A Protective Role for Bile Acids in Neurodegenerative Conditions
In addition to aiding lipid absorption in the intestines and regulating cholesterol homeostasis, bile acids have hormone-like signaling activity that exerts far-reaching influence on an array of biological processes, including those that affect neurological health.1 Cholesterol and related lipid molecules are critical components of myelin, and neuronal and glial cell membranes,2,3 but the neurological impact of bile acids extends even further than that. Research continues to highlight the crucial role the gut microbiome-brain axis plays in neurological health. Bile acid-mediated signaling is likely bidirectional within this axis to modulate metabolic status and cholesterol balance centrally. Dysregulation in this pathway has been associated with neurodegenerative conditions. For example, higher levels of secondary bile acids are found in the neurodegenerating brain, possibly due to increased bile acid production by a disordered microbiome. And increased levels of bile acids in systemic circulation can adversely affect blood-brain barrier permeability.4
Given that bile acids play a key role in regulating lipid and glucose metabolism,5 and that epidemiological studies have identified metabolic syndrome as an independent risk factor for neurodegenerative disorders, the signaling pathways of bile acids, such as TUDCA, are being studied for their therapeutic potential. TUDCA, or tauroursodeoxycholic acid, is one of the most hydrophilic of the bile acids. It is synthesized in the liver by conjugation of the amino acid taurine with ursodeoxycholic acid, which is made in the gut.6 The greatest risk factor by far for neurodegenerative disorders is aging. The aging process can affect the gut in several ways that potentially disrupt the gut microbiome-brain axis. This includes persistent inflammation; mucosal thinning; reduced microbiome diversity and stability; and diminished bioavailability of microbial metabolites, like secondary bile acids and short-chain fatty acids, which have immunoregulatory properties.7,8,9 Hydrophilic bile acids, in particular TUDCA, are able to cross the blood–brain barrier. They can act as bile acid receptor agonists and appear to confer neuroprotective effects.10,11
Evidence for the neuroprotective effects of TUDCA was first shown in experimental or animal models of Alzheimer’s disease,12,13,14,15,16 Parkinson’s disease,17 Huntington’s disease,10 multiple sclerosis,18 and amyotrophic lateral sclerosis (ALS).19 These preclinical studies found that TUDCA regulates and inhibits apoptosis; reduces production of reactive oxygen species; protects mitochondria; and acts as a chemical chaperone to stabilize the unfolded protein response.8 Several clinical trials are now underway to evaluate the safety and efficacy of TUDCA in the treatment of neurodegeneration. Data from these trials has shown that TUDCA is safe and potentially effective in ALS, which is now the first neurodegenerative condition to be treated with hydrophilic bile acids. Further evidence is being collected with regard to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis.
Diverse neurodegenerative conditions share some common features, such as neuronal loss, disordered protein aggregation, mitochondrial dysfunction, and oxidative stress. TUDCA, which is one of the most hydrophilic of the bile acids, is able to cross the blood–brain barrier, and potentially exert neuroprotective effects in ways that mitigate many of these neurodegenerative mechanisms. As such, it could prove to be a powerful component of therapeutic protocols aimed at boosting neurological health.