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

Alzheimer's & Dementia - Tập 15 Số 1 - Trang 76-92 - 2019
Siamak MahmoudianDehkordi1,2, Matthias Arnold1,2,3, Kwangsik Nho4,2, Shahzad Ahmad5, Jia Wang6,7, Guoxiang Xie7, Gregory Louie1, Alexandra Kueider‐Paisley1, M. Arthur Moseley8, Paul M. Thompson8, Lisa St John Williams8, Jessica D. Tenenbaum9, Colette Blach10, Rebecca Baillie11, Xianlin Han12, Sudeepa Bhattacharyya13, Jon B. Toledo14, Simon Schafferer15, Sebastian Klein15, Therese Koal15, Shannon L. Risacher4, Allan I. Levey16, Alison A. Motsinger‐Reif17, Daniel M. Rotroff17, John Jack17, Thomas Hankemeier18, David A. Bennett19, Philip L. De Jager20, John Q. Trojanowski21, Leslie M. Shaw21, Michael W. Weiner22, P. Murali Doraiswamy23,1,24, Cornelia M. van Duijn5, Andrew J. Saykin4, Gabi Kastenmüller25,3, Rima Kaddurah‐Daouk1,24,25
1Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
2Equal contributors
3Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
4Department of Radiology and Imaging Sciences and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA
5Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands
6Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
7University of Hawaii Cancer Center, Honolulu, HI, USA
8Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Durham, NC, USA
9Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
10Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
11Rosa & Co LLC San Carlos CA USA
12University of Texas Health Science Center at San Antonio, San Antonio, TX USA
13Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
14Department of Neurology, Houston Methodist Hospital, Houston, TX, USA
15BIOCRATES Life Sciences AG, Innsbruck, Austria
16Behavioral Health Service, Crescenz VA Medical Center and Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
17Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA
18Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, RA Leiden, the Netherlands
19Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago IL, USA
20Columbia University College of Physicians and Surgeons Department of Neurology, Center for Translational & Computational Neuroimmunology, New York, NY, USA
21Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
22Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California San Francisco, San Francisco, CA, USA
23Department of Medicine, Duke University, Durham, NC, USA.
24Duke Institute of Brain Sciences, Duke University, Durham, NC, USA
25German Center for Diabetes Research (DZD), Neuherberg, Germany

Tóm tắt

AbstractIntroductionIncreasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut‐brain axis in neurodegeneration. Bile acids (BAs), 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's disease (AD).MethodsSerum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, 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 confounders and multiple testing.ResultsIn AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid: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.DiscussionWe 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.

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