Intestinal mucus and gut-vascular barrier: FxR-modulated entry sites for pathological bacterial translocation in liver cirrhosis
Intestinal mucus and gut-vascular barrier: FxR-modulated entry sites for pathological bacterial translocation in liver cirrhosis
Abstract Background and aimsPathological bacterial translocation (PBT) in liver cirrhosis (LC) is the hallmark for spontaneous bacterial infections increasing mortality several-fold. Factors known to contribute to PBT in LC are among others an increased intestinal permeability of which however, the mucus layer has not been addressed so far in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined but we hypothesize that the recently described gut vascular barrier (GVB) is impaired in experimental portal hypertension leading to increased accessibility of the vascular compartment for translocating bacteria. ResultsHealthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-Escherichia coli from the small intestine to the liver whereas bile-duct-ligated (BDL) and CCl4-induced cirrhotic mice demonstrate pathological translocation which is not altered by prior thoracic-duct ligation. Mucus layer is reduced in thickness with loss of goblet-cells and Muc2-staining and expression in cirrhotic but not PPVL-mice associated with bacterial overgrowth in inner mucus layer and pathological translocation of GFP-E.coli through the ileal epithelium. GVB is profoundly altered in BDL and CCl4-mice with Ileal extravasation of large-sized 150 kDa-FITC-dextran but only minor in PPVL-mice. This pathological endothelial permeability and accessibility in cirrhotic mice associates with an augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB whereas both FXR-agonists ameliorate gut-liver-translocation of GFP-E.coli. ConclusionsLiver cirrhosis but not portal hypertension per se grossly impairs the endothelial and muco-epithelial barriers promoting PBT to the portal-venous circulation. Both barriers appear FXR-modulated with –agonists reducing PBT via the portal-venous route.
Li H.、Noser Y.、Albillos A.、Juanola O.、Spadoni I.、Rescigno M.、Yilmaz B.、Hassan M.、Wiest R.、Moghadamrad S.、Jakob M. O.、Stutz D.、Sorribas M.、Franc¨|s R.、de Gottardi A.
Maurice M¨1ller Laboratories, Department for Biomedical Research, University of BernDepartment of Visceral Surgery and Medicine, Bern University Hospital, University of BernDepartment of Gastroenterology, Hospital Universitario Ram¨?n y CajalHepatic and Intestinal Immunobiology Group, Universidad Miguel Hern¨￠ndez-CIBERehdHumanitas University, Department of Biomedical SciencesHumanitas University, Department of Biomedical Sciences||Humanitas Clinical and Research CenterMaurice M¨1ller Laboratories, Department for Biomedical Research, University of BernMaurice M¨1ller Laboratories, Department for Biomedical Research, University of BernMaurice M¨1ller Laboratories, Department for Biomedical Research, University of Bern||Department of Visceral Surgery and Medicine, Bern University Hospital, University of BernMaurice M¨1ller Laboratories, Department for Biomedical Research, University of BernDepartment of Visceral Surgery and Medicine, Bern University Hospital, University of BernDepartment of Visceral Surgery and Medicine, Bern University Hospital, University of BernMaurice M¨1ller Laboratories, Department for Biomedical Research, University of BernHepatic and Intestinal Immunobiology Group, Universidad Miguel Hern¨￠ndez-CIBERehdDepartment of Visceral Surgery and Medicine, Bern University Hospital, University of Bern
基础医学内科学生理学
portal hypertensionliver cirrhosisgut-liver-axisgut-vascular barrierintestinal permeabilitymucusFXR
Li H.,Noser Y.,Albillos A.,Juanola O.,Spadoni I.,Rescigno M.,Yilmaz B.,Hassan M.,Wiest R.,Moghadamrad S.,Jakob M. O.,Stutz D.,Sorribas M.,Franc¨|s R.,de Gottardi A..Intestinal mucus and gut-vascular barrier: FxR-modulated entry sites for pathological bacterial translocation in liver cirrhosis[EB/OL].(2025-03-28)[2025-05-09].https://www.biorxiv.org/content/10.1101/690057.点此复制
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