Microbial-host co-metabolites are prodromal markers predicting phenotypic heterogeneity in behavior, obesity, and impaired glucose tolerance

Marc-Emmanuel Dumas (1) , Alice R. Rothwell (2, 3) , Lesley Hoyles (1) , Thomas Aranias (4, 5, 6, 7) , Julien Chilloux (8, 9) , Sophie Calderari (10, 4, 5, 6, 7) , Elisa M. Noll (1) , Noémie Péan (7, 4, 5, 6) , Claire L. Boulangé (1) , Christine Blancher (2, 3) , Richard H. Barton (1) , Quan Gu (1) , Jane F. Fearnside (2, 3) , Chloé Deshayes (1) , Christophe Hue (4, 5, 6, 7) , James Scott (11) , Jeremy K Nicholson (1) , Dominique Gauguier (1, 2, 3, 4, 5, 6, 7)

1 Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine
2 Wellcome Trust Centre for Human Genetics
3 University of Oxford
4 UPMC - Université Pierre et Marie Curie - Paris 6
5 UPD5 - Université Paris Descartes - Paris 5
6 SU - Sorbonne Université
7 CRC - Centre de Recherche des Cordeliers
8 Division of Computational and Systems Medicine, Department of Surgery and Cancer
9 Faculty of Medicine
10 BDR - Biologie du Développement et Reproduction
11 Department of Medicine

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 (1)H-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.

Mots clés: TMAO; anxiety; endoplasmic reticulum stress; impaired glucose tolerance; insulin secretion; metabolome; microbiome; natural phenotypic variation; obesity; transcriptome; trimethylamine-N-oxide; anxiety disorder

Mots clés: anxiete; obésité; sécrétion d'insuline

Domaines: Biologie du développement

Marc-Emmanuel Dumas, Alice R. Rothwell, Lesley Hoyles, Thomas Aranias, Julien Chilloux, et al.. Microbial-host co-metabolites are prodromal markers predicting phenotypic heterogeneity in behavior, obesity, and impaired glucose tolerance. Cell Reports, 2017, 20 (1), pp.136-148. ⟨10.1016/j.celrep.2017.06.039⟩. ⟨hal-01608420⟩