Role of indole-3-propionic acid, a gut microbiota-derived metabolite, in endothelial dysfunction

Background and Aims: Indole-3-propionic acid (IPA) is a molecule pro- duced by the intestinal microbiota, after tryptophan ingestion. From the gut, IPA is absorbed through the intestinal barrier and enters the systemic circulation, where it plays several physiological roles, such as regulation of the intestinal barrier function, antioxidant and anti-inflammatory activity, anticancer potential, and protective role in neurodegenerative disease. Furthermore, the effect of IPA on cardiovascular disease has been inves- tigated, with conflicting results. Aim of this research is to investigate the role of IPA in endothelial dysfunction, by studying the effects on the BAE-1 (bovine aortic endothelial) cell line. Methods: IPA cytotoxicity was evaluated by MTS assay, while ROS and NO production were studied by fluorescent microscopy (with CellRox-Green and DAR4M-AM probes). Finally, immunoblotting analysis for eNOS phosphorylation were performed. Results: MTS assays did not show any cytotoxic effect of IPA (from 10 nM to 5 mM) after 24h and 4h treatments, while after 48h a reduction in cell viability only at the highest concentration was observed. Furthermore, IPA treatments did not modify the intracellular production of reactive oxygen species, both in basal condition and in the presence of an oxidative stress inducer (menadione). On the other hand, 1mM IPA induced a significative reduction of the nitric oxide released by ATP-stimulated BAE-1 cells, suggesting a potential role of the molecule in altering the physiological vascular tone. Conclusions: This research is a starting point to understand the mecha- nisms underlying the relationship between IPA and endothelial function, which further supports recent findings relating gut microbiota to car- diometabolic health.