Microbial-Host Co-metabolites Are Prodromal Markers Predicting Phenotypic Heterogeneity in Behavior, Obesity, and Impaired Glucose Tolerance
Marc-Emmanuel Dumas,
Alice R. Rothwell,
Lesley Hoyles,
Thomas Aranias,
Julien Chilloux,
Sophie Calderari,
Elisa M. Noll,
Noémie Péan,
Claire L. Boulangé,
Christine Blancher,
Richard H. Barton,
Quan Gu,
Jane F. Fearnside,
Chloé Deshayes,
Christophe Hue,
James Scott,
Jeremy K. Nicholson,
Dominique Gauguier
Affiliations
Marc-Emmanuel Dumas
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
Alice R. Rothwell
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
Lesley Hoyles
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
Thomas Aranias
Cordeliers Research Centre, INSERM UMR_S 1138, University Pierre & Marie Curie and University Paris Descartes, Sorbonne Paris Cité, Sorbonne Universities, 15 Rue de l’École de Médecine, 75006 Paris, France
Julien Chilloux
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
Sophie Calderari
Cordeliers Research Centre, INSERM UMR_S 1138, University Pierre & Marie Curie and University Paris Descartes, Sorbonne Paris Cité, Sorbonne Universities, 15 Rue de l’École de Médecine, 75006 Paris, France
Elisa M. Noll
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
Noémie Péan
Cordeliers Research Centre, INSERM UMR_S 1138, University Pierre & Marie Curie and University Paris Descartes, Sorbonne Paris Cité, Sorbonne Universities, 15 Rue de l’École de Médecine, 75006 Paris, France
Claire L. Boulangé
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
Christine Blancher
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
Richard H. Barton
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
Quan Gu
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
Jane F. Fearnside
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
Chloé Deshayes
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
Christophe Hue
Cordeliers Research Centre, INSERM UMR_S 1138, University Pierre & Marie Curie and University Paris Descartes, Sorbonne Paris Cité, Sorbonne Universities, 15 Rue de l’École de Médecine, 75006 Paris, France
James Scott
Department of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK
Jeremy K. Nicholson
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
Dominique Gauguier
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
The influence of the gut microbiome on metabolic and behavioral traits is widely accepted, though the microbiome-derived metabolites involved remain unclear. We carried out untargeted urine 1H-NMR spectroscopy-based metabolic phenotyping in an isogenic C57BL/6J mouse population (n = 50) and show that microbial-host co-metabolites are prodromal (i.e., early) markers predicting future divergence in metabolic (obesity and glucose homeostasis) and behavioral (anxiety and activity) outcomes with 94%–100% accuracy. Some of these metabolites also modulate disease phenotypes, best illustrated by trimethylamine-N-oxide (TMAO), a product of microbial-host co-metabolism predicting future obesity, impaired glucose tolerance (IGT), and behavior while reducing endoplasmic reticulum stress and lipogenesis in 3T3-L1 adipocytes. Chronic in vivo TMAO treatment limits IGT in HFD-fed mice and isolated pancreatic islets by increasing insulin secretion. We highlight the prodromal potential of microbial metabolites to predict disease outcomes and their potential in shaping mammalian phenotypic heterogeneity.
