초록
<▼1><P>Non-alcoholic steatohepatitis (NASH) is the severe form of non-alcoholic fatty liver disease, and is characterized by liver inflammation and fat accumulation. Dietary interventions, such as fibre, have been shown to alleviate this metabolic disorder in mice via the gut microbiota. Here, we investigated the mechanistic role of the gut microbiota in ameliorating NASH via dietary fibre in mice. Soluble fibre inulin was found to be more effective than insoluble fibre cellulose to suppress NASH progression in mice, as shown by reduced hepatic steatosis, necro-inflammation, ballooning and fibrosis. We employed stable isotope probing to trace the incorporation of <SUP>13</SUP>C-inulin into gut bacterial genomes and metabolites during NASH progression. Shotgun metagenome sequencing revealed that the commensal <I>Parabacteroides distasonis</I> was enriched by <SUP>13</SUP>C-inulin. Integration of <SUP>13</SUP>C-inulin metagenomes and metabolomes suggested that <I>P. distasonis</I> used inulin to produce pentadecanoic acid, an odd-chain fatty acid, which was confirmed in vitro and in germ-free mice. <I>P. distasonis</I> or pentadecanoic acid was protective against NASH in mice. Mechanistically, inulin, <I>P. distasonis</I> or pentadecanoic acid restored gut barrier function in NASH models, which reduced serum lipopolysaccharide and liver pro-inflammatory cytokine expression. Overall this shows that gut microbiota members can use dietary fibre to generate beneficial metabolites to suppress metabolic disease.</P></▼1><▼2><P>The gut commensal <I>Parabacteroides distasonis</I> uses inulin to produce the odd-chain fatty acid pentadecanoic acid, which alleviates non-alcoholic steatohepatitis via improved barrier function in mice.</P></▼2>