RT Journal Article SR Electronic T1 Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 2233 OP 2252 DO 10.1136/gutjnl-2021-326269 VO 71 IS 11 A1 Chun Chen A1 Jianming Liao A1 Yiyuan Xia A1 Xia Liu A1 Rheinallt Jones A1 John Haran A1 Beth McCormick A1 Timothy Robert Sampson A1 Ashfaqul Alam A1 Keqiang Ye YR 2022 UL http://gut.bmj.com/content/71/11/2233.abstract AB 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.All data relevant to the study are included in the article or uploaded as online supplemental information.