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

eLife

Aswin Verhoeven¹  Martin Giera¹  Sabina Tahirovic²  Finn Peters²  Alessio Vittorio Colombo²  Laura Sebastian Monasor²  Edith Winkler³  Harald Steiner³  Christian Haass⁴  Jochen Herms⁵  Steffanie Heindl⁶  Gemma Llovera⁶  Vikramjeet Singh⁶  Corinne Benakis⁶  Rebecca Katie Sadler⁶  Stefan Roth⁶  Martin Dichgans⁷  Arthur Liesz⁷  Andrew J MacPherson⁸  Mercedes Gomez de Aguero⁸  Frits Kamp⁹  Samira Parhizkar⁹ 

[1] Center for Proteomics and Metabolomics, Leiden University Medical Center (LUMC), Leiden, Netherlands;German Center for Neurodegenerative Diseases (DZNE), Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Germany;Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Germany;Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany;Munich Cluster for Systems Neurology (SyNergy), Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Germany;Munich Cluster for Systems Neurology (SyNergy), Munich, Germany;Center for Neuropathology and Prion Research, Ludwig-Maximilians University Munich, Munich, Germany;Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany;Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany;Munich Cluster for Systems Neurology (SyNergy), Munich, Germany;Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, Bern, Switzerland;Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany;

关键词: alzheimer's disease;    microbiome;    microglia;    neuroinflammation;    amyloid;    metabolites;    Mouse;   

DOI  :  10.7554/eLife.59826

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY