Non-selective dampening of the host immune response after hepatitis C clearance and its association with circulating chemokine and endotoxin levels

Gabriella Quinn, Rabab O. Ali, Grace Y. Zhang, Kareen Hill, Elizabeth Townsend, Regina Umarova, Moumita Chakraborty, Maleeha F. Ahmad, Meital Gewirtz, James Haddad, Sergio Rosenzweig, Shakuntala Rampertaap, Megan Schoenfeld, Shanna Yang, Christopher Koh, Elliot Levy, David E. Kleiner, Ohad Etzion, Theo Heller

Research output: Contribution to journalArticlepeer-review

Abstract

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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)2701-2712
Number of pages12
JournalLiver International
Volume43
Issue number12
DOIs
StatePublished - 1 Dec 2023
Externally publishedYes

Keywords

  • gut-liver axis
  • innate immunity
  • interferon
  • microbiome
  • sustained virologic response

ASJC Scopus subject areas

  • Hepatology

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