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Microbiome and metabolome features of the cardiometabolic disease spectrum.

MetaGenoPolis, INRAe, AgroParisTech, Université Paris-Saclay, Paris, France. Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, Germany. Experimental and Clinical Research Center, a cooperation of Charité-Universitätsmedizin and the Max-Delbrück Center, Berlin, Germany. Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany. Charité University Hospital, Berlin, Germany. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany. Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK. School of Public Health, Faculty of Medicine, Imperial College London, Medical School Building, St. Mary's Hospital, London, UK. Genomic and Environmental Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK. Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics), Paris, France. Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Nutrition Department, Paris, France. Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden. Unité de modélisation mathématique et informatique des systèmes complexes, UMMISCO, Bondy, France. Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. Department of Cardiology, Rabin Medical Center, Petah Tikva, Israel. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Institute of Cardiometabolism and Nutrition, Integromics Unit, Paris, France. Integrative Phenomics, Paris, France. Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven, Belgium. Center for Microbiology, VIB, Leuven, Belgium. Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Département de biochimie-pharmacologie-biologie moléculaire-génétique médicale, Créteil, France. Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Cardiology Department, Paris, France. Nottingham Trent University, Department of Bioscience, School of Science and Technology, Nottingham, UK. AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology, UNICO Cardio-oncology Program, CIC-1421; INSERM, Sorbonne Université, Paris, France. Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Université de Paris, INSERM UMR 1124, Paris, France. Department of Clinical Biochemetry, Rigshopitalet, University of Copenhagen, Copenhagen, Denmark. Department of Medicine, Bornholms Hospital, Rønne, Denmark. Sorbonne Paris Cité Epidemiology and Statistics Research Centre (CRESS), U1153 Inserm, U1125, Inra, Cnam, University of Paris 13, Nutritional Epidemiology Research Team (EREN), Bobigny, France. Biobyte Solutions GmbH, Heidelberg, Germany. Sorbonne Université, INSERM, Nutrition and obesities; systemic approaches (NutriOmics), Paris, France. karine.clement@inserm.fr. Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Nutrition Department, Paris, France. karine.clement@inserm.fr. Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK. m.dumas@imperial.ac.uk. Genomic and Environmental Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK. m.dumas@imperial.ac.uk. European Genomics Institute for Diabetes, UMR1283/8199 INSERM, CNRS, Institut Pasteur de Lille, Lille University Hospital, University of Lille, Lille, France. m.dumas@imperial.ac.uk. MetaGenoPolis, INRAe, AgroParisTech, Université Paris-Saclay, Paris, France. s.ehrlich@ucl.ac.uk. Department of Clinical and Movement Neurosciences, University College London, London, UK. s.ehrlich@ucl.ac.uk. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. oluf@sund.ku.dk.

Nature medicine. 2022;(2):303-314
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Abstract

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.