Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
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Abstract
Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer’s disease (AD) progression. However, the mechanisms of microbiome–brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aβ deposition. Germ-free (GF) AD mice exhibit a substantially reduced Aβ plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Aβ plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Aβ plaques upon SCFA supplementation, microglia contained less intracellular Aβ. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Aβ deposition likely via modulation of the microglial phenotype.
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Gut microbiota imbalance induces intestinal inflammation and further leads to systemic inflammation through release of immune-stimulating substances and metabolites into blood circulation.
“Gut microbiota imbalance induces intestinal inflammation and further leads to systemic inflammation through the release of immune-stimulating substances and metabolites into blood circulation.103”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [103]
The Discussion (page unavailable) says gut bacteria help maintain the intestinal barrier and that microbial metabolites can act beyond the gut through blood-borne pathways. It does not say that microbiota imbalance induces intestinal inflammation or that this leads to systemic inflammation through substances released into the bloodstream. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSCFAs induce microglial activation and worsen Aβ pathology in both SPF and GF APP/PS1 mice.
“Interestingly, it has been demonstrated that SCFAs induce microglial activation and worsen Aβ pathology in both SPF and GF APP/PS1 mice.199”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [199]
Individual SCFA treatment fails to achieve comparable effects to combined SCFA treatment in primary microglia.
“However, individual SCFA failed to achieve comparable effects as the combined SCFA treatment.199”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [199]
Butyrate and propionate show abundant overlap in microglial transcriptomic profile.
“On the other hand, a comparison between acetate, propionate, and butyrate in primary microglia has reported an abundant overlap between butyrate and propionate in microglial transcriptomic profile.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [199]
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Denman, C. R., Park, S. M., & Jo, J. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1268419 · Cited by 43 · see citing works
- Authors
- Colombo, A. V., Sadler, R. K., Llovera, G., Singh, V., Roth, S., Heindl, S., Sebastian Monasor, L., Verhoeven, A., Peters, F., Parhizkar, S., Kamp, F., Gomez de Aguero, M., MacPherson, A. J., Winkler, E., Herms, J., Benakis, C., Dichgans, M., Steiner, H., Giera, M., Haass, C., Tahirovic, S., & Liesz, A.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Institut für Schlaganfall- und Demenzforschung (DE)
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Leiden University Medical Center (NL)
- Ludwig-Maximilians-Universität München (DE)
- Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, Bern, Switzerland
- University Hospital of Bern (CH)
- Munich Cluster for Systems Neurology (DE)
- Corresponding author
- Liesz, Arthur
- ORCID
- Colombo, Alessio Vittorio
- Sadler, Rebecca Katie
- Llovera, Gemma
- Singh, Vikramjeet
- Roth, Stefan
- Heindl, Steffanie
- Sebastian Monasor, Laura
- Verhoeven, Aswin
- Peters, Finn
- Parhizkar, Samira
- Kamp, Frits
- Gomez de Aguero, Mercedes
- MacPherson, Andrew J
- Herms, Jochen
- Benakis, Corinne
- Dichgans, Martin
- Steiner, Harald
- Giera, Martin
- Haass, Christian
- Tahirovic, Sabina
- Liesz, Arthur
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2021-04-13
- Volume
- 10
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8043748
- OpenAlex
- W3153691725
- Cited by
- 354
- References
- 75
- Citations by year
- 2026: 58 · 2025: 82 · 2024: 73 · 2023: 61 · 2022: 61 · 2021: 18 · 2020: 1
- FWCI
- 33.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, other-oa)
- Open Access CRIS of the University of Bern
- Funders
- Vascular Dementia Research Foundation
- Deutsche Forschungsgemeinschaft (STE847/6-1, HA1737/16-1, EXC 2145 SyNergy - ID 390857198, LI-2534/7-1)
- H2020 European Research Council (ERC-StG 802305, NMP-2015-686271)
- Helmholtz Association (Zukunftsthema "Immunology and Inflammation"))
- NCL Foundation
- Alzheimer Forschung Initiative (18014)
- Alzheimer's Association (ADSF-21-831226-C)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- short-chain fatty acids, gut microbiota, Alzheimer's disease, amyloid plaques, microglia, gut-brain axis, germ-free mice, microbial metabolites, apolipoprotein E, microglial phenotype
- MeSH terms
- Gastrointestinal Microbiome, Alzheimer Disease, Animals, Fatty Acids, Volatile, Female, Male, Specific Pathogen-Free Organisms, Microglia, Mice, Plaque, Amyloid
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