Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation

Study information

Reviewed Marked as Reviewed by Folakunmi on 2024-3-27

study design

laboratory experiment
time series / longitudinal observational

Citation

PMID PubMed identifier for scientific articles.

35017199

DOI Digital object identifier for electronic documents.

10.1136/gutjnl-2021-326269

URI

Authors

Chen C, Liao J, Xia Y, Liu X, Jones R, Haran J, McCormick B, Sampson TR, Alam A, Ye K

Journal

Gut

Year

2022

Keywords:

brain/gut interaction

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.

Experiment 1

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Reviewed Marked as Reviewed by Folakunmi on 2024-3-26

Curated date: 2024/03/09

Curator: Graycepaul

Revision editor(s): Graycepaul, Folakunmi

Subjects

Location of subjects: United States of America

Host species Species from which microbiome was sampled. Contact us to have more species added.: Mus musculus

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Alzheimer's disease [X]Dementia in Alzheimer's disease,[X]Dementia in Alzheimer's disease (disorder),AD,AD - Alzheimer's disease,Alzheimer Dementia,Alzheimer dementia,Alzheimer Dementia, Presenile,ALZHEIMER DIS,Alzheimer Disease,Alzheimer disease,Alzheimer disease, familial,Alzheimer Type Dementia,Alzheimer's,Alzheimer's Dementia,Alzheimer's dementia,Alzheimer's disease,Alzheimer's disease (disorder),Alzheimer's disease, NOS,Alzheimers,Alzheimers Dementia,Alzheimers dementia,ALZHEIMERS DIS,Alzheimers disease,DAT - Dementia Alzheimer's type,Dementia in Alzheimer's disease,Dementia in Alzheimer's disease (disorder),Dementia in Alzheimer's disease, unspecified (disorder),Dementia of the Alzheimer's type,Dementia, Alzheimer Type,Dementia, Presenile,Dementia, Presenile Alzheimer,Disease, Alzheimer,Disease, Alzheimer's,Presenile Alzheimer Dementia,sporadic Alzheimer's disease,alzheimer's disease

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Healthy control FMT mice

Group 1 name Corresponds to the case (exposed) group for case-control studies: Alzheimer's disease FMT mice

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: ex germ-free mice inoculated with fecal samples from human Alzheimer's disease donors

Group 0 sample size Number of subjects in the control (unexposed) group: 3

Group 1 sample size Number of subjects in the case (exposed) group: 3

Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any): human donors had no antimicrobial exposure within the preceding 4 weeks

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: V4

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: relative abundances

Statistical test: ANOVA

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: Yes

Matched on Factors on which subjects have been matched on in a case-control study: age

Signature 1

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Reviewed Marked as Reviewed by Folakunmi on 2024-3-26

Curated date: 2024/03/09

Curator: Graycepaul

Revision editor(s): Graycepaul, Welile, Folakunmi

Source: Figure 5

Description: Microbiome analysis in humanised ex-germ-free 3xTg mouse stool, revealing the significant abundance in the faeces from human AD fecal inoculated germ-free mice and faeces from healthy human inoculated germ-free mice

Abundance in Group 1: increased abundance in Alzheimer's disease FMT mice

NCBI	Quality Control	Links
Bacteroides fragilis
Bacteroides intestinalis
Bacteroides xylanisolvens

Revision editor(s): Graycepaul, Welile, Folakunmi

Signature 2

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Reviewed Marked as Reviewed by Folakunmi on 2024-3-26

Curated date: 2024/03/09

Curator: Graycepaul

Revision editor(s): Graycepaul, Welile, Muqtadirat, Folakunmi

Source: Figure 5

Description: Microbiome analysis in humanised ex-germ-free 3xTg mouse stool, revealing the significant abundance in the faeces from human AD fecal inoculated germ-free mice and faeces from healthy human inoculated germ-free mice

Abundance in Group 1: decreased abundance in Alzheimer's disease FMT mice

NCBI	Quality Control	Links
Enterocloster bolteae
Parabacteroides goldsteinii

Revision editor(s): Graycepaul, Welile, Muqtadirat, Folakunmi