Multi-omics Analyses Identify Gut Microbiota-fecal Metabolites-brain-cognition Pathways in the Alzheimer's Disease Continuum

Overview

Journal Alzheimers Res Ther

Date 2025 Feb 1

PMID 39893498

Authors

Han Zhao

Xia Zhou

Yu Song

Wenming Zhao

Zhongwu Sun

Jiajia Zhu

Yongqiang Yu

Affiliations

Soon will be listed here.

Abstract

Background: Gut microbiota dysbiosis is linked to Alzheimer's disease (AD), but our understanding of the molecular and neuropathological bases underlying such association remains fragmentary.

Methods: Using 16S rDNA amplicon sequencing, untargeted metabolomics, and multi-modal magnetic resonance imaging, we examined group differences in gut microbiome, fecal metabolome, neuroimaging measures, and cognitive variables across 30 patients with AD, 75 individuals with mild cognitive impairment (MCI), and 61 healthy controls (HC). Furthermore, we assessed the associations between these multi-omics changes using correlation and mediation analyses.

Results: There were significant group differences in gut microbial composition, which were driven by 8 microbial taxa (e.g., Staphylococcus and Bacillus) exhibiting a progressive increase in relative abundance from HC to MCI to AD, and 2 taxa (e.g., Anaerostipes) showing a gradual decrease. 26 fecal metabolites (e.g., Arachidonic, Adrenic, and Lithocholic acids) exhibited a progressive increase from HC to MCI to AD. We also observed progressive gray matter atrophy in broadly distributed gray matter regions and gradual micro-structural integrity damage in widespread white matter tracts along the AD continuum. Integration of these multi-omics changes revealed significant associations between microbiota, metabolites, neuroimaging, and cognition. More importantly, we identified two potential mediation pathways: (1) microbiota → metabolites → neuroimaging → cognition, and (2) microbiota → metabolites → cognition.

Conclusion: Aside from elucidating the underlying mechanism whereby gut microbiota dysbiosis is linked to AD, our findings may contribute to groundwork for future interventions targeting the microbiota-metabolites-brain-cognition pathways as a therapeutic strategy in the AD continuum.

References

Rathore S, Habes M, Iftikhar M, Shacklett A, Davatzikos C . A review on neuroimaging-based classification studies and associated feature extraction methods for Alzheimer's disease and its prodromal stages. Neuroimage. 2017; 155():530-548. PMC: 5511557. DOI: 10.1016/j.neuroimage.2017.03.057. View

Frisoni G, Testa C, Zorzan A, Sabattoli F, Beltramello A, Soininen H . Detection of grey matter loss in mild Alzheimer's disease with voxel based morphometry. J Neurol Neurosurg Psychiatry. 2002; 73(6):657-64. PMC: 1757361. DOI: 10.1136/jnnp.73.6.657. View

Smith S, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols T, Mackay C . Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage. 2006; 31(4):1487-505. DOI: 10.1016/j.neuroimage.2006.02.024. View

Chen C, Liao J, Xia Y, Liu X, Jones R, Haran J . Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation. Gut. 2022; 71(11):2233-2252. PMC: 10720732. DOI: 10.1136/gutjnl-2021-326269. View

Bijlsma S, Bobeldijk I, Verheij E, Ramaker R, Kochhar S, Macdonald I . Large-scale human metabolomics studies: a strategy for data (pre-) processing and validation. Anal Chem. 2006; 78(2):567-74. DOI: 10.1021/ac051495j. View

Cho H, Choi J, Hwang M, Kim Y, Lee H, Lee H . In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann Neurol. 2016; 80(2):247-58. DOI: 10.1002/ana.24711. View

Vogt N, Kerby R, Dill-McFarland K, Harding S, Merluzzi A, Johnson S . Gut microbiome alterations in Alzheimer's disease. Sci Rep. 2017; 7(1):13537. PMC: 5648830. DOI: 10.1038/s41598-017-13601-y. View

Friedland R, McMillan J, Kurlawala Z . What Are the Molecular Mechanisms by Which Functional Bacterial Amyloids Influence Amyloid Beta Deposition and Neuroinflammation in Neurodegenerative Disorders?. Int J Mol Sci. 2020; 21(5). PMC: 7084682. DOI: 10.3390/ijms21051652. View

Bui T, Manneras-Holm L, Puschmann R, Wu H, Troise A, Nijsse B . Conversion of dietary inositol into propionate and acetate by commensal Anaerostipes associates with host health. Nat Commun. 2021; 12(1):4798. PMC: 8355322. DOI: 10.1038/s41467-021-25081-w. View

10.

Want E, OMaille G, Smith C, Brandon T, Uritboonthai W, Qin C . Solvent-dependent metabolite distribution, clustering, and protein extraction for serum profiling with mass spectrometry. Anal Chem. 2006; 78(3):743-52. DOI: 10.1021/ac051312t. View

11.

Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti G . Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms. Expert Rev Neurother. 2017; 18(1):83-90. PMC: 5958896. DOI: 10.1080/14737175.2018.1400909. View

12.

Chandra S, Sisodia S, Vassar R . The gut microbiome in Alzheimer's disease: what we know and what remains to be explored. Mol Neurodegener. 2023; 18(1):9. PMC: 9889249. DOI: 10.1186/s13024-023-00595-7. View

13.

Tomasi D, Volkow N . Functional connectivity density mapping. Proc Natl Acad Sci U S A. 2010; 107(21):9885-90. PMC: 2906909. DOI: 10.1073/pnas.1001414107. View

14.

Ibrahim B, Suppiah S, Ibrahim N, Mohamad M, Hassan H, Syed Nasser N . Diagnostic power of resting-state fMRI for detection of network connectivity in Alzheimer's disease and mild cognitive impairment: A systematic review. Hum Brain Mapp. 2021; 42(9):2941-2968. PMC: 8127155. DOI: 10.1002/hbm.25369. View

15.

Hagve T, CHRISTOPHERSEN B . Evidence for peroxisomal retroconversion of adrenic acid (22:4(n-6)) and docosahexaenoic acids (22:6(n-3)) in isolated liver cells. Biochim Biophys Acta. 1986; 875(2):165-73. DOI: 10.1016/0005-2760(86)90165-7. View

16.

Tsugawa H, cajka T, Kind T, Ma Y, Higgins B, Ikeda K . MS-DIAL: data-independent MS/MS deconvolution for comprehensive metabolome analysis. Nat Methods. 2015; 12(6):523-6. PMC: 4449330. DOI: 10.1038/nmeth.3393. View

17.

Chen J, Liu S, Wang C, Zhang C, Cai H, Zhang M . Associations of Serum Liver Function Markers With Brain Structure, Function, and Perfusion in Healthy Young Adults. Front Neurol. 2021; 12:606094. PMC: 7947675. DOI: 10.3389/fneur.2021.606094. View

18.

Horgusluoglu E, Neff R, Song W, Wang M, Wang Q, Arnold M . Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease. Alzheimers Dement. 2021; 18(6):1260-1278. PMC: 9085975. DOI: 10.1002/alz.12468. View

19.

Pavlidis P, Noble W . Analysis of strain and regional variation in gene expression in mouse brain. Genome Biol. 2001; 2(10):RESEARCH0042. PMC: 57797. DOI: 10.1186/gb-2001-2-10-research0042. View

20.

Singh V, Chertkow H, Lerch J, Evans A, Dorr A, Kabani N . Spatial patterns of cortical thinning in mild cognitive impairment and Alzheimer's disease. Brain. 2006; 129(Pt 11):2885-93. DOI: 10.1093/brain/awl256. View