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.
Unidad de Biomarcadores y Dianas Terapéuticas, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.
J Hepatol. 2016 May;64(5):1049-1057. doi: 10.1016/j.jhep.2015.12.010. Epub 2015 Dec 23.
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.
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.
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.
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.
在晚期肝硬化中，肠道细菌易位是肠道屏障破坏的结果，导致细菌感染。肝硬化中的胆汁酸异常可能在肠道屏障的完整性和微生物群的控制中发挥作用，主要通过法尼醇 X 受体。我们研究了法尼醇 X 受体激动剂奥贝胆酸对 CCl4 诱导的伴有腹水的肝硬化大鼠肠道细菌易位、肠道微生物群组成、屏障完整性和炎症的长期影响。
肝硬化大鼠在出现腹水后接受为期 2 周的奥贝胆酸或载体治疗。然后我们通过肠系膜淋巴结培养确定细菌易位：通过 qPCR 测定回肠抗菌肽和紧密连接蛋白的表达，通过 qPCR 和焦磷酸测序测定粪便白蛋白丢失、肠内细菌负荷和微生物群组成，通过炎症细胞浸润的流式细胞术测定肠道炎症。
奥贝胆酸将细菌易位从 78.3%降低到 33.3%（p<0.01），并上调了法尼醇 X 受体相关基因小异二聚体伴侣的表达。治疗改善了回肠抗菌肽、血管生成素-1 和 α-5-防御素、紧密连接蛋白 zonulin-1 和闭合蛋白的表达，减少了粪便白蛋白丢失和肝纤维化。肠内细菌负荷正常化，肝硬化特有的黏膜微生物群减少。肠道免疫细胞浸润减少，炎症细胞因子和 Toll 样受体 4 的表达正常化。
在腹水性肝硬化大鼠中，奥贝胆酸通过肠道水平的几种互补机制减少肠道细菌易位。这种药物可作为抗生素的替代品，预防肝硬化中的细菌感染。
