Gene expression profile of endothelial cells during perturbation of the gut vascular barrier

Abstract

It has been widely demonstrated that tolerance against gut microbiota is compartmentalized to mucosal sites where microbes mostly reside. How the commensal bacteria are excluded from the entrance into the blood stream via intestinal capillaries that are located beneath the gut epithelium was not clear. We recently described the existence of a new anatomical structure, the 'gut vascular barrier' (GVB), both in murine and human intestines that plays a fundamental role in avoiding indiscriminate trafficking of bacteria from the gut into the blood circulation. The vascular barrier integrity could be altered by Salmonella typhimurium, a pathogen capable of systemic dissemination, through the modulation of the Wnt/b-catenin signaling pathway. Here we have analyzed the differences in gut endothelial gene expression profiles during Salmonella infection and have identified some interesting characteristics of endothelial to mesenchymal transition. These findings add new insights in the gut-liver axis. The intestine is continuously exposed to a huge amount of foreign antigens, mostly food proteins and commensal microorganisms. These harmless antigens induce oral tolerance, which is however different when considering gut bacteria or food antigens. Tolerance to food proteins affects both local and systemic immune responses 1 indeed fed soluble antigens can gain access to the lymphatics to reach the mesenteric lymph nodes (mLN) 2 and the blood stream to reach the liver 3 where oral tolerance is established. By contrast, gut microbes are confined at mucosal sites by the mLNs that function like a firewall avoiding the spreading of intestinal microflora through the thoracic duct into the blood circulation. [4][5][6] Therefore at steady state the systemic immune system is left ignorant to the microbiota. Only during intestinal pathology bacteria can reach the liver that acts as a firewall preventing the bacteria from spreading to other systemic sites. 7 How the microbiota recirculates through the lymphatics has been widely studied, while how intestinal bacteria are excluded from the blood circulation was completely unexplored, even though it is known that intestinal capillaries are located just underneath the epithelial layer whereas the lymphatics are much deeper in the lamina propria.In our recent work, we hypothesized the existence of a barrier at the endothelial level, the 'gut vascular barrier' (GVB), 8 that similarly to the blood brain barrier (BBB) is able to control the type of antigens that can translocate into the blood stream and that is not permissive to bacterial penetration.Drawing a parallelism between the well-known BBB and the newly identified GVB many similarities can be found. Both are able to avoid the indiscriminate movement of molecules, cells and bacteria from blood to the brain parenchyma in the BBB and from the intestinal lumen into the blood circulation in the case of the GVB.

Berberine Exerts a Protective Effect on Gut-Vascular Barrier via the Modulation of the Wnt/Beta-Catenin Signaling Pathway During Sepsis

“…Recently, Spadoni et al have confirmed the existence of GVB with the morphological and functional characteristics resembling to the blood brain barrier in murine and human intestines that plays a key role in avoiding indiscriminate trafficking of bacteria from the gut into bloodstream, and the vascular barrier integrity can be altered by Salmonella typhimurium via the modulation of the Wnt/beta-catenin pathway [34]. Thus, the alteration of gut capillary influences GVB [2]. The murine CLP procedure is a classical model of sepsis, which may adversely influence GVB.…”

“…Spadoni et al have demonstrated that Salmonella typhimurium is capable of inhibiting the activation of Wnt/beta-catenin pathway [2,34]. This signaling has been reported elsewhere to exert the anti-inflammatory or pro-inflammatory properties [35][36][37][38][39].…”

“…Conversely, the survival rate of rats in berberine groups (II-III) reached to 100%. It is known that Wnt/beta-catenin signaling plays a positive role in the maintenance of GVB integrity [2]. Thus, ICG001 was employed to repress Wnt/beta-catenin signaling.…”

“…In the intestine, the vascular permeability is strictly regulated and thus vascular endothelial layer possesses barrier properties. Therefore, the impairment of GVB plays a key role in touching off bacterial and toxin translocation [2].…”

“…Under physiological condition, lipopolysaccharide from gram negative flora is absorbed in minute quantities [1]. However, during severe intestinal pathology with a result of perturbation of the gut-vascular barrier (GVB), a large amount of bacteria and toxins can translocate into the bloodstream and reach the distant organs such as the liver [2].…”