METHODS: C57BL/6 wild-type mice were fed with either a healthy control diet (CD) or a
fructose,
palmitate, and
cholesterol (FPC)-enriched diet since weaning. When mice were 3-months old, FPC diet-fed mice were randomly assigned to receive either FPC-enriched diet with or without 6%
inulin supplementation. At 8 months of age, all three groups of mice were euthanized followed by analysis of inflammatory signaling in the liver and brain, gut microbiota, and cecal metabolites.
RESULTS: Our data showed that FPC diet intake induced hepatic steatosis and
inflammation in the liver and brain along with elevated RORĪ³ and
IL-17A signaling. Accompanied by microglia activation and reduced hippocampal long-term potentiation, FPC diet intake also reduced postsynaptic density-95 and
brain derived neurotrophic factor, whereas
inulin supplementation prevented diet-reduced neuroplasticity and the development of
NAFLD. In the gut, FPC diet increased Coriobacteriaceae and Erysipelotrichaceae, which are implicated in
cholesterol metabolism, and the genus Allobaculum, and
inulin supplementation reduced them. Furthermore, FPC diet reduced FXR and TGR5 signaling, and
inulin supplementation reversed these changes. Untargeted cecal metabolomics profiling uncovered 273 metabolites, and 104 had significant changes due to FPC diet intake or
inulin supplementation. Among the top 10 most affected metabolites, FPC-fed mice had marked increase of
zymosterol, a
cholesterol biosynthesis metabolite, and reduced
2,8-dihydroxyquinoline, which has known benefits in reducing
glucose intolerance; these changes were reversible by
inulin supplementation. Additionally, the abundance of Barnesiella, Coprobacter, Clostridium XIVa, and Butyrivibrio were negatively correlated with FPC diet intake and the concentration of cecal
zymosterol but positively associated with
inulin supplementation, suggesting their benefits.
CONCLUSION: Taken together, the presented data suggest that diet alters the gut microbiota and their metabolites, including
bile acids. This will subsequently affect
IL-17A signaling, resulting in systemic impacts on both hepatic metabolism and cognitive function.