Commensal microbe-derived acetate suppresses NAFLD/NASH development via hepatic FFAR2 signalling in mice

Ryo Aoki, Masayoshi Onuki, Koya Hattori, Masato Ito, Takahiro Yamada, Kohei Kamikado, Yun Gi Kim, Nobuhiro Nakamoto, Ikuo Kimura, Julie M. Clarke, Takanori Kanai, Koji Hase

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear. Results: We found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue. Conclusion: These findings demonstrated that the commensal microbiome–acetate–FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH. [MediaObject not available: see fulltext.]

Original languageEnglish
Article number188
JournalMicrobiome
Volume9
Issue number1
DOIs
Publication statusPublished - 2021 Dec

Keywords

  • Acetate
  • Bacteroides
  • Blautia
  • FFAR2
  • Inulin
  • NAFLD
  • NASH
  • Prebiotics
  • Short-chain fatty acids

ASJC Scopus subject areas

  • Microbiology
  • Microbiology (medical)

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