevalier, Mickael

AU - Le Chatelier, Emmanuelle

AU - Olanipekun, Michael T

AU - Hoyles, Lesley

AU - Alves, Renato

AU - Helft, Gerard

AU - Isnard, Richard

AU - Køber, Lars

AU - Coelho, Luis Pedro

AU - Rouault, Christine

AU - Gauguier, Dominique

AU - Gøtze, Jens Peter

AU - Prifti, Edi

AU - Froguel, Philippe

AU - Zucker, Jean-Daniel

AU - Bäckhed, Fredrik

AU - Vestergaard, Henrik

AU - Hansen, Torben

AU - Oppert, Jean-Michel

AU - Blüher, Matthias

AU - Nielsen, Jens

AU - Raes, Jeroen

AU - Bork, Peer

AU - Yaqoob, Muhammad M

AU - Stumvoll, Michael

AU - Pedersen, Oluf

AU - Ehrlich, S Dusko

AU - Clément, Karine

AU - Dumas, Marc-Emmanuel

AU - MetaCardis Consortium

A2 - Engelbrechtsen, Line

PY - 2023/9/20

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N2 - 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.

AB - 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.

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KW - Causality

KW - Methylamines

KW - Endocrinology

KW - Kidney

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SN - 2041-1722

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5843

ER -

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

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Keywords

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