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.

Isoproterenol Disrupts Intestinal Barriers Activating Gut-Liver-Axis: Effects on Intestinal Mucus and Vascular Barrier as Entry Sites

“…Here we observed likewise an increased PV1-abundance in ileal capillaries in isoproterenol-treated animals displaying a disrupted GVB. This is also in line with up-regulation of PV1 being associated with dysfunctional GVB observed in high-fed-diet induced non-alcoholic fatty liver disease steatohepatitis [43] and liver cirrhosis [44]. In fact, increased PV1 and extravasation of large-sized FITC-dextran in ileal capillaries of cirrhotic mice was demonstrated in conjunction with pathological accessibility of the microcirculation for FITC-dextran and even living bacteria then reaching the liver via the portal-venous circulation [44].…”

Influence of the gut microbiota on endometriosis: Potential role of chenodeoxycholic acid and its derivatives

“…After activation, FXR can inhibit the expression of the apical sodium-dependent bile acid transporter (ASBT) and increase the expression of two transporters, i.e., organic solute transporter α (OSTα) and β (OSTβ), to reduce the uptake of BA, promote the secretion of BA in basal cells and reduce the Frontiers in Pharmacology frontiersin.org concentration of BA in basal cells (Ding et al, 2015). Moreover, FXR is involved in intestinal immune regulation and intestinal mucosal barrier function, reduces inflammation and maintains the integrity of the intestinal epithelial barrier by regulating the degree of inflammation, maintaining the integrity and function of the intestinal wall barrier, and preventing bacterial translocation in the intestine (Gadaleta et al, 2010;Gadaleta et al, 2011a;Sorribas et al, 2019). Vavassori et al noticed that the expression of proinflammatory cytokine mRNA in the colon of FXR-deficient mice was increased (Vavassori et al, 2009).…”