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Beyond Intestinal Barrier: The Blood Endothelium as a Second Wall of Defense Against Bacterial Invasion
Gastroenterology 2016;-:1–3
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SELECTED SUMMARIES Philip S. Schoenfeld, Section Editor John Y. Kao, Section Editor STAFF OF CONTRIBUTORS Joseph Anderson, White River Junction, VT Johanna L. Chan, Houston, TX Matthew A. Ciorba, St. Louis, MO Massimo Colombo, Milan, Italy Gregory A. Cote, Charleston, SC Evan S. Dellon, Chapel Hill, NC Alex Ford, Leeds, United Kingdom Lauren B. Gerson, San Francisco, CA David S. Goldberg, Philadelphia, PA Samir Gupta, San Diego, CA
Reena Khanna, London, Ontario, Canada W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Uma Mahadevan, San Francisco, CA Baha Moshiree, Miami, FL Swati G. Patel, Aurora, CO Laurent Peyrin-Biroulet, Vandoeuvre-lès-Nancy, France Jesus Rivera-Nieves, San Diego, CA
Beyond Intestinal Barrier: The Blood Endothelium as a Second Wall of Defense Against Bacterial Invasion Spadoni I, Zagato E, Bertocchi A, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 2015;350:830–834. The human gut is home to millions of microbes, some of which are beneficial, and others harmful. Friend or foe, the access to the rest of the body of these bacteria must be prevented, to avoid severe pathologic consequences. The existence of an intestinal epithelial barrier provides both a physical wall against microbial intrusion, as well as a biochemical one, characterized by antimicrobial proteins (Eur Rev Med Pharmacol Sci 2015;19:1077–1085). However, commensal bacteria that for any reason were able to enter the body have never been found in the liver, but rather tended to end up in the nearby lymph nodes (Science 2004;303:1662–1665; Sci Transl Med 2014;6:237ra66237ra66). Starting from this evidence, Spadoni et al raised the question that there may be something else other than just the epithelial barrier, and demonstrated for the first time the existence of a gut–vascular barrier (GVB), both in human and mice. Taking advantage of immunofluorescence studies on the murine intestine, and of mice intravenously injected with fluorescein isothiocyanate–dextran of different molecular sizes, they discovered that the GVB shares common features with the blood–brain barrier (BBB), which separates circulating blood from the brain’s extracellular fluids (Neurobiol Dis 2010;37:13–25; Nat Rev Neurosci 2006;7:41–53). In fact, as for the BBB, endothelial cells (ECs) of the GVB were characterized by intercellular tight junctions and adherens junctions. Tight junctions consisted of occludin, zonula occludens-1, cingulin, and junctional adhesion molecule-A, whereas adherens junctions were formed by vascular endothelial cadherin and b-catenin. Moreover, similarly to the BBB, in the gut vascular unit glial cells and pericytes are in close contact with intestinal vascular ECs; however, the GVB allows diffusion of molecules as large as 4 kDa, 8 times the maximal size observed for the BBB, and has a size exclusion of <70 kDa, thus
Sameer Saini, Ann Arbor, MI Ekihiro Seki, Los Angeles, CA Amit Singal, Dallas, TX Ryan W. Stidham, Ann Arbor, MI Akbar Waljee, Ann Arbor, MI Sachin Wani, Aurora, CO Alastair J. M. Watson, Norwich, United Kingdom Yana Zavros, Cincinnati, OH
resulting in a second checkpoint for pathologic microorganisms. Although the GVB seems to prevent most bacteria from entering the bloodstream, certain pathogenic species are capable of establishing infections in the blood, liver, and other organs. Spadoni et al therefore investigated how Salmonella typhimurium, a Gram-negative bacterial pathogen that primarily infects the intestine, disseminating to the liver, gallbladder and spleen, manages to invade the body. The study revealed that Salmonella disrupts the GVB, allowing the spread of 70-kDa molecules to the blood, liver, and spleen in infected mice. The increased vascular permeability was confirmed by overexpression of the plasmalemma vesicle–associated protein-1, an EC permeability marker (Proc Natl Acad Sci U S A 2006;103:16770–5; Dev Cell 2012;23:1203–1218) on blood vessels of jejunum and ileum already 6 hours after Salmonella infection. The ability of this pathogen to invade the body systemically was not simply owing to its capacity to cross the epithelium, but rather resulted from an active interaction with the endothelial barrier. This was demonstrated infecting mice with a nonpathogenic strain of Escherichia coli modified to cross the epithelium and penetrate through the gut; the engineered bacterium was unable to reach neither the liver nor the spleen, thus suggesting the Salmonella ability to interplay with the gut endothelium. Interestingly, upon intestinal injection of 70-kDa fluorescein isothiocyanate–dextran in Salmonella-infected mice, the dye reached the liver but not the spleen nor any other tissues, suggesting dissemination through the portal circulation, and not through the lymphatics–thoracic duct. To dissect the mechanism(s) underlying Salmonella spreading through the GVB, Spadoni et al paid specific attention to the well-characterized Wnt/b-catenin signaling (Int J Dev Biol 2011;55:467–476). Through gene expression analysis, they demonstrated that in vitro infection of primary lung ECs with Salmonella dampened the transcript level of Axin2, a b-catenin target gene. Moreover, by infecting the cells with a Salmonella mutant strain, carrying a deletion for the pathogenicity island 2 (Spi2), they found that Axin2 expression was not affected. These results were supported by in vivo data showing that Salmonella Spi2 mutant was unable to disseminate neither in the liver nor in the spleen. Furthermore, in transgenic mice expressing a
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Selected Summaries
Gastroenterology Vol.
