Dysregulated bile acid receptor-mediated signaling and IL-17A induction are implicated in diet-associated hepatic health and cognitive function

Abstract

Background Chronic consumption of high sugar and high fat diet associated with liver inflammation and cognitive decline. This paper tests a hypothesis that the development and resolution of diet-induced nonalcoholic fatty liver disease (NAFLD) has an impact on neuroplasticity and cognition. 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 RORγ 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.

Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease—Current Knowledge, Mechanisms and Perspectives

“…An increasing number of experimental studies have shown evidence of cognitive dysfunction and neuroinflammation in animal models of NASH. Collectively, these studies indicate that NASH is associated with impaired spatial learning and memory as well as depression-like behaviour, and that these neurobehavioral changes are accompanied by microglia activation and increased release of proinflammatory cytokines in brain tissue [ 61 , 62 , 63 ]. Furthermore, the induction of NAFLD in models of Alzheimer’s disease (AD) and haemorrhagic brain injury exacerbates cognitive impairment and neuroinflammation [ 64 , 65 ].…”

Intestinal Microbiota Remodeling Protects Mice from Western Diet-Induced Brain Inflammation and Cognitive Decline

“…In addition, BAs also modulate GABAergic and N-methyl-D-aspartate receptor-mediated neurotransmission [70]. Our previous data showed that fructose-enriched WD induced gut and brain inflammation [2,34]. Moreover, reducing BA pool size effectively reduces skin inflammation and liver damage [71][72][73].…”

“…Untargeted, semi-quantitative metabolomics profiling was performed using cecal metabolites. Gas chromatography time of flight mass spectrometry was conducted at the UC Davis West Coast Metabolomics Center based on published methods [30,33,34]. BinBase database was used to process acquired spectra, filtered, and matched with the Fiehn mass spectral library of 1200 authentic metabolite spectra with retention index and mass spectrum information or against the NIST library.…”

“…Cecal metabolomics data were analyzed with MetaboAnalyst and ChemRICH [34,39]. Brain lipidomics data were analyzed with MetaboAnalyst and R program.…”

Interaction of Gut Microbiota and Brain Function in Patients With Chronic Insomnia: A Regional Homogeneity Study

“…Notably, ReHo values in the LAG were positively associated with the RA of Coprobacter in our study. Genus Coprobacter has been found to be positively associated with insulin supplementation ( Jena et al, 2020 ), an indigestible fiber that can generate short-chain fatty acids ( Weitkunat et al, 2015 ) and improve digestion, memory, and mood in humans ( Smith et al, 2015 ). Our results showed that the RA of this bacteria was positively correlated with better cognitive performance in CI patients, which may indicate potential benefits of this gut bacteria.…”