María Úbeda1, Margaret Lario1, Leticia Muñoz1, María-José Borrero1, Macarena Rodríguez-Serrano2, Ana-María Sánchez-Díaz3, Rosa Del Campo3, Lourdes Lledó4, Óscar Pastor5, Laura García-Bermejo2, David Díaz6, Melchor Álvarez-Mon6, Agustín Albillos7. 1. 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. 2. Unidad de Biomarcadores y Dianas Terapéuticas, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain. 3. Servicio de Microbiología, Hospital Universitario Ramón y Cajal, IRYCIS, Red Española de Investigación en Enfermedades Infecciosas (REIPI), Instituto de Salud Carlos III, Madrid, Spain. 4. Departamento de Microbiología, Universidad de Alcalá, Alcalá de Henares, Spain. 5. Servicio de Bioquímica Clínica, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain. 6. 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. 7. 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.
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.
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 cirrhoticrats, 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: Brett Williams; Mimi Ghosh; Charles A B Boucher; Frederic Bushman; Stacy Carrington-Lawrence; Ronald G Collman; Satya Dandekar; Que Dang; Angela Malaspina; Roger Paredes; Cara C Wilson; Piotr Nowak; Nichole R Klatt; Laurel Lagenaur; Alan L Landay Journal: AIDS Res Hum Retroviruses Date: 2017-10-26 Impact factor: 2.205