Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome

Abstract

Introduction: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD). Methods: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing. Results: In AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles. Conclusion: We report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.

A metabolite‐based machine learning approach to diagnose Alzheimer‐type dementia in blood: Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort

“…Pathway analyses using the top 20 AD predicting metabolites derived from the Relief method showed that the nitrogen pathway was overrepresented. Some of the molecules selected have been reported in metabolomics studies and have been implicated in neurodegeneration: dodecanoate, which is a C12 fatty acid, was found correlated to longitudinal measures of cognition in the ADNI cohort [3] and so was the bile acid glycolithocholate, which was associated to both AD and cognition measures (ADAS-Cog13) in one of the biggest cross-sectional studies on cognition, AD and the microbiome [18]. Plasmalogens were also found in decreased levels in our cohort in agreement with an earlier report [19].…”

Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

“…We observed consistent expression of CYP27A1 and CYP7B1, which are involved in the initial steps of the alternative bile acid pathway depicted in Figure 3, from the analysis of transcriptomic data of post-mortem brain samples from three independent cohorts (Supplementary file 1). In the figure, the bile acids have been marked as cytotoxic and neuroprotective 7,23 , but all bile acids become toxic at elevated concentrations because of their ability to solubilize membranes 23 . We did not observe expression of CYP7A1 and CYP8B1, suggesting that the classical bile acid biosynthesis pathway is not prevalent in the brain samples.…”

“…Bile acids are derived from cholesterol and their synthesis is regulated by complex feedback mechanisms 12,18 . Recent studies have identified bile acids in brain samples and linked them with cognitive decline in AD 7,10,19 . To understand the physiological role of bile acids in the brain of AD and CN individuals, we analyzed transcriptome data from post-mortem brain samples obtained from three independent cohorts and identified genes involved in the alternative bile acid pathway were expressed compared to the classical pathway in the brain.…”

“…Recent studies have shown that metabolic dysfunction is one of the factors associated with neurodegenerative disorders 3,4 . Various physiological processes such as lipid metabolism, immune function, amyloid precursor protein metabolism, oxidative stress, neurotransmitter function as well as mitochondrial functions are altered in AD that can affect metabolism 5,6,7 . Interest in the transport of biochemical compounds between the brain and the gut and their possible role in regulating metabolic changes centrally and peripherally has increased recently across several neurodegenerative diseases 8,9 .…”

“…Interest in the transport of biochemical compounds between the brain and the gut and their possible role in regulating metabolic changes centrally and peripherally has increased recently across several neurodegenerative diseases 8,9 . There is increasing evidence to suggest a role in AD for primary and secondary bile acids 7,10,11 . Bile acids are amphipathic molecules and primary bile acids are derived from cholesterol mostly in the liver, whereas secondary bile acids are typically produced by bacteria in the gut 12 .…”