Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.59826
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Funding
- Vascular Dementia Research Foundation
- Deutsche Forschungsgemeinschaft [STE847/6-1, HA1737/16-1, EXC 2145, 390857198, LI-2534/7-1]
- H2020 European Research Council [ERC-StG 802305, NMP-2015-686271]
- Helmholtz Association
- NCL Foundation
- Alzheimer Forschung Initiative [18014]
- Alzheimer's Association [ADSF-21-831226-C]
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Microbiota-derived SCFA play a critical role in promoting A beta deposition in Alzheimer's disease by modulating the microglial phenotype along the gut-brain axis.
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 A beta deposition. Germ-free (GF) AD mice exhibit a substantially reduced A beta plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Al3 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 A beta plaques upon SCFA supplementation, microglia contained less intracellular A beta. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote A beta deposition likely via modulation of the microglial phenotype.
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