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

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; Winkler, Edith; Herms, Jochen; Benakis, Corinne; Dichgans, Martin; Steiner, Harald; Giera, Martin; Haass, Christian; ... (2021). Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition. eLife, 10 eLife Sciences Publications 10.7554/eLife.59826

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie

UniBE Contributor:

Gomez de Agüero Tamargo, Maria de la Mercedes and Macpherson, Andrew

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2050-084X

Publisher:

eLife Sciences Publications

Language:

English

Submitter:

Rahel Fuhrer

Date Deposited:

20 Sep 2021 11:21

Last Modified:

20 Sep 2021 11:21

Publisher DOI:

10.7554/eLife.59826

PubMed ID:

33845942

Uncontrolled Keywords:

alzheimer's disease amyloid immunology inflammation metabolites microbiome microglia mouse neuroinflammation neuroscience

BORIS DOI:

10.48350/159085

URI:

https://boris.unibe.ch/id/eprint/159085

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