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

ABSTRACT 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...

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Autores principales:	John P. Haran, Shakti K. Bhattarai, Sage E. Foley, Protiva Dutta, Doyle V. Ward, Vanni Bucci, Beth A. McCormick
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Alzheimer’s Disease dementia elderly gut-brain axis intestinal homeostasis intestinal microbiome Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2aebc885e90a4bd7bd0d7aef98886dd4
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spelling	oai:doaj.org-article:2aebc885e90a4bd7bd0d7aef98886dd42021-11-15T15:55:24ZAlzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway10.1128/mBio.00632-192150-7511https://doaj.org/article/2aebc885e90a4bd7bd0d7aef98886dd42019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00632-19https://doaj.org/toc/2150-7511ABSTRACT 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.John P. HaranShakti K. BhattaraiSage E. FoleyProtiva DuttaDoyle V. WardVanni BucciBeth A. McCormickAmerican Society for MicrobiologyarticleAlzheimer’s Diseasedementiaelderlygut-brain axisintestinal homeostasisintestinal microbiomeMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alzheimer’s Disease dementia elderly gut-brain axis intestinal homeostasis intestinal microbiome Microbiology QR1-502
spellingShingle	Alzheimer’s Disease dementia elderly gut-brain axis intestinal homeostasis intestinal microbiome Microbiology QR1-502 John P. Haran Shakti K. Bhattarai Sage E. Foley Protiva Dutta Doyle V. Ward Vanni Bucci Beth A. McCormick Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway
description	ABSTRACT 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.
format	article
author	John P. Haran Shakti K. Bhattarai Sage E. Foley Protiva Dutta Doyle V. Ward Vanni Bucci Beth A. McCormick
author_facet	John P. Haran Shakti K. Bhattarai Sage E. Foley Protiva Dutta Doyle V. Ward Vanni Bucci Beth A. McCormick
author_sort	John P. Haran
title	Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway
title_short	Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway
title_full	Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway
title_fullStr	Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway
title_full_unstemmed	Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway
title_sort	alzheimer’s disease microbiome is associated with dysregulation of the anti-inflammatory p-glycoprotein pathway
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/2aebc885e90a4bd7bd0d7aef98886dd4
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Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway

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