title: Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats.
abstract: OBJECTIVE
  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.
authors.affiliation: Laboratorio de Enfermedades del Sistema Inmune, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Úbeda
authors.affiliation: Laboratorio de Enfermedades del Sistema Inmune, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Margaret
authors.initials: M
authors.lastname: Lario
authors.affiliation: Laboratorio de Enfermedades del Sistema Inmune, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Muñoz
authors.affiliation: Laboratorio de Enfermedades del Sistema Inmune, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: María-José
authors.initials: MJ
authors.lastname: Borrero
authors.affiliation: Unidad de Biomarcadores y Dianas Terapéuticas, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.
authors.forename: Macarena
authors.initials: M
authors.lastname: Rodríguez-Serrano
authors.affiliation: Servicio de Microbiología, Hospital Universitario Ramón y Cajal, IRYCIS, Red Española de Investigación en Enfermedades Infecciosas (REIPI), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ana-María
authors.initials: AM
authors.lastname: Sánchez-Díaz
authors.affiliation: Servicio de Microbiología, Hospital Universitario Ramón y Cajal, IRYCIS, Red Española de Investigación en Enfermedades Infecciosas (REIPI), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Del Campo
authors.affiliation: Departamento de Microbiología, Universidad de Alcalá, Alcalá de Henares, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Lledó
authors.affiliation: Servicio de Bioquímica Clínica, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Pastor
authors.affiliation: Unidad de Biomarcadores y Dianas Terapéuticas, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: García-Bermejo
authors.affiliation: Laboratorio de Enfermedades del Sistema Inmune, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Servicio de Enfermedades del Sistema Inmune y Oncología, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Díaz
authors.affiliation: Laboratorio de Enfermedades del Sistema Inmune, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Servicio de Enfermedades del Sistema Inmune y Oncología, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain.
authors.forename: Melchor
authors.initials: M
authors.lastname: Álvarez-Mon
authors.affiliation: Laboratorio de Enfermedades del Sistema Inmune, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain. Electronic address: agustin.albillos@uah.es.
authors.forename: Agustín
authors.initials: A
authors.lastname: Albillos
mesh_terms: D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; C464660:obeticholic acid; D002635:Chenodeoxycholic Acid
keywords: Ascites; Dysbiosis; Inflammation; Permeability