Bile Acid Metabolism Correlates with Cognitive Impairment

Researchers here show that bile acid metabolism makes a meaningful contribution to age-related neurodegeneration and cognitive decline. Bile acids produced by the gut microbiome leave the intestines in growing amounts with advancing age, and cause harm to the brain. In animal models, the researchers demonstrate a that sequestering bile acids in the intestine with suitable molecules can reduce the bile acid contribution to brain aging. It is plausible that adjusting the balance of populations in the aged gut microbiome via fecal microbiota transplant from a young individual could produce similar benefits, but that has yet to be rigorously assessed.

Recent studies have suggested a link between changes in bile acids (BAs) and age-related cognitive impairment. Investigations into Alzheimer's disease and Parkinson's disease reveal that lower serum levels of unconjugated primary BAs (UPBAs), such as cholic acid and chenodeoxycholic acid, along with elevated levels of glycochenodeoxycholic acid, a conjugated primary BA metabolite, are closely associated with the severity of cognitive decline symptoms.

Current understanding suggests that the gut microbiota, which produces secondary BAs in the gastrointestinal lumen, undergoes age-related alterations. These changes significantly impact the levels of BAs circulating in the body and present within the brain. Additionally, there is a notable correlation between certain serum BA metabolites, particularly increased levels of glycolithocholic acid and tauro-lithocholic acid, which are bacterially derived secondary BAs, and elevated cerebrospinal fluid total tau levels. BAs can communicate between the periphery and the brain either through specific BA transporters or by passive diffusion across the blood-brain barrier.

In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. In vitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice.