Microbiota-Mediated Crosstalk Between the Gut and the Vascular System: Protective Effects of Novel Postbiotic Formulations on Human Endothelial and Vascular Smooth Muscle Cells

The close connections between the intestine and distal systems, known as axes, are a growing focus of scientific research; however, the gut-vascular axis, particularly as a target of microbial metabolites, remains underexplored. In this study, three supernatants derived from probiotic formulations composed of <i>Lactobacillus</i> and <i>Bifidobacterium</i> strains (MIX-1, MIX-2, and MIX-3) were evaluated in counteracting vascular alterations associated with dysbiosis. Human aortic smooth muscle (HASMCs) and endothelial (HAECs) cells were exposed to pro-oxidative (H₂O₂) and pro-inflammatory (TMAO) stimuli. Concentrations up to 5-10% (<i>v</i>/<i>v</i>) were tolerated in both cell lines, with MIX-1 and MIX-3 showing the greatest protective efficacy. These formulations exerted antioxidant effects by reducing H₂O₂-induced ROS production and cell viability loss, and anti-inflammatory effects by limiting TMAO-induced IL-1β release. MIX-1 also attenuated TMAO-induced IL-6 release. Further analyses indicated a partial involvement of the SIRT1-pathway in its vascular antioxidant effects. Chromatographic profiling revealed comparable qualitative metabolites among the probiotic supernatants, while quantitative differences were observed, with higher lactate levels in MIX-1 and MIX-3 compared to MIX-2. Finally, we have determined that <i>Limosilactobacillus reuteri</i>-PBS072 is mainly responsible for the antioxidant effect of MIX-1 and MIX-3. Overall, these findings highlight the potential of probiotic-derived metabolites in modulating the gut-vascular axis and promoting vascular protection.