Abstract
The microbiota–gut–liver axis has emerged as an important player in developing nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease (NAFLD). Higher mushroom intake is negatively associated with the prevalence of NAFLD. This study examined whether lentinan, an active ingredient in mushrooms, could improve NAFLD and gut microbiota dysbiosis in NAFLD mice induced by a high-fat (HF) diet. Dietary lentinan supplementation for 15 weeks significantly improved gut microbiota dysbiosis in HF mice, evidenced by increased the abundance of phylum Actinobacteria and decreased phylum Proteobacteria and Epsilonbacteraeota. Moreover, lentinan improved intestinal barrier integrity and characterized by enhancing intestinal tight junction proteins, restoring intestinal redox balance, and reducing serum lipopolysaccharide (LPS). In the liver, lentinan attenuated HF diet-induced steatohepatitis, alteration of inflammation–insulin (NFκB-PTP1B-Akt-GSK3β) signaling molecules, and dysregulation of metabolism and immune response genes. Importantly, the antihepatic inflammation effects of lentinan were associated with improved gut microbiota dysbiosis in the treated animals, since the Spearman's correlation analysis showed that hepatic LPS-binding protein and receptor (Lbp and Tlr4) and pro- and antiinflammatory cytokine expression were significantly correlated with the abundance of gut microbiota of phylum Proteobacteria, Epsilonbacteraeota and Actinobacteria. Therefore, lentinan supplementation may be used to mitigate NAFLD by modulating the microbiota–gut–liver axis.
Highlights
Nonalcoholic fatty liver disease (NAFLD), one of the most common liver diseases worldwide, affects up to 30% of the adult population [1]
Principal coordinate analysis (PCoA) of microbiota showed a clear cluster separation among the LF, HF, and high-fat diet supplemented with lentinan (HFL) groups (Figure 1B), whereas the LF diet-fed mice with lentinan supplementation had a similar cluster with the LF mice (Supplementary Figure S1A)
The gut microbiota of these three groups was mainly dominated by Firmicutes, Bacteroidetes, Proteobacteria, Epsilonbacteraeota, and Actinobacteria at the phylum level (Figure 1C), in which Proteobacteria and Epsilonbacteraeota increased, and Bacteroidetes decreased in the HF group (p < 0.05, Figure 1H)
Summary
Nonalcoholic fatty liver disease (NAFLD), one of the most common liver diseases worldwide, affects up to 30% of the adult population [1]. Compelling evidence links NASH with the alteration of the gut microbiome and intestinal barrier integrity. The gut integrity is disrupted by a redox imbalance in the intestine [7,8,9,10]. Antioxidant enzymes, such as haem oxygenase 1 (HO1), NAD(P)H quinone dehydrogenase 1 (NQO1), and glutamatecysteine ligase catalytic subunit (Gclc), play important roles in maintaining intestinal barrier integrity [10]. The transcription factor of these antioxidant enzymes, nuclear factor erythroid 2related factor 2 (Nrf2), ameliorates intestinal barrier dysfunction induced by lipopolysaccharide (LPS, present in the outer membrane of gram-negative bacteria) [11]. Gut microbiota dysbiosis and redox imbalance may disrupt gut integrity and lead to overtranslating the gut bacteria-derived toxin, such as LPS, into the port vein, thereby promoting inflammatory responses in the liver
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