Abstract
The gut microbiota is a newly identified contributor to the development of non-alcoholic fatty liver disease (NAFLD). Previous studies of Bifidobacterium adolescentis (B. adolescentis), a species of Bifidobacterium that is common in the human intestinal tract, have demonstrated that it can alleviate liver steatosis and steatohepatitis. Fibroblast growth factor 21 (FGF21) has long been considered as a biomarker of NAFLD, and recent studies have shown the protective effect of FGF21 analogs on NAFLD. We wondered whether B. adolescentis treatment would alleviate NAFLD via the interaction with FGF21. To this end, male C57BL/6J mice on a choline-deficient high-fat diet (CDHFD) were treated with drinking water supplemented with B. adolescentis for 8 weeks, followed by the acute administration of recombinant mouse FGF21 protein (rmFGF21) to conduct the FGF21 response test. Consistent with previous studies, B. adolescentis supplementation reversed the CDHFD-induced liver steatosis and steatohepatitis. This was evaluated on the NAFLD activity score (NAS), reduced liver enzymes, and lipid accumulation. Further studies demonstrated that B. adolescentis supplementation preserved the gut barrier, reduced the gut microbiota-derived lipopolysaccharide (LPS), and inhibited the hepatic TLR4/NF-κB pathway. This was accompanied by the elevated expressions of the receptors of FGF21, fibroblast growth factor receptor 1 (FGFR1) and β-klotho (KLB), in the liver and the decreased expression of FGF21. The results of FGF21 response test showed that B. adolescentis supplementation alleviated the CDHFD-induced FGF21 resistance. In vivo experiments suggested that LPS could suppress the expression of FGF21 and KLB in a dose-dependent manner. Collectively, this study showed that B. adolescentis supplementation could alleviate NAFLD by increasing FGF21 sensitivity.
Highlights
Non-alcoholic fatty liver disease (NAFLD) has emerged as an escalating public health problem, with about 1/4 of the world’s population being affected [1], resulting in increased risks of liver damage and extrahepatic diseases [2, 3]
Eight-week-old male C57BL/6J mice on control diet or choline-deficient high-fat diet (CDHFD) were allocated to treatment of drinking water, water with B. adolescentis (CDHFD-B.a), or water with heatkill B. adolescentis for 8 weeks (Figure 1A), followed by further assessments
To investigate if circulating LPS can alter the signaling of the hepatic Fibroblast growth factor 21 (FGF21) pathway, we examined the expression of FGF21, as well as fibroblast growth factor receptor 1 (FGFR1) and KLB in the liver
Summary
Non-alcoholic fatty liver disease (NAFLD) has emerged as an escalating public health problem, with about 1/4 of the world’s population being affected [1], resulting in increased risks of liver damage and extrahepatic diseases [2, 3]. The role of the gut microbiota in the occurrence and development of NAFLD pathogenesis and development has been demonstrated in both animal and human studies. Germfree mice on high-fat diet exhibit much less lipid accumulation in liver than control mice, suggesting the indispensable role of the gut microbiota in this disease [7]. Fecal transplantation confirmed that hepatic steatosis could be passed on from donors to germfree mice by the gut microbiota [6]. Bifidobacterium adolescentis (B. adolescentis), one of the common microbiota colonizing human intestinal, has shown its protective effects against the diet-induced hepatic steatosis and nonalcoholic steatohepatitis (NASH) [9, 10]. The mechanism by which the gut microbiota act on NAFLD is thought to involve bile acid regulation, short chain fatty acid release, gut barrier preservation, and gut-derived toxin reduction.
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