Cited by 120Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsGut microbiota and health

Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia

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Dodiya, Hemraj B., Lutz, Holly L., Weigle, Ian Q., Patel, Priyam, Michalkiewicz, Julia, Roman-Santiago, Carlos J., Zhang, Can Martin, Liang, Yingxia +10 more·2022·Journal of Experimental Medicine

Abstract

We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid β (Aβ) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aβ amyloidosis. Thus, microglia play a critical role in driving gut microbiome–mediated alterations of cerebral Aβ deposition.

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  • Studies on animal models have provided compelling evidence that the altered gut microbiome drives neurodegenerative disease pathogenesis, primarily through the modulation of microglial functions and activation.

    “Moreover, studies on animal models have provided compelling evidence that the altered gut microbiome drives neurodegenerative disease pathogenesis, primarily through the modulation of microglial functions and activation.54–57”
  • Microglia are essential mediators of the microbiota-gut-brain axis in Aβ pathology.

    “These results suggest that microglia are essential mediators of the microbiota–gut–brain axis in Aβ pathology.54”

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Authors
Dodiya, H. B., Lutz, H. L., Weigle, I. Q., Patel, P., Michalkiewicz, J., Roman-Santiago, C. J., Zhang, C. M., Liang, Y., Srinath, A., Zhang, X., Xia, J., Olszewski, M., Zhang, X., Schipma, M. J., Chang, E. B., Tanzi, R. E., Gilbert, J. A., & Sisodia, S. S.
Affiliations
  • University of Chicago (US)
  • Scripps Institution of Oceanography (US)
  • Northwestern University (US)
  • Harvard University (US)
Corresponding author
Sisodia, Sangram S.
Venue
Journal of Experimental Medicine
Published
2021-12-02
Volume
219
Issue
1
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
OpenAlex
W3216844018
Cited by
120
References
112
Citations by year
2026: 27 · 2025: 31 · 2024: 27 · 2023: 21 · 2022: 14
FWCI
9.88
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
Funders
  • Cure Alzheimer’s Fund
  • Open Philanthropy Project
  • Good Ventures Foundation
  • Bright Focus Foundation (A2019032F)
  • Alzheimer’s Association
  • Luminescence Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
gut microbiota, amyloid-beta, Alzheimer's disease, microglia, antibiotic therapy, fecal microbiota transplantation, amyloid plaques, CSF1R inhibitor, microglial depletion, sex differences, transcriptome, neurodegeneration
MeSH terms
Gastrointestinal Microbiome, Fecal Microbiota Transplantation, RNA-Seq, Amyloidosis, Animals, Antibodies, Brain, Feces, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Sex Factors, Cytokines, Amyloid beta-Peptides, Microglia, Chemokines, Gene Expression Profiling, Mice, Gene Ontology

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