Identification and characterization of the “GUT VASCULAR BARRIER” that is exploited by Salmonella typhimurium for its systemic dissemination

Orally administered antigens can reach systemic sites inducing a systemic state of tolerance, while the microbiota is contained in the mucosal compartment and is systemically ignored. How this discrimination is achieved is unknown.We describe the existence of a gut vascular barrier (GVB) both in human and mouse that plays an important role in controlling the translocation of bacteria to systemic sites. We characterized the intestinal endothelial cells (ECs) in terms of expression of tight and adherent junction proteins. In addition, we observed that the ECs were associated with enteric glial cells and pericytes forming together the “gut vascular unit”.GVB integrity could be modified by Salmonella typhimurium. Indeed, upon infection the vascular ECs up-regulated the expression of PV1, marker of damaged vascular barriers, which correlated with higher endothelial permeability.S. typhimurium could modify barrier properties of the ECs through the negative regulation of the Wnt/β-catenin signaling pathway. Indeed, we found that β-catenin activation was reduced upon infection in vitro. Consistently, Salmonella was incapable to modify ECs permeability and to spread systemically in mice where β-catenin was constitutively activated by genetic means in vascular ECs. Furthermore, we demonstrated that Salmonella pathogenicity island (spi)-2 was involved in the regulation of Wnt/β-catenin signaling pathway.