Injection of amyloid-β to lateral ventricle induces gut microbiota dysbiosis in association with inhibition of cholinergic anti-inflammatory pathways in Alzheimer's disease

Study information

Needs review

study design

laboratory experiment

Citation

PMID PubMed identifier for scientific articles.

36171620

DOI Digital object identifier for electronic documents.

10.1186/s12974-022-02599-4

URI

Authors

Qian XH, Liu XL, Chen G, Chen SD, Tang HD

Journal

Journal of neuroinflammation

Year

2022

Keywords:

Alzheimer’s disease, Aβ, Cholinergic anti-inflammatory pathway, Gut microbiota

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease and its pathogenesis is still unclear. There is dysbiosis of gut microbiota in AD patients. More importantly, dysbiosis of the gut microbiota has been observed not only in AD patients, but also in patients with mild cognitive impairment (MCI). However, the mechanism of gut microbiota dysbiosis in AD is poorly understood. Cholinergic anti-inflammatory pathway is an important pathway for the central nervous system (CNS) regulation of peripheral immune homeostasis, especially in the gut. Therefore, we speculated that dysfunction of cholinergic anti-inflammatory pathway is a potential pathway for dysbiosis of the gut microbiota in AD. METHODS: In this study, we constructed AD model mice by injecting Aβ1-42 into the lateral ventricle, and detected the cognitive level of mice by the Morris water maze test. In addition, 16S rDNA high-throughput analysis was used to detect the gut microbiota abundance of each group at baseline, 2 weeks and 4 weeks after surgery. Furthermore, immunofluorescence and western blot were used to detect alteration of intestinal structure of mice, cholinergic anti-inflammatory pathway, and APP process of brain and colon in each group. RESULTS: Aβ1-42 i.c.v induced cognitive impairment and neuron damage in the brain of mice. At the same time, Aβ1-42 i.c.v induced alteration of gut microbiota at 4 weeks after surgery, while there was no difference at the baseline and 2 weeks after surgery. In addition, changes in colon structure and increased levels of pro-inflammatory factors were detected in Aβ1-42 treatment group, accompanied by inhibition of cholinergic anti-inflammatory pathways. Amyloidogenic pathways in both the brain and colon were accelerated in Aβ1-42 treatment group. CONCLUSIONS: The present findings suggested that Aβ in the CNS can induce gut microbiota dysbiosis, alter intestinal structure and accelerate the amyloidogenic pathways, which were related to inhibiting cholinergic anti-inflammatory pathways.

Experiment 1

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Subjects

Location of subjects: China

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: Control group

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

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Mice in the sham-operated group injected in the lateral ventricle with PBS (Baseline).

Group 0 sample size Number of subjects in the control (unexposed) group: 10

Group 1 sample size Number of subjects in the case (exposed) group: 10

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: V3-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)?: No

Alpha Diversity

Chao1 Abundance-based estimator of species richness: unchanged

Simpson Estimator of species richness and species evenness: more weight on species evenness: unchanged

Richness Number of species: unchanged

Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample: unchanged

Experiment 2

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Differences from previous experiment shown

Subjects

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Mice in the sham-operated group injected in the lateral ventricle with PBS (2 weeks after surgery).

Lab analysis

Statistical Analysis

Alpha Diversity

Chao1 Abundance-based estimator of species richness: unchanged

Simpson Estimator of species richness and species evenness: more weight on species evenness: unchanged

Richness Number of species: unchanged

Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample: unchanged

Experiment 3

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Differences from previous experiment shown

Subjects

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Mice in the sham-operated group injected in the lateral ventricle with PBS (4 weeks after surgery).

Lab analysis

Statistical Analysis

Alpha Diversity

Chao1 Abundance-based estimator of species richness: unchanged

Simpson Estimator of species richness and species evenness: more weight on species evenness: unchanged

Richness Number of species: increased

Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample: increased

Signature 1

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Source: Figure 3 (I, M)

Description: The difference in the diversity of gut microbiota in the PBS sham-operated group at the fourth week.

Abundance in Group 1: increased abundance in Alzheimer’s disease

NCBI	Quality Control	Links
Alloprevotella
Streptococcus

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Signature 2

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Source: Figure 3 (J, K, L, N)

Description: The difference in the diversity of gut microbiota in the PBS sham-operated group at the fourth week.

Abundance in Group 1: decreased abundance in Alzheimer’s disease

NCBI	Quality Control	Links
Ruminiclostridium
Akkermansia
Rikenella
Adlercreutzia

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Experiment 4

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Curated date: 2024/03/13

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Differences from previous experiment shown

Subjects

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Mice in the Aβ intracerebroventricular injection (i.c.v) group injected in the lateral ventricle with Aβ1–42 (Baseline).

Lab analysis

Statistical Analysis

Alpha Diversity

Chao1 Abundance-based estimator of species richness: unchanged

Simpson Estimator of species richness and species evenness: more weight on species evenness: unchanged

Richness Number of species: unchanged

Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample: unchanged

Experiment 5

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Curated date: 2024/03/13

Curator: Flo

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Differences from previous experiment shown

Subjects

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Mice in the Aβ intracerebroventricular injection (i.c.v) group injected in the lateral ventricle with Aβ1–42 (2 weeks after surgery).

Lab analysis

Statistical Analysis

Alpha Diversity

Chao1 Abundance-based estimator of species richness: unchanged

Simpson Estimator of species richness and species evenness: more weight on species evenness: unchanged

Richness Number of species: unchanged

Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample: unchanged

Experiment 6

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Mark reviewed

Your review change was submittedDuplicate this Experiment Add a new Signature

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Curated date: 2024/03/13

Curator: Flo

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Differences from previous experiment shown

Subjects

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Mice in the Aβ intracerebroventricular injection (i.c.v) group injected in the lateral ventricle with Aβ1–42 (4 weeks after surgery).