Effect of High-Fibre Diet and Short Chain Fatty Acids on Macrophage Function

Inflammation has been implicated in the progression of a variety of lung diseases and a high-fibre diet (HFiD) has been shown to demonstrate anti-inflammatory properties, an effect that to date has mainly been associated with the microbiota-derived short chain fatty acids (SCFAs) which are thought to elicit anti-inflammatory effects via the activation of G protein-coupled receptors (GPCRs) and via their ability to act as epigenetic regulators and inhibit histone deacetylases (HDAC) activity. The cellular and molecular mechanisms behind the ability of HFiD to mediate its protective effects remain poorly understood, and the overall aims of our study were to investigate differences in the transcriptional profiles between the lung-resident inflammatory cells of low-fibre diet (LFiD)- and high-fibre diet (HFiD)-fed mice for 12 weeks using RNA-sequencing, assess the ability of diet to particularly modulate adherent bronchoalveolar lavage (BAL) cells phenotype and function in the context of inflammatory lung disease using a multiplex enzyme-linked immunosorbent assay (ELISA) and to investigate the possibility that SCFAs function via regulating chromatin structure in monocytes/macrophages using chromatin immunoprecipitation (ChIP) followed by sequencing. We demonstrated that 680 differentially expressed genes were statistically significant between lung-resident inflammatory cells isolated from LFiD- and HFiD-fed mice, of which 385 genes were up- or down- regulated by more than 1.5 fold. Pro-inflammatory mediators secreted by lipopolysaccharide (LPS)-induced adherent BAL cells of HFiD-fed male mice were higher than those of LFiD-fed mice. However, adherent BAL cells from female mice fed a HFiD had dampened inflammatory responses compared to those fed a LFiD. Finally, a mixture of SCFAs at physiological concentrations and ratios induced a significant increase in histone 3 at lysine 9 (H3K9) acetylation in human monocytic THP-1 cells. However, the HDAC inhibitory effects of SCFAs induced a genome-wide H3K9 hyperacetylation resulting in a genome-wide enrichment and spreading of the ChIP signal.