FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis.

Sorribas, Marcel; Jakob, Manuel O.; Yilmaz, Bahtiyar; Li, Hai; Stutz, David; Noser, Yannik; De Gottardi, Andrea; Moghadamrad, Sheida; Hassan, Mohsin; Albillos, Agustin; Francés, Ruben; Juanola, Oriol; Spadoni, Ilaria; Rescigno, Maria; Wiest, Reiner (2019). FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis. Journal of hepatology, 71(6), pp. 1126-1140. 10.1016/j.jhep.2019.06.017

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

UniBE Contributor:

Sorribas Olivera, Marcel; Jakob, Manuel; Yilmaz, Bahtiyar; Li, Hai; De Gottardi, Andrea; Moghadamrad, Sheida; Hassan, Mohsin and Wiest, Reiner

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1600-0641

Language:

English

Submitter:

Thi Thao Anh Pham

Date Deposited:

17 Jan 2020 15:45

Last Modified:

17 Jan 2020 15:45

Publisher DOI:

10.1016/j.jhep.2019.06.017

PubMed ID:

31295531

Uncontrolled Keywords:

FXR Gut-liver axis Gut-vascular barrier Intestinal permeability Liver cirrhosis Mucus Portal hypertension

BORIS DOI:

10.7892/boris.137309

URI:

https://boris.unibe.ch/id/eprint/137309

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