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Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition

Authors :
Alessio Vittorio Colombo
Rebecca Katie Sadler
Gemma Llovera
Vikramjeet Singh
Stefan Roth
Steffanie Heindl
Laura Sebastian Monasor
Aswin Verhoeven
Finn Peters
Samira Parhizkar
Frits Kamp
Mercedes Gomez de Aguero
Andrew J MacPherson
Edith Winkler
Jochen Herms
Corinne Benakis
Martin Dichgans
Harald Steiner
Martin Giera
Christian Haass
Sabina Tahirovic
Arthur Liesz
Source :
eLife, Vol 10 (2021)
Publication Year :
2021
Publisher :
eLife Sciences Publications Ltd, 2021.

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.

Details

Language :
English
ISSN :
2050084X
Volume :
10
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.f7e1c8681be24568b1770df48198e501
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.59826