Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia
Open accessAbstract
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”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [54]
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”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [54]
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Self-citationThe Mouse Microbiome Is Required for Sex-Specific Diurnal Rhythms of Gene Expression and Metabolism
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Gut microbiota: a potential regulator of neurodevelopment
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
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Mechanisms of sex differences in Alzheimer’s disease
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Emerging roles of innate and adaptive immunity in Alzheimer’s disease
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The gut microbiome in Alzheimer’s disease: what we know and what remains to be explored
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Self-citationMicrobiota–neuroepithelial signalling across the gut–brain axis
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Self-citationChandra, S., Di Meco, A., Dodiya, H. B., Popovic, J., Cuddy, L. K., Weigle, I. Q., Zhang, X., Sadleir, K., Sisodia, S. S., & Vassar, R. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00635-2 · Cited by 58 · see citing works
Self-citationJana, A., Wang, X., Leasure, J. W., Magana, L., Wang, L., Kim, Y.-M., Dodiya, H., Toth, P. T., Sisodia, S. S., & Rehman, J. (2022) · Scientific Reports · doi:10.1038/s41598-022-20889-y · Cited by 43 · see citing works
Self-citation
- 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.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2021-12-02
- Volume
- 219
- Issue
- 1
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC8647415
- 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
- hybrid
- doi.org
- Licence
- 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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