Chronic obstructive pulmonary disease (COPD) affects >250 million people worldwide causing ~3 million deaths annually. Epidemiological studies suggest that high-fibre diets reduce COPD risk; however the underlying mechanisms of protection remain unclear. A new connection between the gut and the lungs has emerged defining the Gut-Lung axis of immune regulation that links intestinal dysbiosis to worsening of inflammatory lung conditions and respiratory infections. However, how the gut microbiome affects COPD phenotypes remains unknown. Short-chain fatty acids (SCFA) derived from microbial fermentation of dietary fibre emerged as important modulators of lung function. Our exciting unpublished data show that the SCFA butyrate protects against murine pneumococcal pneumonia promoting bactericidal phenotypes in macrophages. Here we hypothesize that gut dysbiosis linked to recurrent antibiotic use in COPD patients results in loss of SCFA-producing bacteria, increasing the risk for recurrent infections and exacerbations of COPD. Using 16S-rRNA sequencing and shotgun metagenomic analysis we will characterise gut microbiome profiles in COPD patients versus that of healthy volunteers, and correlate microbiome composition and SCFA levels in faeces and plasma to lung function and COPD phenotypes. Increased respiratory colonisation of COPD patients with bacteria including Pseudomonas aeruginosa and Streptococcus pneumoniae has been linked to COPD exacerbations. We propose that by promoting bactericidal phenotypes in macrophages butyrate may prevent infection-triggered exacerbations.To prove this we will evaluate the killing capacity of human alveolar macrophages and peripheral blood monocytes isolated from COPD patients stimulated ex vivo with butyrate and infected with pneumococci and P. aeruginosa. Finally we will evaluate the efficacy of oral butyrate supplementation therapy to prevent COPD progression and exacerbations. This project will allow us to harness the power of the gut microbiome and develop nutritional and microbiome-based therapies for improved clinical
