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

Chun Chen, Jianming Liao, Yiyuan Xia, Xia Liu, Rheinallt Jones, John Haran, Beth McCormick, Timothy Robert Sampson, Ashfaqul Alam, Keqiang Ye

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Article number326269
JournalGut
DOIs
StatePublished - Nov 1 2022

Bibliographical note

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.

Funding Information:
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. The metabolomics analysis on the feces, serum and brain samples from the AD and HC humanised ex-GF mice and the brains from the GF and SPF 3xTg mice was performed by Metabolon, Morrisville, North Carolina, USA.

Publisher Copyright:
© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

  • brain/gut interaction

ASJC Scopus subject areas

  • Gastroenterology

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