Liver Steatosis and Steatohepatitis Alter Bile Acid Receptors in Brain and Induce Neuroinflammation: A Contribution of Circulating Bile Acids and Blood-Brain Barrier

Abstract

A tight relationship between gut-liver diseases and brain functions has recently emerged. Bile acid (BA) receptors, bacterial-derived molecules and the blood-brain barrier (BBB) play key roles in this association. This study was aimed to evaluate how non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) impact the BA receptors Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) expression in the brain and to correlate these effects with circulating BAs composition, BBB integrity and neuroinflammation. A mouse model of NAFLD was set up by a high-fat and sugar diet, and NASH was induced with the supplementation of dextran-sulfate-sodium (DSS) in drinking water. FXR, TGR5 and ionized calcium-binding adaptor molecule 1 (Iba-1) expression in the brain was detected by immunohistochemistry, while Zonula occludens (ZO)-1, Occludin and Plasmalemmal Vesicle Associated Protein-1 (PV-1) were analyzed by immunofluorescence. Biochemical analyses investigated serum BA composition, lipopolysaccharide-binding protein (LBP) and S100β protein (S100β) levels. Results showed a down-regulation of FXR in NASH and an up-regulation of TGR5 and Iba-1 in the cortex and hippocampus in both treated groups as compared to the control group. The BA composition was altered in the serum of both treated groups, and LBP and S100β were significantly augmented in NASH. ZO-1 and Occludin were attenuated in the brain capillary endothelial cells of both treated groups versus the control group. We demonstrated that NAFLD and NASH provoke different grades of brain dysfunction, which are characterized by the altered expression of BA receptors, FXR and TGR5, and activation of microglia. These effects are somewhat promoted by a modification of circulating BAs composition and by an increase in LBP that concur to damage BBB, thus favoring neuroinflammation.

Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases

“…Bile acids may also affect the progression of NAFLD through adjusting the intestinal barrier [105][106][107]. Long-term HFD intake can lead to gut dysbiosis and the aberrant metabolism of bile acids.…”

Intermittent Fasting on Neurologic Diseases: Potential Role of Gut Microbiota

“…Bile acid is a byproduct of the metabolic process of cholesterol and serves a crucial function in the metabolism of fats and energy. The presence of bile acid in the bloodstream enables its direct interaction with the brain via the blood-brain barrier [107]. Additionally, it can modulate neuronal function via stimulating intestinal receptors, leading to the secretion of GLP-1 [108].…”

TGR5 deficiency in excitatory neurons ameliorates Alzheimer’s pathology by regulating APP processing

“…Abnormal metabolism of BAs has been detected in the brain tissue of patients with AD ( 12 – 14 ). BAs can cross the blood-brain barrier (BBB) to accumulate in the brain ( 1 , 15 , 16 ). The BAs metabolic abnormality is closely related to the occurrence of AD and appears in the early stage of this disease, accompanying its development ( 17 ).…”