Bacteroides Fragilis in the gut microbiomes of Alzheimer’s disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice

Yiyuan Xia, Yifan Xiao, Zhi-Hao Wang, Xia Liu, Ashfaqul M. Alam, John P. Haran, Beth A. McCormick, Xiji Shu (), Xiaochuan Wang () and Keqiang Ye ()
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Yiyuan Xia: Emory University School of Medicine
Yifan Xiao: Jianghan University
Zhi-Hao Wang: Emory University School of Medicine
Xia Liu: Emory University School of Medicine
Ashfaqul M. Alam: University of Kentucky, Microbiology, Immunology & Molecular Genetics Office - MN 376
John P. Haran: University of Massachusetts Chan Medical School
Beth A. McCormick: University of Massachusetts Chan Medical School
Xiji Shu: Jianghan University
Xiaochuan Wang: Tongji Medical College, Huazhong University of Science and Technology
Keqiang Ye: Emory University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Gut dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors’ fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPβ transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPβ transgenic mice.

Date: 2023
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DOI: 10.1038/s41467-023-41283-w

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