Microbiome\u2013host systems interactions: protective effects of propionate upon the blood\u2013brain barrier

Lesley Hoyles,Simon R Carding,Simon Mcarthur,Umm-Kulthum Umlai,Tom Snelling,Robert C Glen,Jeremy K Nicholson

doi:10.1186/s40168-018-0439-y

Abstract

BackgroundGut microbiota composition and function are symbiotically linked with host health and altered in metabolic, inflammatory and neurodegenerative disorders. Three recognised mechanisms exist by which the microbiome influences the gut–brain axis: modification of autonomic/sensorimotor connections, immune activation, and neuroendocrine pathway regulation. We hypothesised 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.ResultsAfter 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) signalling.ConclusionsTogether, these results suggest gut-derived microbial metabolites interact with the BBB, representing a fourth facet of the gut–brain axis that warrants further attention.

Highlights

Gut microbiota composition and function are symbiotically linked with host health and altered in metabolic, inflammatory and neurodegenerative disorders
Microarray analyses Following initial confirmation of the expression of FFAR3 in human brain endothelium (Fig. 1a) and on hCMEC/D3 cells (Fig. 1b), we investigated the effect of exposure of a b c d e f
Mechanistic studies have identified three principal aspects to the gut–brain axis: modification of autonomic sensorimotor connections [29], immune activation [30] and regulation of neuroendocrine pathways [31], all of which incorporate a role for soluble gut-derived microbial agents, whether metabolic products or structural microbial components (e.g. LPS) themselves

Summary

Introduction

Gut microbiota composition and function are symbiotically linked with host health and altered in metabolic, inflammatory and neurodegenerative disorders. The human body plays host to, and exists in symbiosis with, a significant number of microbial communities, including those of the skin, the oral and vaginal mucosae and, most prominently, the gut [1] This relationship extends beyond simple commensalism to represent a major regulatory influence in health and disease, with changes in abundance of members of the faecal microbiota having been associated with numerous pathologies, including diabetes, hepatic diseases, inflammatory bowel disease, viral infections and neurodegenerative disorders [2,3,4,5,6,7,8]. A major aspect of microbe–host systemslevel communication that is receiving increased attention is the influence the gut microbiota exerts upon the central nervous system (CNS), the so-called gut–brain axis [18].

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