A gut-vascular barrier controls the systemic dissemination of bacteria

Spadoni, Ilaria; Zagato, Elena; Bertocchi, Alice; Paolinelli, Roberta; Hot, Edina; Sabatino, Antonio Di; Caprioli, Flavio; Bottiglieri, Luca; Oldani, Amanda; Viale, Giuseppe; Penna, Giuseppe; Dejana, Elisabetta; Rescigno, María

doi:10.1126/science.aad0135

Cited by 458 publications

(440 citation statements)

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“…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].…”

Section: Discussionmentioning

confidence: 94%

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

Yuan

Zuo

et al. 2018

Cell Physiol Biochem

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Background/Aims: The gut-vascular barrier (GVB) has recently been depicted to dampen the bacterial invasion of the bloodstream. The intestinal mucosa is a tissue rich in small vessels including capillaries. In this study, the protective effect of berberine on GVB in small bowel mucosa was investigated. Methods: The rat cecal ligation and puncture (CLP) sepsis model was employed to evaluate the effect of berberine on serum endotoxin level and intestinal vascular permeability to Evans blue in vivo. The rat intestinal microvascular endothelial cells (RIMECs) treated by lipopolysaccharide (LPS) were used to assess the effect of berberine on endothelial permeability to FITC-labeled dextran, transendothelial electrical resistance (TEER), and tight junction (TJ) and adherens junction (AJ) expression in vitro. Results: After 24-hr CLP operation the serum endotoxin concentration and gut vascular permeability were significantly increased, while berberine markedly reduced endotoxin level and vascular leakage. In vitro, LPS not only dramatically increased endothelial permeability of RIMECs to FITC-dextran, but also decreased TEER and inhibited claudin-12, beta-catenin and VE-cadherin expression. These effects of LPS were antagonized by berberine. In addition, our in vivo and vitro studies also confirmed that the effect of berberine on GVB could be partially abolished by ICG001. Conclusion: Berberine exerted a protective effect on GVB function in sepsis, which was strictly related to the modulation of the Wnt/beta-catenin signaling pathway.

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Section: Discussionmentioning

confidence: 94%

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

Yuan

Zuo

et al. 2018

Cell Physiol Biochem

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“…This may also be the case in humans [48]. In mice and humans, commensal gut bacterial strains do not reach the liver via the portal circulation as systemic dissemination is strictly controlled by the gut-vascular barrier [50]. Hence, in mice, in the absence of intestinal inflammation or liver disease, no culturable bacteria were found in the liver, but nevertheless, significant amounts of radiolabelled bacterial products reach the liver at day 5 after reversible colonization with E. coli HA107 [51,52].…”

Section: Nutritional Influences On the Adult Gut Microbiota Regulatimentioning

confidence: 99%

The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

2018

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Commensal gut microbiota have recently been implicated in cardiovascular disease (CVD) and cerebrovascular disease. Atherosclerotic plaque formation depends on the colonization status of the host. In addition to host nutrition and the related microbiota-dependent metabolic changes, activation of innate immune pathways triggers the development of atherosclerosis and supports arterial thrombosis. Gnotobiotic mouse models have uncovered that activation of Toll-like receptor-2 by gut microbial ligands supports von Willebrand factor-integrin mediated platelet deposition to the site of vascular injury. Depending on nutritional factors, the microbiota-derived choline-metabolite trimethylamine Noxide (TMAO) increases atherosclerotic plaque size, triggers prothrombotic platelet function and promotes arterial thrombus growth. Hence, the composition of the commensal microbiota is an emerging risk factor for CVD. Here, we provide an overview on microbiota-dependent pathomechanisms that drive the development of CVD and arterial thrombosis.Keywords: Arterial thrombosis r Atherosclerosis r Cardiovascular disease r Microbiota r Toll-like receptors IntroductionAt birth, our body surfaces are colonized by microbial communities (microbiota), representing one of the most densely colonized microbial ecosystems [1]. This process is strongly influenced by genetic, nutritional, and environmental factors [2]. The commensal microbiota constitutes a permanent inflammatory stimulus [3], which is kept in check by the host's immune responses [4]. The microbiota can be viewed as an organ that impacts host physiology [5,6]. Changes in gut microbiota composition were associated with intestinal diseases (e.g. inflammatory bowel disease, colon cancer) and cardiometabolic disease states, such as diet-induced obesity, type 2 diabetes, atherosclerosis, and arterial thrombosis [7]. The results from recent experimental and clinical studies have led to the assumption that Correspondence: Christoph Reinhardt e-mail: Christoph.Reinhardt@unimedizin-mainz.de molecules synthesized by the intestinal microbiota are involved in the development of cardiovascular disease (CVD) [8] and may increase the risk of arterial thrombosis [9, 10] as well as the outcome of ischemic stroke [11]. Experimental evidence from germ-free mouse studies and metagenomics analyses have associated the gut microbiota with obesity [12][13][14][15], type 2 diabetes [3, 16, 17], stroke [11, 18], and CVD [8, 9, 19]. Therefore, targeting the composition and metabolic function of the intestinal microbiota may represent a therapeutic option that in the future may allow prevention and treatment of cardiometabolic diseases [20].Here, we provide a comprehensive overview on the emerging link between gut microbiota and CVD. We delineate the contribution of this complex microbial ecosystem to metabolic inflammation and its impact on host metabolism. The main focus of this review is to highlight how gut microbiota may contribute to the development of CVD, cerebrovascular disease and arterial thromb...

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“…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.…”

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confidence: 99%

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

et al. 2016

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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.

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A gut-vascular barrier controls the systemic dissemination of bacteria

Cited by 458 publications

References 27 publications

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

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

The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

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

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