Mass spectrometry plasma metabolomic profiling identifies metabolites associated with obesity in humans: pathophysiological role of the gut microbial metabolite indolelactic acid in obese mice

Background: Molecular phenotyping can improve knowledge of disease risks through dissection of disease status into intermediate phenotypes. Objectives: To identify metabolites associated with obesity, hyperlipidemia and the regulation of plasma cholesterol, we profiled the metabolome of plasma samples from a cohort of obese cases and controls. Methods: We used a custom mass spectrometry based targeted metabolomic method designed to simultaneously quantify 101 metabolites. Results: We identified 27 metabolites significantly correlated with at least one of the targeted phenotypes. Groups of metabolites (metabotypes) were consistently associated with both body mass index and hyperlipidemia (arabinose, fructose, glucose, mannose, 1,5-anhydro-D-sorbitol, 2-aminoadipic acid, indolelactic acid, valine, gluconic acid, 2-hydroxybutyric acid, 3-hydroxyisobutyric acid, 2-hydroxyisovaleric acid), whereas others were exclusively associated with hyperlipidemia (ribulose, 5-oxoproline, lactic acid, phenol, 3-hydroxyisovaleric acid) or with body weight (ribose, 2-aminobutyric acid, isoleucine, leucine, phenylalanine, 4-cresol). Several of these compounds are products of microbial metabolism and may underlie functional consequences of architectural changes in the gut microbiome. Conclusions: We provide the first evidence for the role of indolelactic acid, a bacterial product of tryptophan degradation, in lipid metabolism and obesity in humans. We demonstrate diet dependent effects of chronic exposure to indolelactic acid in mice characterized by mild glucose intolerance in lean animals. Our results illustrate the power of metabolomics in the definition of metabotype biomarkers that can be applied in disease diagnosis and personalized nutrition strategies.