The metabolome, the small molecule chemical entities involved in metabolism, has traditionally been studied with the aim of identifying biomarkers in the diagnosis and prediction of disease. However, the value of metabolomics has been redefined from a simple biomarker identification tool to a technology for the discovery of active drivers of biological processes. In this review, we describe the molecular mechanisms by which the active cell metabolome affects cellular physiology through modulation of other ‘omic’ levels, including the genome, epi-genome, transcriptome and proteome. This concept of activity screening guided by metabolomics to identify biologically active metabolites, or “activity metabolomics”, is having broad impact on biology.

Highlights d Cardiac fibroblasts and endothelial cells induce hiPSCcardiomyocyte maturation d CX43 gap junctions form between cardiac fibroblasts and cardiomyocytes d cAMP-pathway activation contributes to hiPSCcardiomyocyte maturation d Patient-derived hiPSC-cardiac fibroblasts cause arrhythmia in microtissues

Butyrate acts on the gut-brain neural circuit to improve energy metabolism via reducing energy intake and enhancing fat oxidation by activating BAT.