Alzheimer's Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway

Study information

Needs review

study design

time series / longitudinal observational

Citation

PMID PubMed identifier for scientific articles.

31064831

DOI Digital object identifier for electronic documents.

10.1128/mBio.00632-19

URI

Authors

Haran JP, Bhattarai SK, Foley SE, Dutta P, Ward DV, Bucci V, McCormick BA

Journal

mBio

Year

2019

Keywords:

Alzheimer’s Disease, dementia, elderly, gut-brain axis, intestinal homeostasis, intestinal microbiome

The microbiota-gut-brain axis is a bidirectional communication system that is poorly understood. Alzheimer's disease (AD), the most common cause of dementia, has long been associated with bacterial infections and inflammation-causing immunosenescence. Recent studies examining the intestinal microbiota of AD patients revealed that their microbiome differs from that of subjects without dementia. In this work, we prospectively enrolled 108 nursing home elders and followed each for up to 5 months, collecting longitudinal stool samples from which we performed metagenomic sequencing and in vitro T84 intestinal epithelial cell functional assays for P-glycoprotein (P-gp) expression, a critical mediator of intestinal homeostasis. Our analysis identified clinical parameters as well as numerous microbial taxa and functional genes that act as predictors of AD dementia in comparison to elders without dementia or with other dementia types. We further demonstrate that stool samples from elders with AD can induce lower P-gp expression levels in vitro those samples from elders without dementia or with other dementia types. We also paired functional studies with machine learning approaches to identify bacterial species differentiating the microbiome of AD elders from that of elders without dementia, which in turn are accurate predictors of the loss of dysregulation of the P-gp pathway. We observed that the microbiome of AD elders shows a lower proportion and prevalence of bacteria with the potential to synthesize butyrate, as well as higher abundances of taxa that are known to cause proinflammatory states. Therefore, a potential nexus between the intestinal microbiome and AD is the modulation of intestinal homeostasis by increases in inflammatory, and decreases in anti-inflammatory, microbial metabolism.IMPORTANCE Studies of the intestinal microbiome and AD have demonstrated associations with microbiome composition at the genus level among matched cohorts. We move this body of literature forward by more deeply investigating microbiome composition via metagenomics and by comparing AD patients against those without dementia and with other dementia types. We also exploit machine learning approaches that combine both metagenomic and clinical data. Finally, our functional studies using stool samples from elders demonstrate how the c microbiome of AD elders can affect intestinal health via dysregulation of the P-glycoprotein pathway. P-glycoprotein dysregulation contributes directly to inflammatory disorders of the intestine. Since AD has been long thought to be linked to chronic bacterial infections as a possible etiology, our findings therefore fill a gap in knowledge in the field of AD research by identifying a nexus between the microbiome, loss of intestinal homeostasis, and inflammation that may underlie this neurodegenerative disorder.

Experiment 1

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Curated date: 2024/12/16

Curator: AaishahM

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Subjects

Location of subjects: United States of America

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

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: No Dementia (Controls)

Group 1 name Corresponds to the case (exposed) group for case-control studies: Alzheimer's Disease (AD) patients

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Elders with Alzheimer's Disease

Group 0 sample size Number of subjects in the control (unexposed) group: 51

Group 1 sample size Number of subjects in the case (exposed) group: 24

Lab analysis

Sequencing type: WMS

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: Not specified

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: Mixed-Effects Regression

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

Signature 1

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Source: Figure 2

Description: Relative abundance of bacterial taxa in AD patients and controls

Abundance in Group 1: increased abundance in Alzheimer's Disease (AD) patients

NCBI	Quality Control	Links
Alistipes
Bacteroides
Barnesiella
Odoribacter
Collinsella

Revision editor(s): AaishahM