Inulin and NASH: Metabolomics Insights into Fiber's Healing Power

Non-alcoholic steatohepatitis (NASH), a severe manifestation of non-alcoholic fatty liver disease (NAFLD), extends beyond mere steatosis, representing a pathogenic condition linked to inflammation and damage to liver cells. It manifests primarily through liver inflammation and the accumulation of fat, with potential progression to fibrosis, cirrhosis, and hepatocellular carcinoma if left untreated. Projections indicate a doubling of NASH incidence and associated mortality by 2030. Although current research suggests that dietary fiber supplementation may alleviate NAFLD, the precise mechanisms underlying the impact of dietary fiber on NAFLD remain unclear.

On June, 2023, Jun Yu and colleagues published a study titled "Parabacteroides distasonis uses dietary inulin to suppress NASH via its metabolite pentadecanoic acid" in the journal Nature Microbiology. This research demonstrated that the soluble fiber inulin is more effective in impeding NASH progression in mice compared to insoluble fiber cellulose. The study also elucidated the alterations in the microbial community induced by fiber and their impact on intestinal metabolites.

Initially, the study induced an NASH model in mice by feeding them a choline-deficient high-fat diet (CDHFD). The researchers fed CDHFD mixed with a representative soluble fiber, inulin (CDHFD-i), and a representative insoluble fiber, cellulose (CDHFD-c). In comparison to mice fed CDHFD alone, both inulin and cellulose reduced weight gain, improved insulin resistance, and decreased liver weight, body weight, and liver weight ratio. Inulin significantly mitigated liver fat degeneration and oxidative stress induced by CDHFD, proving more effective than cellulose. This effect was further confirmed in a second NASH model induced by a high-fat, high-cholesterol diet (HFHCD) combined with high-fructose drinking water. These findings underscore the superior effectiveness of inulin over cellulose in ameliorating diet-induced NASH and associated metabolic disorders in mice.

Subsequent metagenomic sequencing results revealed a notable difference in the gut microbiota composition of mice fed inulin instead of cellulose when compared to those fed only with CDHFD. Specifically, there was a significant enrichment of Bacteroidetes, Bacteroides, and Parabacteroides. This outcome was further confirmed in the 16S sequencing results. Ecological network analysis suggested that inulin promotes beneficial microbes like Parabacteroides distasonis while restraining pathogenic microorganisms. Administering Parabacteroides distasonis to mice markedly reduced liver fat accumulation and necrotic inflammation. Untargeted metabolomic analysis demonstrated that inulin, unlike cellulose, modifies the range of intestinal metabolites, including pentadecanoic acid. A combined analysis of microbiome and metabolome data showed a positive relationship between Parabacteroides distasonis and pentadecanoic acid. Both CDHFD and HFHCD led to increased LPS levels, an effect that could be reversed by inulin, Parabacteroides distasonis, or pentadecanoic acid. Furthermore, transcriptomic sequencing of mouse liver tissues indicated that inulin, Parabacteroides distasonis, or pentadecanoic acid reverses the activation of NF-κB induced by NASH.

In conclusion, this study reveals that soluble fiber inulin enhances diet-induced NASH by regulating the gut microbiota, specifically Parabacteroides distasonis, and the metabolite pentadecanoic acid.

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