degradation-resistant form of b-catenin specifically in ECs, Salmonella could not alter gut vascular permeability, thus losing its ability to enter the portal circulation. Overall, these results indicated that Salmonella disseminate through the bloodstream by interfering with endothelial b-catenin activation via a Spi2-mediated mechanism. Ex vivo organotypic cultures of human colon and ileum revealed the GVB to be altered, upon infection with Salmonella, indicating this vascular unit to be likely functional and susceptible to pathogenic antigens also in humans. In consideration of the portal circulation, which links the gut to the liver, the authors concluded by questioning whether disruption of the GVB might lead to liver damage. To verify this hypothesis, they correlated plasmalemma vesicle–associated protein-1 with serum levels of alanine transaminase (ALT), a marker of liver damage, in celiac disease patients in whom no epithelial barrier defects were observed and other causes of liver damage were excluded. Data showed that patients with high ALT levels displayed increased expression of plasmalemma vesicle–associated protein-1 in the gut, suggesting that endothelial barrier alterations may be responsible for liver damage. Of note, GVB disruption did not seem to be a secondary phenomenon to liver damage. In fact, mice in which liver inflammation has been induced by concanavalin A treatment, did not present any endothelial barrier alterations. Comment. The vascular endothelium lining the inner surface of blood vessels serves as the first interface for circulating blood components to interact with cells of the vascular wall and surrounding extravascular tissues. In addition to regulating blood delivery and perfusion, a major function of vascular endothelia, is to provide a semipermeable barrier that controls blood–tissue exchange of fluids, nutrients, and metabolic wastes while preventing pathogens or harmful materials in the circulation from entering into tissues. All endothelial barriers share several common features. Anatomically, the structural components responsible for endothelial permeability include tight junctions, adherens junctions, junctional adhesion molecules, and focal adhesions. However, with different functional demands of site and condition, including different levels of exposure to pathogens and exogenous agents, the endothelium becomes extremely heterogeneous. Continuous endothelium is, for example, characteristic of brain, lung, retina, and muscular capillaries, and although ECs in brain and lung exhibit close junctional apposition to one another and a tight permeability barrier to fluid and solutes (ie, the BBB and the lung–endothelial barrier), fenestrated endothelium is found in endocrine glands and the kidney, thus facilitating selective permeability required for efficient secretion and filtering (Adv Mol Cell Biol 2005;35:277–310). ECs are also actively involved in host responses to infectious agents (J Immunol 2004;172:5056–5062; J Immunol 2003;170:5956–5964). Human bacterial pathogens that colonize and sometimes breach the skin or the mucosal epithelia are in fact a cause of blood-borne infections; however, what determines antigen access to the bloodstream remains unknown.
-,
No.
