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Microbiome–host systems interactions: Protective effects of propionate upon the blood–brain barrier

View ORCID ProfileLesley Hoyles, Tom Snelling, Umm-Kulthum Umlai, View ORCID ProfileJeremy K. Nicholson, View ORCID ProfileSimon R. Carding, View ORCID ProfileRobert C. Glen, View ORCID ProfileSimon McArthur
doi: https://doi.org/10.1101/170548
Lesley Hoyles
1Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK
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  • For correspondence: lesley.hoyles11@imperial.ac.uk s.mcarthur@qmul.ac.uk
Tom Snelling
1Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK
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Umm-Kulthum Umlai
1Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK
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Jeremy K. Nicholson
1Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK
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Simon R. Carding
2Norwich Medical School, University of East Anglia, UK
3The Gut Health and Food Safety Research Programme, The Quadram Institute, Norwich Research Park, Norwich, UK
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Robert C. Glen
1Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK
4Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK
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Simon McArthur
5Institute of Dentistry, Barts & the London School of Medicine & Dentistry, Blizard Institute, Queen Mary University of London, London, UK
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  • ORCID record for Simon McArthur
  • For correspondence: lesley.hoyles11@imperial.ac.uk s.mcarthur@qmul.ac.uk
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Abstract

Gut microbiome composition and function are symbiotically linked with host health, and altered in metabolic, inflammatory and neurodegenerative disorders. Three recognized mechanisms exist by which the microbiome influences the gut–brain axis: modification of autonomic/sensorimotor connections, immune activation, and neuroendocrine pathway regulation. We hypothesized interactions between circulating gut-derived microbial metabolites and the blood–brain barrier (BBB) also contribute to the gut–brain axis. Propionate, produced from dietary substrates by colonic bacteria, stimulates intestinal gluconeogenesis and is associated with reduced stress behaviours, but its potential endocrine role has not been addressed. After demonstrating expression of the propionate receptor FFAR3 on human brain endothelium, we examined the impact of a physiologically relevant propionate concentration (1 μM) on BBB properties in vitro. Propionate inhibited pathways associated with non-specific microbial infections via a CD14-dependent mechanism, suppressed expression of LRP-1 and protected the BBB from oxidative stress via NRF2 (NFE2L2) signaling. Together, these results suggest gut-derived microbial metabolites interact with the BBB, representing a fourth facet of the gut–brain axis that warrants further attention.

ADHD
attention-deficit hyperactivity disorder
ASD
autism spectrum disorder
BBB
blood–brain barrier
CNS
central nervous system
FFAR
free fatty acid receptor
KEGG
Kyoto Encyclopaedia of Genes and Genomes
GO
Gene Ontology
LPS
lipopolysaccharide
SCFA
short-chain fatty acid
SPIA
Signalling Pathway Impact Analysis
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 01, 2017.
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Microbiome–host systems interactions: Protective effects of propionate upon the blood–brain barrier
Lesley Hoyles, Tom Snelling, Umm-Kulthum Umlai, Jeremy K. Nicholson, Simon R. Carding, Robert C. Glen, Simon McArthur
bioRxiv 170548; doi: https://doi.org/10.1101/170548
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Microbiome–host systems interactions: Protective effects of propionate upon the blood–brain barrier
Lesley Hoyles, Tom Snelling, Umm-Kulthum Umlai, Jeremy K. Nicholson, Simon R. Carding, Robert C. Glen, Simon McArthur
bioRxiv 170548; doi: https://doi.org/10.1101/170548

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