IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-41283-w.html
   My bibliography  Save this article

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

Author

Listed:
  • Yiyuan Xia

    (Emory University School of Medicine
    Jianghan University)

  • 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
    University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

  • Beth A. McCormick

    (University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

  • Xiji Shu

    (Jianghan University)

  • Xiaochuan Wang

    (Tongji Medical College, Huazhong University of Science and Technology
    Nantong University)

  • Keqiang Ye

    (Emory University School of Medicine
    Shenzhen Institute of Advanced Technology)

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.

Suggested Citation

  • Yiyuan Xia & Yifan Xiao & Zhi-Hao Wang & Xia Liu & Ashfaqul M. Alam & John P. Haran & Beth A. McCormick & Xiji Shu & Xiaochuan Wang & Keqiang Ye, 2023. "Bacteroides Fragilis in the gut microbiomes of Alzheimer’s disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41283-w
    DOI: 10.1038/s41467-023-41283-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-41283-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-41283-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Zhentao Zhang & Mingke Song & Xia Liu & Seong Su Kang & Duc M. Duong & Nicholas T. Seyfried & Xuebing Cao & Liming Cheng & Yi E. Sun & Shan Ping Yu & Jianping Jia & Allan I. Levey & Keqiang Ye, 2015. "Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease," Nature Communications, Nature, vol. 6(1), pages 1-16, December.
    2. Jing Xiong & Seong Su Kang & Zhihao Wang & Xia Liu & Tan-Chun Kuo & Funda Korkmaz & Ashley Padilla & Sari Miyashita & Pokman Chan & Zhaohui Zhang & Pavel Katsel & Jocoll Burgess & Anisa Gumerova & Kse, 2022. "FSH blockade improves cognition in mice with Alzheimer’s disease," Nature, Nature, vol. 603(7901), pages 470-476, March.
    3. Ruslan Medzhitov, 2007. "Recognition of microorganisms and activation of the immune response," Nature, Nature, vol. 449(7164), pages 819-826, October.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Caroline Wasén & Leah C. Beauchamp & Julia Vincentini & Shuqi Li & Danielle S. LeServe & Christian Gauthier & Juliana R. Lopes & Thais G. Moreira & Millicent N. Ekwudo & Zhuoran Yin & Patrick da Silva, 2024. "Bacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer’s disease mouse models," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Andrew E. Warfield & Pooja Gupta & Madison M. Ruhmann & Quiana L. Jeffs & Genevieve C. Guidone & Hannah W. Rhymes & McKenzi I. Thompson & William D. Todd, 2023. "A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Haiyan Gu & Jing Yang & Jiayu Zhang & Ying Song & Yao Zhang & Pengfei Xu & Yuanxiang Zhu & Liangliang Wang & Pengfei Zhang & Lin Li & Dahua Chen & Qinmiao Sun, 2022. "PCBP2 maintains antiviral signaling homeostasis by regulating cGAS enzymatic activity via antagonizing its condensation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Jia Duan & Peiyu Xu & Huibing Zhang & Xiaodong Luan & Jiaqi Yang & Xinheng He & Chunyou Mao & Dan-Dan Shen & Yujie Ji & Xi Cheng & Hualiang Jiang & Yi Jiang & Shuyang Zhang & Yan Zhang & H. Eric Xu, 2023. "Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. Richard G. Everson & Willy Hugo & Lu Sun & Joseph Antonios & Alexander Lee & Lizhong Ding & Melissa Bu & Sara Khattab & Carolina Chavez & Emma Billingslea-Yoon & Andres Salazar & Benjamin M. Ellingson, 2024. "TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Anastasia Mozokhina & Latifa Ait Mahiout & Vitaly Volpert, 2023. "Modeling of Viral Infection with Inflammation," Mathematics, MDPI, vol. 11(19), pages 1-15, September.
    6. Liu, P.F. & Chu, J.K. & Hou, S.J. & Xu, P. & Zheng, J.Y., 2012. "Numerical simulation and optimal design for composite high-pressure hydrogen storage vessel: A review," Renewable and Sustainable Energy Reviews, Elsevier, vol. 16(4), pages 1817-1827.
    7. Yi Cheng & Hong Zhu & Jun Ren & Hai-Yan Wu & Jia-En Yu & Lu-Yang Jin & Hai-Yan Pang & Hai-Tao Pan & Si-Si Luo & Jing Yan & Kai-Xuan Dong & Long-Yun Ye & Cheng-Liang Zhou & Jie-Xue Pan & Zhuo-Xian Meng, 2023. "Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    8. Jinying Tan & Ruangang Pan & Lei Qiao & Xiufen Zou & Zishu Pan, 2012. "Modeling and Dynamical Analysis of Virus-Triggered Innate Immune Signaling Pathways," PLOS ONE, Public Library of Science, vol. 7(10), pages 1-15, October.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41283-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.