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

• Published in: Nature communications Vol. 14; no. 1; p. 5843
• Main Authors: Andrikopoulos, Petros, Aron-Wisnewsky, Judith, Chakaroun, Rima, Myridakis, Antonis, Forslund, Sofia K., Nielsen, Trine, Adriouch, Solia, Holmes, Bridget, Chilloux, Julien, Vieira-Silva, Sara, Falony, Gwen, Salem, Joe-Elie, Andreelli, Fabrizio, Belda, Eugeni, Kieswich, Julius, Chechi, Kanta, Puig-Castellvi, Francesc, Chevalier, Mickael, Le Chatelier, Emmanuelle, Olanipekun, Michael T., Hoyles, Lesley, Alves, Renato, Helft, Gerard, Isnard, Richard, Køber, Lars, Coelho, Luis Pedro, Rouault, Christine, Gauguier, Dominique, Gøtze, Jens Peter, Prifti, Edi, Froguel, Philippe, Zucker, Jean-Daniel, Bäckhed, Fredrik, Vestergaard, Henrik, Hansen, Torben, Oppert, Jean-Michel, Blüher, Matthias, Nielsen, Jens, Raes, Jeroen, Bork, Peer, Yaqoob, Muhammad M., Stumvoll, Michael, Pedersen, Oluf, Ehrlich, S. Dusko, Clément, Karine, Dumas, Marc-Emmanuel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-09-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/95; 140/58; 45/23; 631/553; 64/60; 692/499; 692/699/75; Adult; Antidiabetics; Biochemistry, Molecular Biology; Cardiovascular diseases; Causality; Diabetes; Diabetes mellitus; Drugs; Endocrinology; Health risks; Humanities and Social Sciences; Humans; Kidney; Kidneys; Life Sciences; Machine learning; Metabolites; Methylamines; Microbiota; Microorganisms; multidisciplinary; Phenotypes; Science; Science (multidisciplinary); Transforming growth factor-b1; Trimethylamine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39824-4

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.
TMAO is known to be atherothrombotic. Here the authors show that i) kidney function is the main determinant of serum TMAO, ii) TMAO increases kidney scarring with TGF-β1 signalling and iii) anti-diabetic drugs with reno-protective properties such as GLP1R agonists reduce plasma TMAO.