Microbiome and metabolome features of the cardiometabolic disease spectrum

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  • Sebastien Fromentin
  • Sofia K. Forslund
  • Kanta Chechi
  • Judith Aron-Wisnewsky
  • Rima Chakaroun
  • Trine Nielsen
  • Valentina Tremaroli
  • Boyang Ji
  • Edi Prifti
  • Antonis Myridakis
  • Julien Chilloux
  • Petros Andrikopoulos
  • Michael T. Olanipekun
  • Renato Alves
  • Solia Adiouch
  • Noam Bar
  • Yeela Talmor-Barkan
  • Eugeni Belda
  • Robert Caesar
  • Luis Pedro Coelho
  • Gwen Falony
  • Soraya Fellahi
  • Pilar Galan
  • Nathalie Galleron
  • Gerard Helft
  • Lesley Hoyles
  • Richard Isnard
  • Emmanuelle Le Chatelier
  • Hanna Julienne
  • Lisa Olsson
  • Helle Krogh Pedersen
  • Nicolas Pons
  • Benoit Quinquis
  • Christine Rouault
  • Hugo Roume
  • Joe Elie Salem
  • Thomas S.B. Schmidt
  • Sara Vieira-Silva
  • Peishun Li
  • Maria Zimmermann-Kogadeeva
  • Christian Lewinter
  • Nadja B. Søndertoft
  • Tue H. Hansen
  • Dominique Gauguier
  • Jens Peter Gøtze
  • Ran Kornowski
  • Jean Daniel Zucker
  • Serge Hercberg
  • Ivica Letunic
  • Fredrik Bäckhed
  • Jean Michel Oppert
  • Jens Nielsen
  • Jeroen Raes
  • Peer Bork
  • Michael Stumvoll
  • Eran Segal
  • Karine Clément
  • Marc Emmanuel Dumas
  • S. Dusko Ehrlich

Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages—acute coronary syndrome, chronic IHD and IHD with heart failure—and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.

TidsskriftNature Medicine
Udgave nummer2
Sider (fra-til)303-314
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
We are indebted to the MetaCardis study participants and patient associations (Alliance du Coeur and CNAO) for their input and interface. Similarly, we are indebted to the MetaCardis consortium ( http://www.metacardis.net/ ) collaborators for contributions at multiple levels since the consortium start in 2012. A full list of collaborators is given in the Supplementary Information. We further thank D. Bonnefont-Rousselot (Department of Metabolic Biochemistry, Pitié-Salpêtrière Hospital) for the analysis of plasma lipid profiles. We greatly appreciate the assistance of nurses, dietitians, laboratory technicians, clinical research assistants and data managers at the Novo Nordisk Foundation Center for Basic Metabolic Research; the Clinical Research Unit at Fredriksberg and Bispebjerg Hospitals, Copenhagen; the Clinical Investigation Platform at the Institute of Cardiometabolism and Nutrition for Patient Investigations and the Clinical Investigation Center from Pitié-Salpêtrière Hospital, Paris; and the University of Leipzig Medical Center, Leipzig. Quanta Medical provided regulatory oversight of the clinical study and contributed to the processing and management of electronic data. Our study, Metagenomics in Cardiometabolic Diseases, with the acronym METACARDIS, was sponsored by the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312. Assistance Publique-Hôpitaux de Paris is the promoter of the clinical investigation. Parts of the studies were also supported by Metagenopolis grant ANR-11-DPBS-0001, the Leducq Foundation, the Novo Nordisk Foundation and the NIHR Imperial Biomedical Research Centre and by grants from the French National Research Agency (ANR-10-LABX-46 (European Genomics Institute for Diabetes)), the National Center for Precision Diabetic Medicine, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), the European Union (FEDER), the Hauts-de-France Regional Council (Agreement 20001891/NP0025517), the European Metropolis of Lille (agreement 2019_ESR_11) and site ULNE (R-002-20-TALENT-DUMAS), which is also jointly funded by ANR (ANR-16-IDEX-0004-ULNE), the Hauts-de-France Regional Council (20002845) and the European Metropolis of Lille. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research institution at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation. K. Chechi is supported by the Medical Research Council Skills Development Fellowship (grant no. MR/S020039/1) and the Wellcome Trust-funded Institutional Strategic Support Fellowship (grant no. 204834/Z/16/Z). L.H. was in receipt of a Medical Research Council Intermediate Research Fellowship in Data Science (grant no. MR/L01632X/1, UK Med-Bio). S.K.F. was supported by the German Centre for Cardiovascular Research, the German Research Council (projects SFB1365, SFB1470 and KFO339) and the German Ministry of Education and Research.

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© 2022, The Author(s).

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