The gut, with its extensive microbiota, plays a fundamental role in metabolism. While alterations of the gut microbiota can induce dysfunction of the endothelium, it remains unclear whether the endothelium can directly impact the gut microbiota. To answer this question, in this issue of EMBO Reports Haywood and colleagues deployed a murine model with endothelial-specific overexpression of human insulin-like growth factor-1 receptor (IGF-1R), termed hIGFREO mice (Haywood et al, 2021). When fed a high-fat diet, hIGFREO mice gained less weight and adiposity, with improved glucose tolerance, as compared to their wild-type littermates. Such protection was attributed to the difference in gut microbiota, exemplified by an increase in the beneficial genus Akkermansia. Furthermore, depletion of microbiota through broad-spectrum antibiotics nullified the advantageous metabolic phenotype observed. Collectively, these findings demonstrate a novel communication axis between the endothelium and the gut wall, specifically through endothelial IGF-1R modulation of gut microbiota, that promotes whole body metabolic homeostasis.