Understanding the regulation of the intestinal epithelium in Alzheimer’s disease by commensal bacteria and the role it plays in preventing neurocognitive decline

ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by amyloid beta plaques and neurofibrillary tangles in the brain along with inflammation both in the brain and systemically. This has led to the theory of microbial communities or infections as causative in the development of neuroinflammation, immunosenescence, and inflamm-aging seen in AD. Our own research has demonstrated a decrease in gut microbiota with anti-inflammatory properties and higher abundances of pro-inflammatory gut microbiota in AD elders. However, it is unclear how the AD microbiome exerts effects on the central nervous system. To address this gap in knowledge we have performed gut microbiome profiling, analysis of immune cell populations in blood, serum cytokine profiling, and cognitive assessments of AD elders at 90-day intervals. This analysis identified changes in B cell populations with an increased abundance of class-switched and decreased abundance of naïve B cells at levels of greater cognitive impairment. To better understand how the microbiome may control AD progression, we propose to investigate the connection between the AD microbiome and the adaptive immune system with a focus on regulation of the intestinal epithelium by commensal gut bacteria. Specifically, we intend to use stool and plasma samples collected from our AD cohort to measure makers of intestinal permeability and determine whether metabolites secreted by the AD gut microbiome cause disruptions in the intestinal epithelium. We will directly study the disruptive effects of AD stool by applying stool supernatants to intestinal epithelial cells, quantifying changes in epithelial permeability using established assays, and determining whether specific taxa depleted in AD are sufficient to cause epithelial disruption. In our previously published data, we have observed the loss of the phytoestrogen-metabolizing bacteria, Adlercreutzia equolifaciens (AE), in the microbiome of AD elders. My preliminary studies reveal that a metabolic product of AE, (S)-equol, prevents epithelial damage in the setting of inflammation. Therefore, we aim to determine whether AE or its metabolic products protect the intestinal epithelium. To untangle the role of the AD microbiome on our observed changes in class switched and naïve B cells, I have collected preliminary data which demonstrates that colonization of mice with the microbiome of AD elders promotes B cell class switching when compared with colonization of cognitively impaired elders without AD. This application proposes to expand this finding and characterize the changes in the adaptive immune system caused by the AD microbiome. This continuing work will further establish the connection between AD related neurocognitive decline, the microbiome, and immune system.