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 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.

Where to Look into the Puzzle of Polyphenols and Health? The Postbiotics and Gut Microbiota Associated with Human Metabotypes

“…As an example, two neurodegenerative disorders, Alzheimer's disease, and multiple sclerosis, have recently been associated with a depletion of Adlercreutzia equolifaciens , an equol‐producing bacterium from Eggerthellaceae family. [ 94,95 ]…”

Fecal Microbiota Transplantation in Neurological Disorders

“…In recent years, numerous publications on the relation between AD and the gut microbiota have become available. AD patients have a different gut microbiota composition compared to healthy controls or elderly without dementia (Vogt et al, 2017;Zhuang et al, 2018;Haran et al, 2019;Li B. et al, 2019;Liu et al, 2019), but α-diversity measures show contrasting results (Vogt et al, 2017;Li B. et al, 2019;Liu et al, 2019;Saji et al, 2019). Hypotheses on the role of the gut microbiota include direct actions of bacteria, indirect actions or aging-related processes (Angelucci et al, 2019).…”

“…Several studies suggest an important role of the gut microbiota in the pathophysiology of neurological disorders. A different human gut microbiota composition compared to healthy controls has been reported for several neurological disorders, such as Parkinson's disease (Hasegawa et al, 2015;Keshavarzian et al, 2015;Scheperjans et al, 2015;Unger et al, 2016), multiple sclerosis (Miyake et al, 2015;Chen et al, 2016;Jangi et al, 2016;Cosorich et al, 2017), autism spectrum disorder (Finegold et al, 2002(Finegold et al, , 2010De Angelis et al, 2013Kang et al, 2013;Ma et al, 2019), Alzheimer's disease (Vogt et al, 2017;Zhuang et al, 2018;Haran et al, 2019;Li B. et al, 2019;Liu et al, 2019), neuromyelitis optica (Cree et al, 2016), Rett syndrome (Strati et al, 2016), epilepsy (Xie et al, 2017;Peng et al, 2018;Lindefeldt et al, 2019), amyotrophic lateral sclerosis (Fang et al, 2016;Rowin et al, 2017;Mazzini et al, 2018), cerebral infarction (Karlsson et al, 2012;Yin et al, 2015), spinal cord injury (Gungor et al, 2016), and multiple system atrophy (Tan et al, 2018). However, data on microbiota composition are frequently inconsistent and numerous potential confounders are involved.…”

Peripheral inflammatory response in human tuberculosis treatment is predicted by a combination of pathogen sterilization and microbiome dysbiosis

“…To predict the post-pre fold change in abundance of HRZE and NTZ-affected host genes as a function of the corresponding fold change in abundance of microbiota ASVs and TTP using Random Forest Regression. 30 To perform feature selection for each gene and rank features based on their prediction importance we used Boruta 48 . Boruta is a RF classification and regression wrapper for feature selection that allows identification of variables important for the prediction task while also removing redundant ones.…”