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

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....

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Published in:Microbiome 2021-09, Vol.9 (1), p.1-188, Article 188
Main Authors: Aoki, Ryo, Onuki, Masayoshi, Hattori, Koya, Ito, Masato, Yamada, Takahiro, Kamikado, Kohei, Kim, Yun-Gi, Nakamoto, Nobuhiro, Kimura, Ikuo, Clarke, Julie M., Kanai, Takanori, Hase, Koji
Format: Article
Language:English
Subjects:
Acetate
Acetic acid
Adipose tissue
Animal models
Bacteroides
Cellulose
Cholesterol
Ethanol
Fatty acids
Fatty liver
Fermentation
Fibrosis
Germfree
Hypercholesterolemia
Hypertrophy
Inflammation
Insulin
Insulin resistance
Intestinal microflora
Inulin
Liver
Liver diseases
Metabolic syndrome
Metabolism
Metabolites
Microbiomes
Microorganisms
NAFLD
NASH
Phenotypes
Prebiotics
Short-chain fatty acids
Starch
Steatosis
Weight control
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Summary: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. Video abstract
ISSN:2049-2618
2049-2618
DOI:10.1186/s40168-021-01125-7