Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease (ILD) and is characterised by chronic, progressive, fibrosing interstitial pneumonia of unknown aetiology. The incidence of IPF is increasing steadily, especially in the western world, and due to a lack of effective therapies the mortality rate is rising in parallel.
Fibrotic disease is associated with an M2 macrophage phenotype that favours oxidative phosphorylation and fatty acid oxidation and a reduction in pro-inflammatory M1 macrophages that rely upon glycolysis [1]. In relatively high doses the short-chain fatty-acid (SCFA) acetate has been shown to promote glycolysis in a mouse macrophage cell line [2] . We propose that SCFAs will alter AM metabolism from exaggerated M2-associated oxidative phosphorylation towards that of a homeostatic AM phenotype.
The overall aim of this project is to investigate the impact of diet/microbiome-derived metabolites on alveolar macrophage (AM) metabolic phenotype and function in the context of ILD. Specifically we will assess the impact of diet-derived SCFAs on AM metabolism using Seahorse assays and on metabolic gene expression using QPCR.
Healthy control (buffy coat-derived) and ILD patient PBMC-derived AM-like cells (hAML) will be generated as a model of primary AMs, as described [3] . Cells will be treated with SCFA concentrations that reflect those achieved when consuming a high soluble-fibre diet prior to being stimulated with a pro-fibrotic stimulus. Oxygen consumption rate and extracellular acidification rate will be measured in cultured cells and metabolic gene expression will be assessed in separate cell pellets.