Microbiome-derived metabolite plays key role in kidney and heart health

A new study reveals the kidney's function as a key regulator of a metabolite associated with cardiovascular risk.

The study, led by Dr. Petros Andrikopoulos and Prof. Marc-Emmanuel Dumas from the Department of Metabolism Digestion and Reproduction and the National Heart and Lung Institute, has shed light on the regulation of a metabolite made by the bacteria in our gut called trimethylamine N-oxide (TMAO) that is associated with higher risk for heart attacks and strokes in humans. 

"This study represents a very interesting development showing a direct effect on kidney scarring in absence of cardiometabolic risk." Prof. Marc-Emmanuel Dumas

The research, published in Nature Communications, used machine learning and preclinical models of disease to offer valuable insights into the primary factors influencing circulating TMAO levels in adult Europeans. TMAO, produced in the liver from the product of microbial metabolism in the gut of phosphatidylcholine and carnitine, components of the high-fat, high-red meat western diet has been implicated in higher risk for strokes and heart attacks. However, the precise mechanisms governing its levels in the circulation remained elusive.

Involving 1,741 participants, the study examined various factors such as age, kidney function, microbiota composition, and diet, to uncover the determinants of TMAO levels. 

The findings unveiled kidney function as the primary predictor of circulating TMAO levels, with gut microbiota composition and dietary habits playing a minor role, their influence was still significant. These results highlight the critical relationship between kidney health and TMAO regulation. To confirm these findings, the researchers conducted experiments on preclinical models, demonstrating that exposure to TMAO led to kidney scarring.

A new treatment on the horizon?

In agreement with the study’s findings supporting a bidirectional relationship between TMAO and kidney function, patients receiving GLP-1 receptor agonists, a glucose-lowering medications with kidney-protective properties, were found to have significantly lower levels of circulating TMAO compared to individuals who did not receive such treatment. This observation suggests a potential intervention strategy to mitigate the excess cardiovascular risk associated with elevated TMAO levels.

Dr. Andrikopoulos emphasized the significance of these findings, stating, "Our study elucidates the intricate relationship between kidney function and TMAO, offering new possibilities for clinical intervention. By focusing on reno-protective anti-diabetic drugs, we may have a clinically actionable approach to reduce TMAO-associated cardiovascular risk”. 

Prof. Dumas, Co-Director of the CNRS – ULille – Imperial International Research Project on Integrative Metabolism, Director of the Microbiome Network of Excellence and senior author of the study, said “There is now an abundance of literature about the role of the microbiome and TMAO in cardiovascular, and this study represents a very interesting development showing a direct effect on kidney scarring in absence of cardiometabolic risk. This shows that there is still much to unpick and is clearly calls for further work on the role of the microbiome on the cardiorenal axis and cardiometabolic multimorbidities in general”. 

In conclusion, this study has unearthed the primary role of kidney function in regulating circulating TMAO levels, with age, microbiota composition, and diet playing supplementary roles. The researchers have established a causal relationship between TMAO and kidney function and identified reno-protective anti-diabetic drugs as potential interventions to mitigate the associated cardiovascular risk. These findings represent a significant step towards personalized medicine and offer hope for improved cardiovascular health outcomes.

The study, which also included researchers from CNRS at the University of Lille, INSERM at Sorbonne Universités in Paris, the University of Leipzig Medical Center, the University of Copenhagen and Queen Mary’s University of London, was originally funded by the European Union funded MetaCardis consortium. Deciphering the role of microbiome mechanisms in precision medicine is a flagship project in the CNRS – ULille – Imperial International Research Project on Integrative Metabolism, which is hosted within the CNRS – Imperial International Research Centre for Transformational Science and Technology.

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, The MetaCardis Consortium, 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. Nature Communications volume 14, Article number: 5843 (2023)