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Cited by 108Gut microbiota and healthAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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

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Xia, Yiyuan, Xiao, Yifan, Wang, Zhi-Hao, Liu, Xia, Alam, Ashfaqul M., Haran, John P., McCormick, Beth A., Shu, Xiji +2 more·2023·Nature Communications
DOI 10.1038/s41467-023-41283-wPMC PMC10482867
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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.

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  • Microbial biomarkers, including specific taxa such as Bacteroides fragilis and metabolite signatures such as elevated TMAO, may serve as non-invasive diagnostic tools for early AD detection.

    “Microbial biomarkers, including specific taxa (e.g., Bacteroides fragilis) and metabolite signatures (e.g., elevated TMAO), may also serve as non-invasive diagnostic tools for early AD detection [132].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [132]

    The Discussion reports higher Bacteroides abundance in the AD patient cohort and identifies B. fragilis as a prominent strain; the Results also find it enriched in mice receiving AD fecal transplants. The paper does not establish B. fragilis as a non-invasive tool for early diagnosis, and searches for TMAO and diagnostic biomarkers found no support for the elevated-TMAO example. (LLM, conf=0.87)

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Cited by

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Authors
Xia, Y., Xiao, Y., Wang, Z.-H., Liu, X., Alam, A. M., Haran, J. P., McCormick, B. A., Shu, X., Wang, X., & Ye, K.
Affiliations
  • Emory University (US)
  • Jianghan University (CN)
  • University of Kentucky (US)
  • University of Massachusetts Chan Medical School (US)
  • Nantong University (CN)
Corresponding author
  • Shu, Xiji
  • Wang, Xiaochuan
  • Ye, Keqiang
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-09-06
Volume
14
Issue
1
Pages
5471-5471
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-41283-w
PMC
PMC10482867
OpenAlex
W4386484750
Cited by
108
References
13
Citations by year
2026: 29 · 2025: 49 · 2024: 28 · 2023: 2
FWCI
9.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (AG065177)
  • Natural Science Foundation of Hubei Province (2022CFA104)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Bacteroides fragilis, Alzheimer's disease, gut microbiota, microglial activation, prostaglandin E2, polyunsaturated fatty acid metabolites, C/EBPβ, asparaginyl endopeptidase, fecal microbiota transplantation, gut dysbiosis, cognitive impairment, transgenic mice
MeSH terms
Gastrointestinal Microbiome, Alzheimer Disease, Animals, Bacterial Infections, Bacteroides, Bacteroides fragilis, Hydroxy Acids, Mice, Transgenic, RNA, Ribosomal, 16S, Dinoprostone, Microglia, Mice

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