Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N -oxide with implications for heart and kidney disorders
Petros Andrikopoulos
(1)
,
Judith Aron-Wisnewsky
(2, 3, 4)
,
Rima Chakaroun
(5)
,
Antonis Myridakis
(1)
,
Sofia Forslund
(6)
,
Trine Nielsen
,
Solia Adriouch
(2)
,
Bridget Holmes
,
Julien Chilloux
(1)
,
Sara Vieira-Silva
(7)
,
Gwen Falony
(7)
,
Joe-Elie Salem
(4, 4, 8)
,
Fabrizio Andreelli
(4, 2)
,
Eugeni Belda
(2)
,
Julius Kieswich
,
Kanta Chechi
,
Francesc Puig-Castellvi
(9, 10)
,
Mickael Chevalier
(11)
,
Emmanuelle Le Chatelier
(12)
,
Michael Olanipekun
(1)
,
Lesley Hoyles
,
Renato Alves
,
Gerard Helft
,
Richard Isnard
,
Lars Køber
,
Luis Pedro Coelho
,
Christine Rouault
,
Dominique Gauguier
,
Jens Peter Gøtze
,
Edi Prifti
,
Jean-Daniel Zucker
,
Fredrik Bäckhed
,
Henrik Vestergaard
,
Torben Hansen
,
Jean-Michel Oppert
,
Matthias Blüher
,
Jens Nielsen
,
Jeroen Raes
,
Peer Bork
,
Muhammad Yaqoob
,
Michael Stumvoll
,
Oluf Pedersen
,
S. Dusko Ehrlich
,
Karine Clément
,
Marc-Emmanuel Dumas
(1, 1, 13)
1
Imperial College London
2 Nutriomics - Nutrition et obésités: approches systémiques (UMR-S 1269)
3 Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)
4 CHU Pitié-Salpêtrière [AP-HP]
5 University Hospital Leipzig = Universitätsklinikum Leipzig
6 EMBL - European Molecular Biology Laboratory [Heidelberg]
7 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
8 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
9 SayFood - Paris-Saclay Food and Bioproduct Engineering
10 UR PROSE - Procédés biotechnologiques au service de l'environnement
11 ICV - Institut Charles Viollette (ICV) - ULR 7394
12 MGP (US 1367) - MetaGenoPolis
13 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
2 Nutriomics - Nutrition et obésités: approches systémiques (UMR-S 1269)
3 Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)
4 CHU Pitié-Salpêtrière [AP-HP]
5 University Hospital Leipzig = Universitätsklinikum Leipzig
6 EMBL - European Molecular Biology Laboratory [Heidelberg]
7 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
8 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
9 SayFood - Paris-Saclay Food and Bioproduct Engineering
10 UR PROSE - Procédés biotechnologiques au service de l'environnement
11 ICV - Institut Charles Viollette (ICV) - ULR 7394
12 MGP (US 1367) - MetaGenoPolis
13 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
Petros Andrikopoulos
- Fonction : Auteur
- PersonId : 1194627
- ORCID : 0000-0002-1555-3498
Rima Chakaroun
- Fonction : Auteur
- PersonId : 1194628
- ORCID : 0000-0001-9901-1815
Trine Nielsen
- Fonction : Auteur
Bridget Holmes
- Fonction : Auteur
Joe-Elie Salem
- Fonction : Auteur
- PersonId : 777251
- IdHAL : joe-elie-salem
- ORCID : 0000-0002-0331-3307
- IdRef : 160947227
Julius Kieswich
- Fonction : Auteur
Kanta Chechi
- Fonction : Auteur
Francesc Puig-Castellvi
- Fonction : Auteur
- PersonId : 1321435
- IdHAL : fran-puig
- ORCID : 0000-0003-1064-9586
Lesley Hoyles
- Fonction : Auteur
- PersonId : 764137
- ORCID : 0000-0002-6418-342X
Renato Alves
- Fonction : Auteur
Gerard Helft
- Fonction : Auteur
Richard Isnard
- Fonction : Auteur
Lars Køber
- Fonction : Auteur
- PersonId : 783646
- ORCID : 0000-0002-6635-1466
Luis Pedro Coelho
- Fonction : Auteur
Christine Rouault
- Fonction : Auteur
Dominique Gauguier
- Fonction : Auteur
Jens Peter Gøtze
- Fonction : Auteur
Edi Prifti
- Fonction : Auteur
- PersonId : 1151183
- IdHAL : edi-prifti
- ORCID : 0000-0001-8861-1305
- IdRef : 155572822
Jean-Daniel Zucker
- Fonction : Auteur
Fredrik Bäckhed
- Fonction : Auteur
Henrik Vestergaard
- Fonction : Auteur
Torben Hansen
- Fonction : Auteur
Jean-Michel Oppert
- Fonction : Auteur
Matthias Blüher
- Fonction : Auteur
Jens Nielsen
- Fonction : Auteur
Jeroen Raes
- Fonction : Auteur
Peer Bork
- Fonction : Auteur
Muhammad Yaqoob
- Fonction : Auteur
Michael Stumvoll
- Fonction : Auteur
Oluf Pedersen
- Fonction : Auteur
S. Dusko Ehrlich
- Fonction : Auteur
Karine Clément
- Fonction : Auteur
Résumé
Abstract Objectives The host-microbiota co-metabolite trimethylamine N -oxide (TMAO) is linked to increased thrombotic and cardiovascular risks. Here we, sought to i) characterize which host variables contribute to fasting serum TMAO levels in real-life settings ii) identify potential actionable therapeutic means related to circulating TMAO. Design We applied “explainable” machine learning, univariate-, multivariate- and mediation analyses of fasting plasma TMAO concentration and a multitude of bioclinical phenotypes in 1,741 adult Europeans of the MetaCardis study. We expanded and validated our epidemiological findings in mechanistic studies in human renal fibroblasts and a murine model of kidney fibrosis following TMAO exposure. Results Next to age, kidney function was the primary variable predicting circulating TMAO in MetaCardis, with microbiota composition and diet playing minor, albeit significant roles. Mediation analysis revealed a causal relationship between TMAO and kidney function decline that strengthened at more severe stages of cardiometabolic disease. We corroborated our findings in preclinical models where TMAO exposure augmented conversion of human renal fibroblasts into myofibroblasts and increased kidney scarring in vivo . Mechanistically, TMAO aggravated kidney fibrosis due to ERK1/2 hyperactivation synergistically with TGF-β1 signaling. Consistent with our findings, patients receiving next-generation glucose-lowering drugs with reno-protective properties, had significantly lower circulating TMAO when compared to propensity-score matched control individuals. Conclusion After age, kidney function is the major determinant of fasting circulating TMAO in adults. Our findings of lower TMAO levels in individuals medicated with reno-protective anti-diabetic drugs suggests a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk that merits urgent investigation in human trials. Data availability statement Raw shotgun sequencing data that support the findings of this study have been deposited in the European Nucleotide Archive with accession codes PRJEB37249, PRJEB38742, PRJEB41311 and PRJEB46098. Serum NMR and urine NMR metabolome data have been uploaded to Metabolights with accession number MTBLS3429; serum GC-MS and isotopically quantified serum metabolites (UPLC–MS/MS) are available from MassIVE with accession numbers MSV000088042 and MSV000088043, respectively.