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Propionate has protective and anti-inflammatory effects on the blood–brain barrier

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Title: Propionate has protective and anti-inflammatory effects on the blood–brain barrier
Authors: Hoyles, L
Snelling, T
Umlai, U-K
Nicholson, J
Carding, S
Glen, R
McArthur, S
Item Type: Poster
Abstract: Introduction Propionate is a short-chain fatty acid (SCFA) produced by the human gut microbiota from dietary substrates, and is biologically active via the G protein coupled receptors FFAR2 and FFAR3. It is taken up from the gut and reaches systemic circulation in micromolar quantities. The blood–brain barrier (BBB) is the major interface between the circulation and central nervous system. FFAR3 is expressed on the vascular endothelium and a likely target for propionate in the BBB. We hypothesized exposure of the BBB to propionate influences barrier integrity and function. Methods and materials We investigated the in vitro effects of a physiologically relevant concentration (1 μM) of propionate upon the human immortalised cerebromicrovascular endothelial cell line hCMEC/D3. FFAR3 was present on these cells. We, therefore, performed an unbiased transcriptomic analysis of confluent hCMEC/D3 monolayers treated or not for 24 h with 1 μM propionate, supported by in vitro validation of key findings and assessment of functional endothelial permeability barrier properties. Results Propionate treatment had a significant (PFDR < 0.1) effect on the expression of 1136 genes. It inhibited several inflammation-associated pathways: TLR-specific signalling, NFkappaB signalling, and cytosolic DNA-sensing. Functional validation of these findings confirmed the down-regulation of TLR signalling by propionate, achieved primarily through down-regulation of endothelial CD14 expression. Accordingly, propionate prevented LPS-induced increases in paracellular permeability to 70 kDa FITC-dextran and loss of transendothelial electrical resistance. Propionate activated the NFE2L2 (NRF2)-driven protective response against oxidative stress. Confirming these data, propionate limited free reactive oxygen species induction by the mitochondrial respiratory inhibitor rotenone. Conclusions Our data strongly suggest the SCFA propionate contributes to maintaining BBB integrity and protecting against inflammatory challenge by downregulating BBB responsiveness. In addition to its well-described effects on cholesterol metabolism, maintenance of propionate levels in the circulation may be an additional mechanism whereby this dietary-derived metabolite protects against neurovascular disease.
Issue Date: 20-Mar-2018
URI: http://hdl.handle.net/10044/1/62966
Copyright Statement: © 2018 The Author(s).
Sponsor/Funder: Alzheimer's Research UK
Medical Research Council (MRC)
Funder's Grant Number: ARUK-PPG2016B-6
Conference Name: Alzheimer's Research UK Research Conference 2018
Appears in Collections:Department of Surgery and Cancer