Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma

Jason Behary,Emily Mcgovern,Ragy Ibrahim,Yen Chin Koay,Miriam Jackson,Amany Zekry,John O’Sullivan,Vincenzo Fragomeli,Geoffrey Mccaughan,Hazem Jebeili,Lan Gong,Carlie Stephens,Nadia Amorim,Anita Raposo,Emad El-Omar,Xiao-Tao Jiang,Martin Weltman,Francis Chu

doi:10.1038/s41467-020-20422-7

Abstract

The gut microbiota is reported to modulate the immune response in hepatocellular carcinoma (HCC). Here, we employ metagenomic and metabolomic studies to characterise gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD) related cirrhosis, with or without HCC, and evaluate its effect on the peripheral immune response in an ex vivo model. We find that dysbiosis characterises the microbiota of patients with NAFLD-cirrhosis, with compositional and functional shifts occurring with HCC development. Gene function of the microbiota in NAFLD-HCC supports short chain fatty acid production, and this is confirmed by metabolomic studies. Ex vivo studies show that bacterial extracts from the NAFLD-HCC microbiota, but not from the control groups, elicit a T cell immunosuppressive phenotype, characterised by expansion of regulatory T cells and attenuation of CD8 + T cells. Our study suggest that the gut microbiota in NAFLD-HCC is characterised by a distinctive microbiome/metabolomic profile, and can modulate the peripheral immune response.

Highlights

The gut microbiota is reported to modulate the immune response in hepatocellular carcinoma (HCC)
Subjects with non-alcoholic fatty liver disease (NAFLD)-HCC and NAFLD-cirrhosis were matched for severity of liver disease based on Child-Pugh and Model for End-Stage Liver Disease-Sodium (MELD-Na) scores (Table 1)
The gut microbiota and its metabolites have been proposed as cofactors in liver disease progression and the development of HCC through their interaction with immune compartments via the gut–liver axis

Summary

Introduction

The gut microbiota is reported to modulate the immune response in hepatocellular carcinoma (HCC). We employ metagenomic and metabolomic studies to characterise gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD) related cirrhosis, with or without HCC, and evaluate its effect on the peripheral immune response in an ex vivo model. Our study suggest that the gut microbiota in NAFLD-HCC is characterised by a distinctive microbiome/ metabolomic profile, and can modulate the peripheral immune response. Tregs are increased in the peripheral blood of HCC patients, and are associated with tumour progression[14,15,16,17], mainly by impairing cytotoxic CD8+ T cell function[17] In parallel with these important data, there is mounting evidence that the gut microbiota can modulate T-cell immunity both directly and through metabolites, including short-chain fatty acids (SCFAs)[18,19,20]. SCFAs, in particular butyrate, have important immunomodulatory functions[20,21,22]

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