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

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 whi...

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Autores principales: 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, Winkler, Edith, Herms, Jochen, Benakis, Corinne, Dichgans, Martin, Steiner, Harald, Giera, Martin, Haass, Christian, Tahirovic, Sabina, Liesz, Arthur
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043748/
https://www.ncbi.nlm.nih.gov/pubmed/33845942
http://dx.doi.org/10.7554/eLife.59826
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author 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
Winkler, Edith
Herms, Jochen
Benakis, Corinne
Dichgans, Martin
Steiner, Harald
Giera, Martin
Haass, Christian
Tahirovic, Sabina
Liesz, Arthur
author_facet 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
Winkler, Edith
Herms, Jochen
Benakis, Corinne
Dichgans, Martin
Steiner, Harald
Giera, Martin
Haass, Christian
Tahirovic, Sabina
Liesz, Arthur
author_sort Colombo, Alessio Vittorio
collection PubMed
description 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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spelling pubmed-80437482021-04-21 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 J Winkler, Edith Herms, Jochen Benakis, Corinne Dichgans, Martin Steiner, Harald Giera, Martin Haass, Christian Tahirovic, Sabina Liesz, Arthur eLife Immunology and Inflammation 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. eLife Sciences Publications, Ltd 2021-04-13 /pmc/articles/PMC8043748/ /pubmed/33845942 http://dx.doi.org/10.7554/eLife.59826 Text en © 2021, Colombo et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
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
Winkler, Edith
Herms, Jochen
Benakis, Corinne
Dichgans, Martin
Steiner, Harald
Giera, Martin
Haass, Christian
Tahirovic, Sabina
Liesz, Arthur
Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
title Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
title_full Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
title_fullStr Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
title_full_unstemmed Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
title_short Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
title_sort microbiota-derived short chain fatty acids modulate microglia and promote aβ plaque deposition
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043748/
https://www.ncbi.nlm.nih.gov/pubmed/33845942
http://dx.doi.org/10.7554/eLife.59826
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