-
In the study, Spadoni et al defined for the first time the existence of a distinct vascular barrier (GVB) in the gut, which seems analogous to that in the brain and is present in both mice and humans. Interestingly, the GVB prevents the translocation of large molecules from the gut lumen, thus avoiding invasion of luminal bacteria into the blood circulation and representing a second line of defense after the mucosal barrier. Nevertheless, the most intriguing finding is that a pathogen such as S typhimurium is able to disrupt the murine GVB, thus allowing the translocation of large molecules, as well as spreading of the bacterium itself to the blood, liver, and spleen of infected animals. Of note, the ability of S typhimurium to cross the GVB depends on its capacity to impair Wnt/b-catenin signaling in the endothelium, via the bacterium’s pathogenicity island (spi)-2-encoded type III secretion system, which transfer virulent proteins into the host cells (Nat Rev Microbiol 2008;6:53–66; Microbiology 2012;158:1147–1161). This is interesting, because the canonical Wnt pathway plays a role in the development as well as in the integrity of the BBB (J Cell Biol 2008;183:409–417). What the authors propose is an elegant example of how bacteria establish intimate interactions with intestinal ECs, enabling them to invade, cross, and even disrupt the endothelial barrier, as already shown for other pathogens in different organs, such as Bacillus anthracis, Chlamydia pneumoniae, and Staphylococcus aureus (Nat Rev 2010;8:93–104). Nevertheless, it needs to be determined if and how S typhimurium modifies EC plasma membranes and junctions, directly interacts with the endothelium, promotes its uptake by ECs, and manipulates systemic host innate and adaptive immune responses. It also remains to be established whether the b-catenin signaling is a direct or indirect target of S typhimurium for its in vivo spreading. Additionally, it would be interesting to assess whether other pathogens beside S typhimurium are able to directly or indirectly interact with the GVB to promote their systemic dissemination. There is accumulating evidence that nonimmune mucosal cells such as ECs respond to invading enteric bacteria. ECs residing in mucosal barriers are in fact capable of detecting both extracellular and intracellular microbial invaders by antigen-specific receptor combinations (eg, Toll-like receptor heterodimers) and activation of NOD family proteins (J Clin Invest 2009;119:1921–1930; Thromb Haemost 2009;102:1103–1109). For example, human intestinal ECs have been found to rapidly respond to stimulation with the Toll-like receptor agonists lipopolysaccharide from E coli (J Immunol 2003;170:5956–5964) and flagellin from Salmonella (J Immunol 2004;172: 5056–5062) by expression of proinflammatory effector molecules, including endothelial intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. However, how and if ECs of the GVB react against bacterial pathogens requires further elucidation. Spadoni et al defined and showed not only a GVB that prevents intestinal microbes from accessing the liver and the bloodstream in mice, but also tried to elucidate whether disruption of this GVB in the human gut may lead to liver
DIS 5.4.0 DTD YGAST60436_proof 28 April 2016 4:51 pm ce
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2016
Selected Summaries
damage. Data obtained by the authors from patients with celiac disease whose elevated serum transaminases correlated with increased vascular permeability, independent of an epithelial barrier defect, indicate that GVB dismantling may actually be responsible for liver damage in these patients (reference?). These observations, along with the notion that breaches in the GVB may disrupt systemic immune homeostasis and promote liver damage in patients with autoimmune and intestinal inflammatory disorders, require further investigation in different pathologic settings, including patients with liver diseases, or patients where the epithelial layer is compromised, A pathologic condition such as that of inflammatory bowel disease may be a good example to explain the existence of a GVB. Inflammatory bowel diseases are in fact not only frequently associated with liver damage (Inflamm Bowel Dis 2010;16: 1598–1629), but its pathogenesis is closely correlated with epithelial barrier dysfunction (Inflamm Bowel Dis 2009;15:100–113). The fact that liver damage in inflammatory bowel disease is solely owing to drug-induced hepatotoxicity or fatty liver (Clin Med Insights Gastroenterol 2014;7:25–31), and that has never been associated with bacterial dissemination directly through the portal system, strongly suggests that a second line of defense against microbiota exists beyond the well-known mucosal barrier.
