Intestinal mucus and gut-vascular barrier: FxR-modulated entry sites for pathological bacterial translocation in liver cirrhosis
Authored by M. Sorribas, M. O. Jakob, B. Yilmaz, H. Li, D. Stutz, Y. Noser, A. de Gottardi, S. Moghadamrad, M. Hassan, A. Albillos, R. Francés, O. Juanola, I. Spadoni, M. Rescigno, and R. Wiest
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- bioRxiv
Abstract
Background and aims
Pathological 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.
Results
Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-Escherichia colifrom 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.colithrough 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.
Conclusions
Liver 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.
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