Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Liver Int. 2023 Dec;43(12):2701-2712. doi: 10.1111/liv.15737. Epub 2023 Sep 26.
BACKGROUND & AIMS: Direct-acting antiviral (DAA) therapy has revolutionized treatment for the hepatitis C virus (HCV). While DAA therapy is common, little is known about the intrahepatic immunological changes after sustained virologic response (SVR). We aim to describe transcriptional alterations of the gut microbiome and the liver after SVR.
Twenty-two HCV patients were evaluated before and 9 months after 12 weeks of sofosbuvir/velpatasvir treatment. All achieved SVR. A liver biopsy, portal blood (direct portal vein cannulation), peripheral blood and stool samples were obtained. RNA-seq and immunofluorescent staining were performed on liver biopsies. RNA-seq and 16S rRNA metagenomics were performed on stool.
Differential expression within liver transcription showed 514 downregulated genes (FDR q < .05; foldchange > 2) enriched in inflammatory pathways; of note, GO:0060337, type 1 IFN signalling (p = 8e-23) and GO:0042742, defence response to bacterium (p = 8e-3). Interestingly, microbial products increased in the portal blood and liver after SVR. Due to the increase in microbial products, the gut microbiome was investigated. There was no dysbiosis by Shannon diversity index or Bacteroides/Firmicutes ratio. There was a differential increase in genes responsible for bacterial lipopolysaccharide production after SVR.
The decrease in the antiviral interferon pathway expression was expected after SVR; however, there was an unanticipated decrease in the transcription of genes involved in recognition and response to bacteria, which was associated with increased levels of microbial products. Finally, the alterations in the function of the gut microbiome are a promising avenue for further investigation of the gut-liver axis, especially in the context of the significant immunological changes noted after SVR.
直接作用抗病毒（DAA）治疗彻底改变了丙型肝炎病毒（HCV）的治疗方法。虽然 DAA 治疗很常见，但对于持续病毒学应答（SVR）后肝内免疫变化知之甚少。我们旨在描述 SVR 后肠道微生物组和肝脏的转录变化。
22 例 HCV 患者在接受 12 周索非布韦/维帕他韦治疗前和治疗后 9 个月进行评估。所有患者均获得 SVR。获取肝活检、门脉血（直接门静脉穿刺）、外周血和粪便样本。对肝活检进行 RNA-seq 和免疫荧光染色。对粪便进行 RNA-seq 和 16S rRNA 宏基因组学分析。
肝转录差异表达显示 514 个下调基因（FDR q <.05；foldchange > 2），富集于炎症途径；值得注意的是，GO：0060337，I 型干扰素信号（p = 8e-23）和 GO：0042742，对细菌的防御反应（p = 8e-3）。有趣的是，SVR 后门静脉血和肝脏中微生物产物增加。由于微生物产物增加，对肠道微生物组进行了研究。Shannon 多样性指数或拟杆菌/厚壁菌比值没有失调。SVR 后，负责细菌脂多糖产生的基因表达呈差异增加。
SVR 后抗病毒干扰素途径表达的降低是预期的；然而，参与识别和对细菌反应的基因转录出乎意料地降低，这与微生物产物水平的增加有关。最后，肠道微生物组功能的改变是进一步研究肠道-肝脏轴的一个有前途的途径，尤其是在 SVR 后注意到的显著免疫学变化的背景下。