3
Understanding the GVB may provide new insights, not only into the interplay between bacteria and intestinal endothelium, but also into the regulation of the gut–liver axis, thus giving a new set of potential therapeutic treatments aimed at closing the vascular barrier to prevent systemic infection. FEDERICA UNGARO Department of Gastrointestinal Immunopathology Humanitas Clinical and Research Center and Department of Medical Biotechnologies and Translational Medicine University of Milan Milan, Italy CARLOTTA TACCONI Department of Gastrointestinal Immunopathology Humanitas Clinical and Research Center Milan, Italy SILVIA D’ALESSIO Department of Gastrointestinal Immunopathology Humanitas Clinical and Research Center and Department of Medical Biotechnologies and Translational Medicine University of Milan Milan, Italy
DIS 5.4.0 DTD YGAST60436_proof 28 April 2016 4:51 pm ce
Q2
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
SELECTED SUMMARIES Philip S. Schoenfeld, Section Editor John Y. Kao, Section Editor STAFF OF CONTRIBUTORS Joseph Anderson, White River Junction, VT Johanna L. Chan, Houston, TX Matthew A. Ciorba, St. Louis, MO Massimo Colombo, Milan, Italy Gregory A. Cote, Charleston, SC Evan S. Dellon, Chapel Hill, NC Alex Ford, Leeds, United Kingdom Lauren B. Gerson, San Francisco, CA David S. Goldberg, Philadelphia, PA Samir Gupta, San Diego, CA
Reena Khanna, London, Ontario, Canada W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Uma Mahadevan, San Francisco, CA Baha Moshiree, Miami, FL Swati G. Patel, Aurora, CO Laurent Peyrin-Biroulet, Vandoeuvre-lès-Nancy, France Jesus Rivera-Nieves, San Diego, CA
Beyond Intestinal Barrier: The Blood Endothelium as a Second Wall of Defense Against Bacterial Invasion Spadoni I, Zagato E, Bertocchi A, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 2015;350:830–834. The human gut is home to millions of microbes, some of which are beneficial, and others harmful. Friend or foe, the access to the rest of the body of these bacteria must be prevented, to avoid severe pathologic consequences. The existence of an intestinal epithelial barrier provides both a physical wall against microbial intrusion, as well as a biochemical one, characterized by antimicrobial proteins (Eur Rev Med Pharmacol Sci 2015;19:1077–1085). However, commensal bacteria that for any reason were able to enter the body have never been found in the liver, but rather tended to end up in the nearby lymph nodes (Science 2004;303:1662–1665; Sci Transl Med 2014;6:237ra66237ra66). Starting from this evidence, Spadoni et al raised the question that there may be something else other than just the epithelial barrier, and demonstrated for the first time the existence of a gut–vascular barrier (GVB), both in human and mice. Taking advantage of immunofluorescence studies on the murine intestine, and of mice intravenously injected with fluorescein isothiocyanate–dextran of different molecular sizes, they discovered that the GVB shares common features with the blood–brain barrier (BBB), which separates circulating blood from the brain’s extracellular fluids (Neurobiol Dis 2010;37:13–25; Nat Rev Neurosci 2006;7:41–53). In fact, as for the BBB, endothelial cells (ECs) of the GVB were characterized by intercellular tight junctions and adherens junctions. Tight junctions consisted of occludin, zonula occludens-1, cingulin, and junctional adhesion molecule-A, whereas adherens junctions were formed by vascular endothelial cadherin and b-catenin. Moreover, similarly to the BBB, in the gut vascular unit glial cells and pericytes are in close contact with intestinal vascular ECs; however, the GVB allows diffusion of molecules as large as 4 kDa, 8 times the maximal size observed for the BBB, and has a size exclusion of <70 kDa, thus
Sameer Saini, Ann Arbor, MI Ekihiro Seki, Los Angeles, CA Amit Singal, Dallas, TX Ryan W. Stidham, Ann Arbor, MI Akbar Waljee, Ann Arbor, MI Sachin Wani, Aurora, CO Alastair J. M. Watson, Norwich, United Kingdom Yana Zavros, Cincinnati, OH
resulting in a second checkpoint for pathologic microorganisms. Although the GVB seems to prevent most bacteria from entering the bloodstream, certain pathogenic species are capable of establishing infections in the blood, liver, and other organs. Spadoni et al therefore investigated how Salmonella typhimurium, a Gram-negative bacterial pathogen that primarily infects the intestine, disseminating to the liver, gallbladder and spleen, manages to invade the body. The study revealed that Salmonella disrupts the GVB, allowing the spread of 70-kDa molecules to the blood, liver, and spleen in infected mice. The increased vascular permeability was confirmed by overexpression of the plasmalemma vesicle–associated protein-1, an EC permeability marker (Proc Natl Acad Sci U S A 2006;103:16770–5; Dev Cell 2012;23:1203–1218) on blood vessels of jejunum and ileum already 6 hours after Salmonella infection. The ability of this pathogen to invade the body systemically was not simply owing to its capacity to cross the epithelium, but rather resulted from an active interaction with the endothelial barrier. This was demonstrated infecting mice with a nonpathogenic strain of Escherichia coli modified to cross the epithelium and penetrate through the gut; the engineered bacterium was unable to reach neither the liver nor the spleen, thus suggesting the Salmonella ability to interplay with the gut endothelium. Interestingly, upon intestinal injection of 70-kDa fluorescein isothiocyanate–dextran in Salmonella-infected mice, the dye reached the liver but not the spleen nor any other tissues, suggesting dissemination through the portal circulation, and not through the lymphatics–thoracic duct. To dissect the mechanism(s) underlying Salmonella spreading through the GVB, Spadoni et al paid specific attention to the well-characterized Wnt/b-catenin signaling (Int J Dev Biol 2011;55:467–476). Through gene expression analysis, they demonstrated that in vitro infection of primary lung ECs with Salmonella dampened the transcript level of Axin2, a b-catenin target gene. Moreover, by infecting the cells with a Salmonella mutant strain, carrying a deletion for the pathogenicity island 2 (Spi2), they found that Axin2 expression was not affected. These results were supported by in vivo data showing that Salmonella Spi2 mutant was unable to disseminate neither in the liver nor in the spleen. Furthermore, in transgenic mice expressing a
DIS 5.4.0 DTD YGAST60436_proof 28 April 2016 4:51 pm ce
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Selected Summaries
Gastroenterology Vol.
