1. Microbial-host co-metabolites are prodromal markers predicting phenotypic heterogeneity in behavior, obesity, and impaired glucose tolerance
- Author
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Dumas, M-E, Rothwell, AR, Hoyles, L, Aranias, T, Chilloux, J, Calderari, S, Noll, EM, Péan, N, Boulangé, CL, Blancher, C, Barton, RH, Gu, Q, Fearnside, JF, Deshayes, C, Hue, C, Scott, J, Nicholson, JK, Gauguier, D, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Wellcome Trust Centre for Human Genetics, University of Oxford, Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Biologie du Développement et Reproduction (BDR), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Department of Medicine, Wellcome Trust 06678 057733, European Commission FGENTCARD LSHG-CT-2006-037683, Medical Research Council MR/L01632X/1, MRC Intermediate Research Fellowship in Data Science (UK MED-BIO) MR/L01632X/1, Nestle RDLS015375, European Project: 305312, ProdInra, Archive Ouverte, Metagenomics in Cardiometabolic Diseases - 305312 - INCOMING, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), University of Oxford [Oxford], Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Wellcome Trust, Commission of the European Communities, Medical Research Council (MRC), Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du développement et reproduction (BDR), and École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)
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anxiete ,Blood Glucose ,Male ,obesity ,insulin secretion ,HIGH-FAT DIET ,HUMAN GUT MICROBIOME ,microbiome ,TMAO ,Anxiety ,natural phenotypic variation ,trimethylamine-N-oxide ,Article ,Cell Line ,BACTERIAL METABOLITES ,Methylamines ,Mice ,ENDOPLASMIC-RETICULUM STRESS ,CONTAINING MONOOXYGENASE 3 ,sécrétion d'insuline ,Insulin-Secreting Cells ,[SDV.BDD] Life Sciences [q-bio]/Development Biology ,Glucose Intolerance ,Adipocytes ,anxiety disorder ,Animals ,Insulin ,lcsh:QH301-705.5 ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,Science & Technology ,UNFOLDED PROTEIN RESPONSE ,Lipogenesis ,CHEMICAL CHAPERONES ,Cell Biology ,Endoplasmic Reticulum Stress ,Oxidants ,INSULIN-RESISTANT MICE ,L-CARNITINE ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,obésité ,Phenotype ,impaired glucose tolerance ,lcsh:Biology (General) ,Host-Pathogen Interactions ,Metabolome ,Life Sciences & Biomedicine ,transcriptome ,Biomarkers - Abstract
Summary 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., Graphical Abstract, Highlights • High-fat diet drives phenotypic heterogeneity in metabolism and behavior • Microbial metabolites, including methylamines, predict phenotypic heterogeneity • TMAO attenuates ER stress and reduces lipogenesis in adipocytes • TMAO improves insulin secretion and restores glucose tolerance in vivo, Dumas et al. study the metabolic and behavioral phenotypic heterogeneity induced by a high-fat diet intervention in an isogenic mouse population model. Using 1H-NMR spectroscopy, they identify pre-interventional urinary metabolic signatures (including microbial-host co-metabolites) predicting future phenotypic heterogeneity. In particular, TMAO corrects endoplasmic reticulum stress and glucose tolerance.
- Published
- 2018
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