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

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Item Type:Article
Title:Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide
Creators Name:Andrikopoulos, P. and Aron-Wisnewsky, J. and Chakaroun, R. and Myridakis, A. and Forslund, S.K. and Nielsen, T. and Adriouch, S. and Holmes, B. and Chilloux, J. and Vieira-Silva, S. and Falony, G. and Salem, J.E. and Andreelli, F. and Belda, E. and Kieswich, J. and Chechi, K. and Puig-Castellvi, F. and Chevalier, M. and Le Chatelier, E. and Olanipekun, M.T. and Hoyles, L. and Alves, R. and Helft, G. and Isnard, R. and Køber, L. and Coelho, L.P. and Rouault, C. and Gauguier, D. and Gøtze, J.P. and Prifti, E. and Froguel, P. and Zucker, J.D. and Bäckhed, F. and Vestergaard, H. and Hansen, T. and Oppert, J.M. and Blüher, M. and Nielsen, J. and Raes, J. and Bork, P. and Yaqoob, M.M. and Stumvoll, M. and Pedersen, O. and Ehrlich, S.D. and Clément, K. and Dumas, M.E.
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.
Keywords:Causality, Endocrinology, Kidney, Methylamines
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:5843
Date:20 September 2023
Official Publication:https://doi.org/10.1038/s41467-023-39824-4
PubMed:View item in PubMed

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