Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation

• Type of Material: Article
• Authors: Chun Chen, Emory University; Jianming Liao, Emory University; Yiyuan Xia, Emory University; Xia Liu, Emory University; Rheinallt M Jones, Emory University; John Haran, University of Massachusetts, Worcester; Beth McCormick, University of Massachusetts, Worcester; Timothy Sampson, Emory University; Ashfaqul Alam, University of Kentucky, Lexington; Keqiang Ye, Emory University
• Language: English
• Date: 2022-01-11
• Publisher: BMJ Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © Author(s) (or their employer(s)) 2022.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): https://doi.org/10.1136/gutjnl-2021-326269
• Title of Journal or Parent Work: Gut Microbiota
• Volume: 71
• Issue: 11
• Start Page: 2233
• End Page: 2252
• Grant/Funding Information: This work is supported by a grant from the National Institute of Health (RO1, AG065177) to KY. Additional support was provided by the Georgia Clinical and Translational Science Alliance of the National Institutes of Health under award number UL1TR002378 and Emory ADRC grant P30 AG066511.; This study was supported in part by the Emory Gnotobiotic Animal (EGAC), which is subsidised by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Rodent Behavioral Core (RBC), which is subsidised by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities; the Emory Integrated Genomics Core (EIGC), which is subsidised by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities; as well as Emory HPLC Bioanalytical Core (EHBC), which was supported by the Department of Pharmacology, Emory University School of Medicine.
• Keywords: Alzheimer’s disease; gut microbiota; human microbiome
• Research Categories: Biology, Microbiology; Health Sciences, Public Health; Biology, Neuroscience

Abstract

Objective This study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer’s disease (AD) pathogenesis. Design We analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors. Results Microbial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients’ gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors’ microbiota transplants. Conclusions These findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.