Abstract
Background Gut microbiota 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.
Results 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.
Conclusions 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.
Footnotes
- Abbreviations
- 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
