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Original research
Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation
  1. Chun Chen1,
  2. Jianming Liao1,2,
  3. Yiyuan Xia1,
  4. Xia Liu1,
  5. Rheinallt Jones3,
  6. John Haran4,5,6,
  7. Beth McCormick6,
  8. Timothy Robert Sampson7,
  9. Ashfaqul Alam8,9,
  10. Keqiang Ye1,10
  1. 1 Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
  2. 2 Department of Neurosurgery, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
  3. 3 Department of Pediatrics, Emory University, Atlanta, Georgia, USA
  4. 4 Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  5. 5 Center for Microbiome Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  6. 6 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  7. 7 Department of Physiology, Emory University, Atlanta, Georgia, USA
  8. 8 Microbiology, Immunology & Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
  9. 9 Markey Cancer Center, University of Kentucky, Lexington, KY, USA
  10. 10 Faculty of Life and Health Sciences, The Brain Cognition and Brain Disorders Institute (BCBDI), Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, Guangdong, China
  1. Correspondence to Dr Keqiang Ye, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA;{at}


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.

  • brain/gut interaction

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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  • CC and JL contributed equally.

  • Contributors KY is responsible for the overall content as the guarantor. KY and CC conceived the project, designed the experiments, analysed the data, and wrote the manuscript. CC, JL and YX designed and performed most of the experiments and analyzed the data. XL conducted genotype and bred the transgenic mice. JH and BM provided human feces samples. RJ, TRS and AA assisted with data analysis and interpretation and critically read the manuscript.

  • Funding 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.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.