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Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation
Open accessAbstract
Objective: This study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer’s disease (AD) pathogenesis. Design: We analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors. Results: Microbial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients’ gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors’ microbiota transplants. Conclusions: These findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.
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“Furthermore, SCFA supplementation has been found to trigger C/EBPβ/AEP signaling activation and induce cognitive impairment in GF 3xTg-AD mice.196”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [196]
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“Moreover, an elevated level of secondary BA taurohyodeoxycholic acid was reported in the serum of GF 3xTg-AD mice receiving FMT from AD patients.196”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [196]
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“Chen et al. recently demonstrated that particular gut microbiota are associated with neuroinflammation resulting in the pathogenesis of Alzheimer's disease. 46”
From Three Tiers to biological escape velocity: The quest to outwit aging (2022) · cites this paper as [46]
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“Importantly, FMT from AD patients to GF 3xTg-AD mice restored the main AD pathologies and microglial activation.196”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [196]
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“Moreover, the majority of studies that reported the detrimental effects of SCFAs were conducted using GF mice,56,190,196,199 which are functionally and structurally abnormal across various physiological functions.313”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [196]
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Metadata
- Authors
- Chen, C., Liao, J., Xia, Y., Liu, X., Jones, R., Haran, J., McCormick, B., Sampson, T. R., Alam, A., & Ye, K.
- Affiliations
- Emory University (US)
- University of Massachusetts Chan Medical School (US)
- University of Kentucky (US)
- Corresponding author
- Ye, Keqiang
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2022-01-11
- Volume
- 71
- Issue
- 11
- Pages
- 2233-2252
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC10720732
- OpenAlex
- W4205897663
- Cited by
- 491
- References
- 76
- Citations by year
- 2026: 116 · 2025: 141 · 2024: 136 · 2023: 79 · 2022: 19
- FWCI
- 31.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Georgia Clinical and Translational Science Alliance (UL1TR002378)
- Alzheimer's Disease Research Center, Emory University (P30 AG066511)
- National Institute of Health (RO1, AG065177)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, gut microbiota, gut dysbiosis, neuroinflammation, polyunsaturated fatty acids, microglial activation, neurofibrillary tangles, germ-free mice, fecal microbiota transplantation, Bacteroides, insulin/IGF-1 signalling, cognitive impairment, hippocampus
- MeSH terms
- Gastrointestinal Microbiome, Neuroinflammatory Diseases, Alzheimer Disease, Animals, Cognition, Disease Models, Animal, Fatty Acids, Unsaturated, Humans, Inflammation, Insulin-Like Growth Factor I, RNA, Ribosomal, 16S, Mice, Plaque, Amyloid, Insulins, Dysbiosis
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