Increased intestinal bile acid absorption contributes to age-related cognitive impairment

Abstract

Cognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. 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. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment. • Age-related cognitive decline linked to CPBAs and ammonia levels • Brain CPBAs and ammonia drive synapse loss • ASBT boosts CPBA and ammonia intake in gut • Cholestyramine reduces CPBA absorption, improving cognitive impairment Ren et al. uncover that enhanced gut absorption of conjugated primary bile acids (CPBAs) and ammonia accelerates cognitive decline with age, which a bile acid sequestrant, cholestyramine, can counter. This study connects bile acid metabolism with cognitive aging and suggests a possible pathway for intervention.