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.
Footnotes
Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
Abbreviations
- AD
- Alzheimer’s disease;
- ADAS-Cog13
- 13-item Alzheimer’s Disease Assessment Scale-Cognitive subscale;
- ADMC
- Alzheimer’s Disease Metabolomics Consortium;
- ADNI
- Alzheimer’s Disease Neuroimaging Initiative;
- APOE
- apolipoprotein E;
- ASBT
- Apical sodium-dependent bile acid transporters;
- BBB
- blood-brain barrier;
- BSEP
- Bile salt export pump;
- BSH
- Bile salt hydrolases;
- BA
- bile acid;
- CA
- Cholic acid;
- cAMP
- Cyclic adenosine monophosphate;
- CDCA
- Chenodeoxycholic acid;
- CN
- Cognitively normal older control;
- DCA
- Deoxycholic acid;
- EMCI
- Early mild cognitive impairment;
- FDR
- False discovery rate;
- FXR
- Farnesoid X Receptor;
- GCA
- Glycocholic acid;
- GCDCA
- Glycochenodeoxycholic acid;
- GDCA
- Glycodeoxycholic acid;
- GLCA
- Glycolithocholic acid;
- GUDCA
- Glycoursodeoxycholic acid;
- LCA
- Lithocholic acid;
- LMCI
- Late mild cognitive impairment;
- MCI
- Mild cognitive impairment;
- NTCP
- Sodium/Taurocholate co-transporting polypeptide;
- OST-α
- Organic solute transporter alpha;
- OST-β
- Organic solute transporter beta;
- ROS/MAP
- The Religious Orders Study (ROS) and the Memory and Aging Project (MAP);
- RS
- Rotterdam Study;
- SHP
- Small heterodimer partner;
- SMC
- Subjective memory concern;
- TCA
- Taurocholic acid;
- TCDCA
- taurochenodeoxycholic acid;
- TDCA
- Taurodeoxycholic acid;
- TLCA
- Taurolithocholic acid;
- TMCA
- Trimethoxycinnamic acid;
- TUDCA
- Tauroursodeoxycholic acid;
- UDCA
- Ursodeoxycholic acid