Bile Acids Act as Double-Edged Swords in Alzheimer's Disease, Modulating Neuroinflammation and Neurodegeneration
Background
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β deposition, tau pathology, and neuroinflammation, lacking disease-modifying treatments. Bile acids, beyond their digestive roles, function as endocrine signaling molecules impacting central nervous system homeostasis. Altered bile acid profiles are observed in AD and mild cognitive impairment, suggesting a critical link between gut-liver physiology and neurodegeneration. Understanding this axis offers novel therapeutic avenues for a devastating condition.
Study Design
This narrative review synthesized current biochemical, experimental, and clinical evidence regarding bile acid signaling in Alzheimer's disease pathogenesis and progression. Researchers explored receptor-mediated pathways, specifically focusing on the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5/GPBAR1). The review also examined microbiota-bile acid interactions, neuroimmune modulation, and the role of gut hormones like glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 19 (FGF19), to propose future AD intervention strategies.
Results
Bile acids dynamically modulate peripheral metabolic and immune pathways with downstream effects on the brain, acting as a 'double-edged sword' in AD. Altered bile acid profiles are consistently reported in AD and mild cognitive impairment. Hydrophobic secondary bile acids may contribute to blood-brain barrier (BBB) disruption and neurotoxicity, potentially exacerbating neurodegeneration. In contrast, hydrophilic bile acids appear to exert neuroprotective and anti-inflammatory effects, offering a potential therapeutic angle. Bile acid signaling through key receptors like FXR and TGR5/GPBAR1 serves as a mechanistic bridge linking liver-gut physiology to neuroinflammatory and neurodegenerative processes. Furthermore, bile acids drive the release of gut hormones such as GLP-1 and FGF19, highlighting indirect neurometabolic pathways relevant to cognition and neurodegeneration.
This review proposes that bile acid-based biomarkers and therapeutic strategies targeting
FXR/TGR5signaling represent promising avenues for future AD intervention.
Key Findings
- Bile acids act as endocrine signals influencing central nervous system homeostasis and Alzheimer's disease pathogenesis.
- Altered bile acid profiles are reported in AD and mild cognitive impairment.
- Hydrophobic bile acids may contribute to blood-brain barrier disruption and neurotoxicity.
- Hydrophilic bile acids may exert neuroprotective and anti-inflammatory effects.
- Bile acid signaling via
FXRandTGR5/GPBAR1links liver-gut physiology to neuroinflammatory and neurodegenerative processes.
Why It Matters
This review significantly advances our understanding of the gut-liver-brain axis in Alzheimer's disease, highlighting bile acids as crucial modulators. For clinicians and biohackers, this suggests that modulating bile acid profiles, potentially through diet, pre/probiotics, or specific compounds targeting FXR or TGR5, could be a novel strategy to influence AD risk or progression. The identification of specific bile acid receptors and gut hormones as mediators provides concrete targets for future drug development. While still preclinical for direct human intervention, this work lays the groundwork for developing bile acid-based biomarkers for early detection and personalized therapeutic strategies, moving beyond symptomatic relief towards disease modification.
bile acids
alzheimer's disease
neurodegeneration
neuroinflammation
gut-brain axis
fxr