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

Alessio Colombo ,Finn Peters,Martin Dichgans,Corinne Benakis,Stefan Roth,Harald Steiner,Vikramjeet Singh,Steffanie Heindl,Gemma Llovera,Edith Winkler,Samira Parhizkar,Christian Haass,Frits Kamp,Jochen Herms,Aswin Verhoeven,Martin Giera,Arthur Liesz,Sabina Tahirović ,Mercedes Gomez De Agüero ,Laura Sebastián Monasor ,Rebecca Sadler ,Andrew J Macpherson

doi:10.7554/elife.59826

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.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the aggregation and deposition of amyloid-b (Ab) and tau
In accordance with these reports, we observed a striking reduction in cerebral Ab plaque load in 5 months old GF APPPS1 animals compared to their littermate GF APPPS1 animals which have been naturally recolonized (Rec) or APPPS1 mice housed under conventional, specific pathogen-free (SPF) conditions (Figure 1A)
As our initial experiments indicated a specific effect of the gut microbiome on the formation of small plaques, we focused our mechanistic studies on the early phase of Ab plaque deposition, which corresponds to the 3 months of age in APPPS1 mouse model

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the aggregation and deposition of amyloid-b (Ab) and tau. Other studies have identified that antibiotic treatment-induced changes in microbiota composition as well as microbial deficiency in germ-free (GF) animals were associated with reduced Ab pathology (Dodiya et al, 2019; Harach et al, 2017; Minter et al, 2017; Minter et al, 2016). This effect could result from reduced Ab production or increased clearance. While previous studies documented a link between the gut microbiome and Ab pathology, the underlying mechanisms and molecular mediators remain elusive To address this key question, we generated a GF amyloidosis mouse model which allowed us to explore and identify bacterial metabolites that mediate gut-brain axis in AD.

Results

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A Cluster 1

Materials and methods

Funding Funder