Plasma short-chain fatty acids are associated with COPD and COPD phenotypes

Abstract Background and aim Short-chain fatty acids (SCFAs) are metabolites largely produced by the gut microbiota, except for formate, which is also produced by the host. SCFAs may influence COPD development by modulating the immune system. This study examined the relationships between circulating SCFA concentrations and COPD and COPD phenotypes. Methods We report findings from a single-centre observational study with 130 patients with COPD and 103 controls. Eight SCFAs (formate, acetate, propionate, butyrate, isobutyrate, valerate, isovalerate and α-methylbutyrate) were quantified in plasma using isotope-labelled gas chromatography-tandem mass spectrometry. Associations between SCFAs, COPD status, and COPD phenotypes (severely obstructive COPD, emphysema, eosinophilic COPD, frequent exacerbations, and symptom burden) were evaluated using multivariable regression analyses adjusted for age, sex, smoking, and body composition. Results Plasma formate concentrations were inversely associated with COPD status (adjusted OR 0.33; 95% CI 0.15 to 0.66; p = 0.004). Propionate and isobutyrate concentrations were inversely associated with severely obstructive COPD (adjusted ORs 0.46; 95% CI 0.24 to 0.86; p = 0.018, and 0.33; 95% CI 0.14 to 0.75; p = 0.012, respectively). Propionate concentrations were also inversely associated with frequent exacerbations of COPD (adjusted OR 0.23; 95% CI 0.07 to 0.62; p = 0.007). Isovalerate was positively associated with symptom burden (CAT score) (estimate 1.76; 95% CI 0.20 to 3.32; p = 0.027). No consistent associations were observed for emphysema or eosinophilic COPD. Conclusions SCFA formate was inversely related to COPD. Several SCFAs were associated with specific COPD phenotypes. Future studies should investigate the underlying mechanisms linking SCFAs to COPD and include the often-overlooked formate, while acknowledging formate’s dual origin.