Obeticholic acid reduces bacterial traslocation, restores intestinal barrier and inhibits inflammation in cirrhotic rats
Authors
Álvarez De Mon Soto, Melchor; Úbeda Cantera, María del Pilar; Lario Martínez, Margaret; Muñoz Zamarrón, María Leticia; Borrero Corte, María José; [et al.]Identifiers
Permanent link (URI): http://hdl.handle.net/10017/61049DOI: 10.1016/j.jhep.2015.12.010
ISSN: 0168-8278
Date
2016-05Affiliation
Universidad de Alcalá. Departamento de Medicina; Universidad de Alcalá. Departamento de Medicina y Especialidades Médicas. Unidad docente Medicina; Universidad de Alcalá. Departamento de Biomedicina y BiotecnologíaFunders
Instituto de Salud Carlos III
Fondo Europeo de Desarrollo Regional
Comunidad de Madrid
Bibliographic citation
Journal of Hepatology, 2016, v. 64, n. 5, p. 1049-1057
Keywords
Ascites
Dysbiosis
Inflammation
Permeability
Description / Notes
9 p.
Project
info:eu-repo/grantAgreement/ISCIII//PS09%00485/ES//
info:eu-repo/grantAgreement/ISCIII//PI14%00876/ES//
info:eu-repo/grantAgreement/ISCIII//PI051871/ES//
info:eu-repo/grantAgreement/ISCIII//PI14%01935/ES//
info:eu-repo/grantAgreement/CAM//MITIC-CM/ES//
info:eu-repo/grantAgreement/CAM//S-BIO-0189/2006/ES//
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/acceptedVersion
Rights
© 2016 European Association for the Study of the Liver
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
Abstract
Background & aims: In advanced cirrhosis, gut bacterial translocation is the consequence of intestinal barrier disruption and leads to bacterial infection. Bile acid abnormalities in cirrhosis could play a role in the integrity of the intestinal barrier and the control of microbiota, mainly through the farnesoid X receptor. We investigated the long-term effects of the farnesoid X receptor agonist, obeticholic acid, on gut bacterial translocation, intestinal microbiota composition, barrier integrity and inflammation in rats with CCl4-induced cirrhosis with ascites. Methods: Cirrhotic rats received a 2-week course of obeticholic acid or vehicle starting once ascites developed. We then determined: bacterial translocation by mesenteric lymph node culture, ileum expression of antimicrobial peptides and tight junction proteins by qPCR, fecal albumin loss, enteric bacterial load and microbiota composition by qPCR and pyrosequencing of ileum mucosa-attached contents, and intestinal inflammation by cytometry of the inflammatory infiltrate. Results: Obeticholic acid reduced bacterial translocation from 78.3% to 33.3% (p<0.01) and upregulated the expression of the farnesoid X receptor-associated gene small heterodimer partner. Treatment improved ileum expression of antimicrobial peptides, angiogenin-1 and alpha-5-defensin, tight junction proteins zonulin-1 and occludin, and reduced fecal albumin loss and liver fibrosis. Enteric bacterial load normalized, and the distinctive mucosal microbiota of cirrhosis was reduced. Gut immune cell infiltration was reduced and inflammatory cytokine and Toll-like receptor 4 expression normalized. Conclusions: In ascitic cirrhotic rats, obeticholic acid reduces gut bacterial translocation via several complementary mechanisms at the intestinal level. This agent could be used as an alternative to antibiotics to prevent bacterial infection in cirrhosis.
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