degradation-resistant form of b-catenin specifically in ECs, Salmonella could not alter gut vascular permeability, thus losing its ability to enter the portal circulation. Overall, these results indicated that Salmonella disseminate through the bloodstream by interfering with endothelial b-catenin activation via a Spi2-mediated mechanism. Ex vivo organotypic cultures of human colon and ileum revealed the GVB to be altered, upon infection with Salmonella, indicating this vascular unit to be likely functional and susceptible to pathogenic antigens also in humans. In consideration of the portal circulation, which links the gut to the liver, the authors concluded by questioning whether disruption of the GVB might lead to liver damage. To verify this hypothesis, they correlated plasmalemma vesicle–associated protein-1 with serum levels of alanine transaminase (ALT), a marker of liver damage, in celiac disease patients in whom no epithelial barrier defects were observed and other causes of liver damage were excluded. Data showed that patients with high ALT levels displayed increased expression of plasmalemma vesicle–associated protein-1 in the gut, suggesting that endothelial barrier alterations may be responsible for liver damage. Of note, GVB disruption did not seem to be a secondary phenomenon to liver damage. In fact, mice in which liver inflammation has been induced by concanavalin A treatment, did not present any endothelial barrier alterations. Comment. The vascular endothelium lining the inner surface of blood vessels serves as the first interface for circulating blood components to interact with cells of the vascular wall and surrounding extravascular tissues. In addition to regulating blood delivery and perfusion, a major function of vascular endothelia, is to provide a semipermeable barrier that controls blood–tissue exchange of fluids, nutrients, and metabolic wastes while preventing pathogens or harmful materials in the circulation from entering into tissues. All endothelial barriers share several common features. Anatomically, the structural components responsible for endothelial permeability include tight junctions, adherens junctions, junctional adhesion molecules, and focal adhesions. However, with different functional demands of site and condition, including different levels of exposure to pathogens and exogenous agents, the endothelium becomes extremely heterogeneous. Continuous endothelium is, for example, characteristic of brain, lung, retina, and muscular capillaries, and although ECs in brain and lung exhibit close junctional apposition to one another and a tight permeability barrier to fluid and solutes (ie, the BBB and the lung–endothelial barrier), fenestrated endothelium is found in endocrine glands and the kidney, thus facilitating selective permeability required for efficient secretion and filtering (Adv Mol Cell Biol 2005;35:277–310). ECs are also actively involved in host responses to infectious agents (J Immunol 2004;172:5056–5062; J Immunol 2003;170:5956–5964). Human bacterial pathogens that colonize and sometimes breach the skin or the mucosal epithelia are in fact a cause of blood-borne infections; however, what determines antigen access to the bloodstream remains unknown.
-,
No.
