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

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.