1. Microbial-Host Co-metabolites Are Prodromal Markers Predicting Phenotypic Heterogeneity in Behavior, Obesity, and Impaired Glucose Tolerance.
- Author
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Dumas ME, 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, and Gauguier D
- Subjects
- Adipocytes drug effects, Adipocytes metabolism, Animals, Anxiety metabolism, Biomarkers metabolism, Blood Glucose metabolism, Cell Line, Endoplasmic Reticulum Stress, Glucose Intolerance metabolism, Host-Pathogen Interactions, Insulin metabolism, Insulin Secretion, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells metabolism, Lipogenesis, Male, Methylamines pharmacology, Mice, Mice, Inbred C57BL, Obesity metabolism, Oxidants pharmacology, Anxiety microbiology, Gastrointestinal Microbiome, Glucose Intolerance microbiology, Metabolome, Obesity microbiology, Phenotype
- Abstract
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., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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