RT Journal Article
SR Electronic
T1 Microbiome–host systems interactions: Protective effects of propionate upon the blood–brain barrier
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 170548
DO 10.1101/170548
A1 Lesley Hoyles
A1 Tom Snelling
A1 Umm-Kulthum Umlai
A1 Jeremy K. Nicholson
A1 Simon R. Carding
A1 Robert C. Glen
A1 Simon McArthur
YR 2017
UL http://biorxiv.org/content/early/2017/08/01/170548.abstract
AB 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.ADHDattention-deficit hyperactivity disorderASDautism spectrum disorderBBBblood–brain barrierCNScentral nervous systemFFARfree fatty acid receptorKEGGKyoto Encyclopaedia of Genes and GenomesGOGene OntologyLPSlipopolysaccharideSCFAshort-chain fatty acidSPIASignalling Pathway Impact Analysis