The gut microbiota play a pivotal role in the onset and development of obesity and cardiometabolic disorders. Obese subjects exhibit significant gut microbial changes, including enrichment for bacterial genes associated with the degradation of tryptophan, which is converted by gut bacteria into indoles. Indoles act as signalling molecules in the microbial-mammalian crosstalk; however, their human targets and mechanisms are not fully understood. In particular, the human kinome remains an unexplored repertoire. The overall hypothesis of this work is that indoles bind human kinases, impact signalling pathways and interfere with cellular processes relevant for obesity and cardiometabolic diseases, thus acting as chemical messengers in the microbiomekinome crosstalk. Gut microbial degradation of tryptophan converges to the production of indoxyl sulfate and indole-3-acetate. Using 1H NMR profiling, indoxyl sulfate was found to be positively correlated with adiposity and plasma levels of leptin; its effect was further confirmed i n vitro , where it increased both lipid accumulation and leptin production. A high-throughput kinase screening revealed that indoxyl sulfate has kinome-wide effects and was subjected to a network analysis to connect its proadipogenic effect. Kinase screening and molecular docking analysis suggest that another indolic compound, indole-3-acetate, inhibits VEGFR-2 - a kinase-linked receptor essential for angiogenesis and involved in several cardiometabolic disorders ( e.g. atherosclerosis, diabetes, and hypertension). This inhibition was validated in vitro by demonstrating that indole-3-acetate reduces the phosphorylation of VEGFR-2 and downstream AKT signalling in endothelial cells. Consistently, indole-3-acetate inhibited endothelial cell migration and tube formation, which are required for angiogenesis i n v i t r o , and decreased vascular network formation in an i n v i v o
angiogenesis model. Altogether, this study unravels a unique microbiome-kinome crosstalk by demonstrating that specific gut microbiota-generated indoles can impact adipogenesis (indoxyl sulfate) and angiogenesis (indole-3-acetate), two key processes in obesity and cardiometabolic disorders.