Marcel Sorribas1, Manuel O Jakob2, Bahtiyar Yilmaz1, Hai Li1, David Stutz2, Yannik Noser2, Andrea de Gottardi2, Sheida Moghadamrad1, Moshin Hassan1, Agustin Albillos3, Ruben Francés4, Oriol Juanola4, Ilaria Spadoni5, Maria Rescigno6, Reiner Wiest7. 1. Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland. 2. Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland. 3. Department of Gastroenterology, Hospital Universitario Ramón y Cajal, IRYCIS, University of Alcalá, CIBEREHD, Madrid, Spain. 4. Hepatic and Intestinal Immunobiology Group, Universidad Miguel Hernández-CIBERehd, San Juan, Spain. 5. Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini, 20090 Pieve Emanuele, MI, Italy. 6. Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini, 20090 Pieve Emanuele, MI, Italy; Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, MI, Italy. 7. Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland; Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland. Electronic address: Reiner.wiest@insel.ch.
Abstract
BACKGROUND & AIMS: Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed 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. MATERIALS: Cirrhosis was induced in mouse models using bile-duct ligation (BDL) and CCl4. Pre-hepatic portal-hypertension was induced by partial portal vein ligation (PPVL). Intestinal permeability was compared in these mice after GFP-Escherichia coli or different sized FITC-dextrans were injected into the intestine. RESULTS: Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl4-induced cirrhotic mice demonstrate pathological translocation, which is not altered by prior thoracic-duct ligation. The mucus layer is reduced in thickness, with loss of goblet cells and Muc2-staining and expression in cirrhotic but not PPVL mice. These changes are associated with bacterial overgrowth in the 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 slightly altered in PPVL mice. This pathological endothelial permeability and accessibility in cirrhotic mice is associated with augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB, whereas both FXR-agonists ameliorate gut to liver translocation of GFP-E. coli. CONCLUSIONS: 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 to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route. LAY SUMMARY: For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis.
BACKGROUND & AIMS: Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed 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. MATERIALS: Cirrhosis was induced in mouse models using bile-duct ligation (BDL) and CCl4. Pre-hepatic portal-hypertension was induced by partial portal vein ligation (PPVL). Intestinal permeability was compared in these mice after GFP-Escherichia coli or different sized FITC-dextrans were injected into the intestine. RESULTS: Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl4-induced cirrhotic mice demonstrate pathological translocation, which is not altered by prior thoracic-duct ligation. The mucus layer is reduced in thickness, with loss of goblet cells and Muc2-staining and expression in cirrhotic but not PPVL mice. These changes are associated with bacterial overgrowth in the 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 slightly altered in PPVL mice. This pathological endothelial permeability and accessibility in cirrhotic mice is associated with augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB, whereas both FXR-agonists ameliorate gut to liver translocation of GFP-E. coli. CONCLUSIONS: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 to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route. LAY SUMMARY: For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis.
Authors: Gabriella V Hernandez; Victoria A Smith; Megan Melnyk; Matthew A Burd; Kimberly A Sprayberry; Mark S Edwards; Daniel G Peterson; Darin C Bennet; Rob K Fanter; Daniel A Columbus; Juan P Steibel; Hunter Glanz; Chad Immoos; Margaret S Rice; Tasha M Santiago-Rodriguez; Jason Blank; Jennifer J VanderKelen; Christopher L Kitts; Brian D Piccolo; Michael R La Frano; Douglas G Burrin; Magdalena Maj; Rodrigo Manjarin Journal: Am J Physiol Gastrointest Liver Physiol Date: 2020-01-31 Impact factor: 4.052
Authors: Ta-Chiang Liu; Justin T Kern; Umang Jain; Naomi M Sonnek; Shanshan Xiong; Katherine F Simpson; Kelli L VanDussen; Emma S Winkler; Talin Haritunians; Atika Malique; Qiuhe Lu; Yo Sasaki; Chad Storer; Michael S Diamond; Richard D Head; Dermot P B McGovern; Thaddeus S Stappenbeck Journal: Cell Host Microbe Date: 2021-05-18 Impact factor: 31.316