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Liver's influence on the brain through the action of bile acids - PubMed

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Review

Liver's influence on the brain through the action of bile acids

Xin Yi Yeo et al. Front Neurosci. 2023.

Abstract

The liver partakes as a sensor and effector of peripheral metabolic changes and a regulator of systemic blood and nutrient circulation. As such, abnormalities arising from liver dysfunction can influence the brain in multiple ways, owing to direct and indirect bilateral communication between the liver and the brain. Interestingly, altered bile acid composition resulting from perturbed liver cholesterol metabolism influences systemic inflammatory responses, blood-brain barrier permeability, and neuron synaptic functions. Furthermore, bile acids produced by specific bacterial species may provide a causal link between dysregulated gut flora and neurodegenerative disease pathology through the gut-brain axis. This review will cover the role of bile acids-an often-overlooked category of active metabolites-in the development of neurological disorders associated with neurodegeneration. Further studies into bile acid signaling in the brain may provide insights into novel treatments against neurological disorders.

Keywords: bile acid; brain; gut microbiome; liver; neurodegeneration.

Copyright © 2023 Yeo, Tan, Chae, Lee, Lee, Wuestefeld and Jung.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1

Bile acid metabolism and circulation. In normal physiological conditions, the classical pathway accounts for 90% of the bile acids (BAs) present in the human body. While BAs are produced as systemic modulators of physiological processes by the liver (classical and alternative pathways), sterols are produced as by-products of the brain cholesterol clearance process (neural cholesterol clearance pathway). Primary BAs produced by the liver are deposited in the gallbladder and released into the intestine upon stimulation by the hunger hormone cholecystokinin for lipid emulsification. Once in the gastrointestinal tract, primary BAs are readily deconjugated, dehydroxylated, or dehydrogenated by gut microbes. The main bacterial enzymes involved in the process are listed in the table at the bottom of the image. These modified BAs (secondary BAs) can proceed to exert their effects as a negative modulator of gut function through bile acid receptor pathways [Takeda G-protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR) signaling] or gut microbiome composition. After which, BAs can be passively reabsorbed into the liver for further conjugation with taurine or glycine and enter the systemic circulation and the central nervous system through simple diffusion or BA transporters present on the blood-brain barrier (NTCP, sodium taurocholate co-transport peptide; OATP, organic anion transporting polypeptides; ASBT, apical sodium bile acid transporter). 24-hydroxycholesterol (24-OHC) produced by the neural cholesterol clearance pathway negatively regulates cholesterol metabolism in the brain, while the physiological function of systemic BAs in the nervous system is unclear. BAs can be transported back into the intestine (ASBT, OATP, and OSTα/β, organic solute transporter α, and β) and further sulfated by sulfotransferase (SULT) or hydroxylated by Cytochrome P450, family 2, subfamily a, polypeptide 4 (CYP3A4) for detoxification or clearance through fecal excretion.

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Grants and funding

This work was supported by the Joint Council Office grant (BMSI/15- 800003-SBIC-00E) from Agency for Science, Technology and Research (A*STAR), Singapore (to SJ), the National Medical Research Council (NMRC, MOH-000331-00) (to Y-AL), and the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (iPET) funded by the MAFRA (32136-05-1-HD050) (to D-YL).