Butyrate increases ICAM-1 expression in primary bovine endothelial cells through MCT1 and histone deacetylase inhibition

Endothelial cells play a crucial role in the migration of leukocytes to sites of infection or inflammation, mainly through the expression of adhesion molecules. Butyrate, a short-chain fatty acid (SCFA) produced by the gut microbiota, exerts anti-inflammatory and pro-inflammatory effects by regulating these molecules. This discrepancy may be related to the activation or inhibition of different targets, such as G-protein-coupled receptors and histone deacetylases. This study aimed to characterize the effect of butyrate on the expression of endothelial adhesion molecule ICAM-1 and its underlying mechanism in primary bovine umbilical vein endothelial cells (BUVEC). We hypothesized that butyrate increases endothelial ICAM-1 expression, and this effect is associated with the activation of the free fatty acid receptor 2 (FFAR2) or hydroxycarboxylic acid receptor 2 (HCA2) and/or inhibition of histone deacetylase 3 (HDAC3). BUVEC were treated with different concentrations of butyrate, and a high increase in ICAM-1 expression and polymorphonuclear neutrophils (PMN) adhesion was observed at 10 mM butyrate. We found that only HCA2 was expressed in BUVEC, and its activation did not induce ICAM-1 expression. Analysis of intracellular pathways revealed that butyrate increased the phosphorylation of ERK1/2, and its inhibition reduced butyrate-induced ICAM-1 expression. We also demonstrated that BUVEC mainly express monocarboxylate transporter 1 (MCT1) and that its inhibition reduces butyrate-induced ICAM-1 expression. Finally, we demonstrated that butyrate acts as an HDAC inhibitor and MCT1 is essential for this response. Overall, these findings provide a possible mechanism for the effects of butyrate on bovine endothelial cells, which could explain the exacerbated inflammatory response during nutritional imbalance in cattle.