Solé Cristina, Guilly Susie, Da Silva Kevin, Llopis Marta, Le-Chatelier Emmanuelle, Huelin Patricia, Carol Marta, Moreira Rebeca, Fabrellas Núria, De Prada Gloria, Napoleone Laura, Graupera Isabel, Pose Elisa, Juanola Adrià, Borruel Natalia, Berland Magali, Toapanta David, Casellas Francesc, Guarner Francisco, Doré Jöel, Solà Elsa, Ehrlich Stanislav Dusko, Ginès Pere
Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigacion en Red de Enfermedades Hepaticas y Digestivas (CIBEReHD), Madrid, Spain.
Université Paris-Saclay, INRAE (Institut National de Recherche pour l'agriculture, l'alimentation et l'environnement), Jouy en Josas, France.
Gastroenterology. 2021 Jan;160(1):206-218.e13. doi: 10.1053/j.gastro.2020.08.054. Epub 2020 Sep 14.
Cirrhosis is associated with changes in gut microbiome composition. Although acute-on-chronic liver failure (ACLF) is the most severe clinical stage of cirrhosis, there is lack of information about gut microbiome alterations in ACLF using quantitative metagenomics. We investigated the gut microbiome in patients with cirrhosis encompassing the whole spectrum of disease (compensated, acutely decompensated without ACLF, and ACLF). A group of healthy subjects was used as control subjects.
Stool samples were collected prospectively in 182 patients with cirrhosis. DNA library construction and sequencing were performed using the Ion Proton Sequencer (ThermoFisher Scientific, Waltham, MA). Microbial genes were grouped into clusters, denoted as metagenomic species.
Cirrhosis was associated with a remarkable reduction in gene and metagenomic species richness compared with healthy subjects. This loss of richness correlated with disease stages and was particularly marked in patients with ACLF and persisted after adjustment for antibiotic therapy. ACLF was associated with a significant increase of Enterococcus and Peptostreptococcus sp and a reduction of some autochthonous bacteria. Gut microbiome alterations correlated with model for end-stage liver disease and Child-Pugh scores and organ failure and was associated with some complications, particularly hepatic encephalopathy and infections. Interestingly, gut microbiome predicted 3-month survival with good stable predictors. Functional analysis showed that patients with cirrhosis had enriched pathways related to ethanol production, γ-aminobutyric acid metabolism, and endotoxin biosynthesis, among others.
Cirrhosis is characterized by marked alterations in gut microbiome that parallel disease stages with maximal changes in ACLF. Altered gut microbiome was associated with complications of cirrhosis and survival. Gut microbiome may contribute to disease progression and poor prognosis. These results should be confirmed in future studies.
肝硬化与肠道微生物群组成的变化有关。尽管慢加急性肝衰竭（ACLF）是肝硬化最严重的临床阶段，但利用定量宏基因组学研究ACLF患者肠道微生物群改变的相关信息却很匮乏。我们研究了涵盖疾病全谱（代偿期、无ACLF的急性失代偿期以及ACLF）的肝硬化患者的肠道微生物群。选取一组健康受试者作为对照。
前瞻性收集182例肝硬化患者的粪便样本。使用Ion Proton测序仪（赛默飞世尔科技公司，马萨诸塞州沃尔瑟姆）进行DNA文库构建和测序。微生物基因被聚类为簇，称为宏基因组物种。
与健康受试者相比，肝硬化患者的基因和宏基因组物种丰富度显著降低。这种丰富度的降低与疾病阶段相关，在ACLF患者中尤为明显，且在调整抗生素治疗后依然存在。ACLF与肠球菌和消化链球菌属的显著增加以及一些本土细菌的减少有关。肠道微生物群的改变与终末期肝病模型、Child-Pugh评分及器官衰竭相关，并与一些并发症有关，尤其是肝性脑病和感染。有趣的是，肠道微生物群能很好地稳定预测3个月生存率。功能分析表明，肝硬化患者富集了与乙醇生成、γ-氨基丁酸代谢和内毒素生物合成等相关的通路。
肝硬化的特征是肠道微生物群发生显著改变，与疾病阶段平行，在ACLF中变化最大。肠道微生物群改变与肝硬化并发症及生存率相关。肠道微生物群可能促进疾病进展并导致预后不良。这些结果有待未来研究进一步证实。
