Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide
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 ,   The MetaCardis Consortium, Alili Rohia , Galijatovic Ehm Astrid Andersson , Barthelemy Olivier , Bastard Jean-Philippe , Batisse Jean-Paul , Bel-Lassen Pierre , Berland Magalie , Bittar Randa , Blottière Hervé , Bosquet Frederic , Boubrit Rachid , Bourron Olivier , Camus Mickael , Ciangura Cecile , Collet Jean-Philippe , Dietrich Arne , Djebbar Morad , Doré Angélique , Engelbrechtsen Line , Fezeu Leopold , Fromentin Sebastien , Pons Nicolas , Graine Marianne , Grünemann Caroline , Hartemann Agnes , Hartmann Bolette , Hornbak Malene , Jaqueminet Sophie , Jørgensen Niklas Rye , Julienne Hanna , Justesen Johanne , Kammer Judith , Karup Nikolaj , Kozlowski Ruby , Kuhn Michael , Lejard Véronique , Letunic Ivica , Levenez Florence , Marko Lajos , Martinez-Gili Laura , Massey Robin , Maziers Nicolas , Moitinho-Silva Lucas , Montalescot Gilles , Neves Ana Luisa , Le Pavin Laetitia Pasero , Pousset Francoise , Rodriguez-Martinez Andrea , Schmidt Sebastien , Schütz Tatjana , Silva Lucas , Silvain Johanne , Svendstrup Mathilde , Swartz Timothy D. , Vanduyvenboden Thierry , Verger Eric O. , Walther Stefanie , 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 
Published: September 2023

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.