Ongoing Projects

„b-adrenergic regulation of gut-vascular barrier (GVB): impact on gut-liver-axis and susceptibility for acute-on-chronic liver failure (ACLF) in cirrhotic mice”

Summary: Catecholamines are released from sympathetic nerve endings which densly innervate the gut with » 40% of total body norepinephrine in healthy conditions being of mesenteric origin. In liver cirrhosis this splanchnic output is increased early on with additional excessive amplification in acute-on-chronic liver failure (ACLF). ACLF is defined as decompensated cirrhosis with associated organ failure carrying a very high risk of mortality. This syndrome is marked by elevated degrees of hepatic and systemic inflammation which has been proposed to be triggered by pathological bacterial translocation (PBT). PBT frequently occurs in advanced cirrhosis causing endotoxinemia and  spontaneous infections which are one of the most frequent causes of ACLF. We have shown previously that PBT in cirrhosis can fuel the “gut-liver-axis” with bacteria/l products directly via the portal-venous route independent of lymphatic translocation. This occurs via disruption of the so-called gut-vascular barrier (GVB) and thus, accessability for bacteria/l products having permeated from the gut lumen into the lamina propria. Key for regulation of endothelial permeability and thus GVB, are cell-cell-junctions. The vascular endothelial (VE)- cadherin/b-catenin-complex as well-known adherens junctions do seal the paracellular route of permeation. b-catenin-silencing increases albumin-extravasation and gain-of-function mice with constitutively active β-catenin in endothelial cells are protected from GVB damage. However, the role of catecholamines for the VE-cadherin/b-catenin-complex and GVB-function are not known. 

              Prelimenary data of us indicate that chronic b-adrenergic splanchnic hyperstimulation i) in-vivo disrupts the GVB enabling pathological translocation from the gut via portal venous circulation to the liver and ii) in-vitro down-regulates VE-cadherin in perfused 3D microvessels. Therefore, our hypothesis is that chronic b-adrenergic hyperstimulation i) disintegrates the GVB with ii) this being aggravated by LPS and thus iii) increases susceptibility of cirrhotic mice (with known chronic b-adrenergic hyperstimulation) for LPS/Endotoxin-induced ACLF iii) via down-regulation of b-catenin/VE-cadherin and associated boost of PBT along the gut-liver-axis hitting the liver.

        This will be investigated in mice a) without liver disease with and without chronic splanchnic b-adrenergic hyperstimulation as well as b) with experimental cirrhosis with and without LPS-induced ACLF being tested in conditions of non-selective beta-blockade, splanchnic specific sympathectomy and gain-of-function for b-catenin. Methods applied include i) a novel in-vivo bioassay for portal-venous gut-liver-bacterial translocation ii) in-vivo utilization of confocal laser endomicroscopy visualizing and quantifying vascular extravasation and interaction of fluorescent-labeled agents at the endothelial barrier and iii) in-vitro assessment in cell-culture, - based 3D round section microvessels at physiological flow including immunostaing and gene expression analysis. By the proposed phenomena catecholamines could support the “gut as motor” of ACLF and multi-organ-failure in cirrhotic patients via PBT. However, this concept could also contribute to harmful events in healthy individuals during events associated with known splanchnic b-adrenergic such as stress, shock or high-fat-diet. Derived data could thus, help to establish pharmacological measures to prevent PBT in those conditions of SNS-hyperactivity protecting the liver and thus, the host.