-
In the study, Spadoni et al defined for the first time the existence of a distinct vascular barrier (GVB) in the gut, which seems analogous to that in the brain and is present in both mice and humans. Interestingly, the GVB prevents the translocation of large molecules from the gut lumen, thus avoiding invasion of luminal bacteria into the blood circulation and representing a second line of defense after the mucosal barrier. Nevertheless, the most intriguing finding is that a pathogen such as S typhimurium is able to disrupt the murine GVB, thus allowing the translocation of large molecules, as well as spreading of the bacterium itself to the blood, liver, and spleen of infected animals. Of note, the ability of S typhimurium to cross the GVB depends on its capacity to impair Wnt/b-catenin signaling in the endothelium, via the bacterium’s pathogenicity island (spi)-2-encoded type III secretion system, which transfer virulent proteins into the host cells (Nat Rev Microbiol 2008;6:53–66; Microbiology 2012;158:1147–1161). This is interesting, because the canonical Wnt pathway plays a role in the development as well as in the integrity of the BBB (J Cell Biol 2008;183:409–417). What the authors propose is an elegant example of how bacteria establish intimate interactions with intestinal ECs, enabling them to invade, cross, and even disrupt the endothelial barrier, as already shown for other pathogens in different organs, such as Bacillus anthracis, Chlamydia pneumoniae, and Staphylococcus aureus (Nat Rev 2010;8:93–104). Nevertheless, it needs to be determined if and how S typhimurium modifies EC plasma membranes and junctions, directly interacts with the endothelium, promotes its uptake by ECs, and manipulates systemic host innate and adaptive immune responses. It also remains to be established whether the b-catenin signaling is a direct or indirect target of S typhimurium for its in vivo spreading. Additionally, it would be interesting to assess whether other pathogens beside S typhimurium are able to directly or indirectly interact with the GVB to promote their systemic dissemination. There is accumulating evidence that nonimmune mucosal cells such as ECs respond to invading enteric bacteria. ECs residing in mucosal barriers are in fact capable of detecting both extracellular and intracellular microbial invaders by antigen-specific receptor combinations (eg, Toll-like receptor heterodimers) and activation of NOD family proteins (J Clin Invest 2009;119:1921–1930; Thromb Haemost 2009;102:1103–1109). For example, human intestinal ECs have been found to rapidly respond to stimulation with the Toll-like receptor agonists lipopolysaccharide from E coli (J Immunol 2003;170:5956–5964) and flagellin from Salmonella (J Immunol 2004;172: 5056–5062) by expression of proinflammatory effector molecules, including endothelial intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. However, how and if ECs of the GVB react against bacterial pathogens requires further elucidation. Spadoni et al defined and showed not only a GVB that prevents intestinal microbes from accessing the liver and the bloodstream in mice, but also tried to elucidate whether disruption of this GVB in the human gut may lead to liver
DIS 5.4.0 DTD YGAST60436_proof 28 April 2016 4:51 pm ce
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Q1
2016
Selected Summaries
damage. Data obtained by the authors from patients with celiac disease whose elevated serum transaminases correlated with increased vascular permeability, independent of an epithelial barrier defect, indicate that GVB dismantling may actually be responsible for liver damage in these patients (reference?). These observations, along with the notion that breaches in the GVB may disrupt systemic immune homeostasis and promote liver damage in patients with autoimmune and intestinal inflammatory disorders, require further investigation in different pathologic settings, including patients with liver diseases, or patients where the epithelial layer is compromised, A pathologic condition such as that of inflammatory bowel disease may be a good example to explain the existence of a GVB. Inflammatory bowel diseases are in fact not only frequently associated with liver damage (Inflamm Bowel Dis 2010;16: 1598–1629), but its pathogenesis is closely correlated with epithelial barrier dysfunction (Inflamm Bowel Dis 2009;15:100–113). The fact that liver damage in inflammatory bowel disease is solely owing to drug-induced hepatotoxicity or fatty liver (Clin Med Insights Gastroenterol 2014;7:25–31), and that has never been associated with bacterial dissemination directly through the portal system, strongly suggests that a second line of defense against microbiota exists beyond the well-known mucosal barrier.
3
Understanding the GVB may provide new insights, not only into the interplay between bacteria and intestinal endothelium, but also into the regulation of the gut–liver axis, thus giving a new set of potential therapeutic treatments aimed at closing the vascular barrier to prevent systemic infection. FEDERICA UNGARO Department of Gastrointestinal Immunopathology Humanitas Clinical and Research Center and Department of Medical Biotechnologies and Translational Medicine University of Milan Milan, Italy CARLOTTA TACCONI Department of Gastrointestinal Immunopathology Humanitas Clinical and Research Center Milan, Italy SILVIA D’ALESSIO Department of Gastrointestinal Immunopathology Humanitas Clinical and Research Center and Department of Medical Biotechnologies and Translational Medicine University of Milan Milan, Italy
DIS 5.4.0 DTD YGAST60436_proof 28 April 2016 4:51 pm ce
Q2
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