Sputum short-chain fatty acids, microbiome, inflammation, and mucus plugging in obstructive airway disease

Abstract

Background: Short-chain fatty acids (SCFAs), produced by anaerobic bacteria through fermentation in the gut, may suppress eosinophilic inflammation while potentially promoting neutrophilic inflammation. However, the role of local SCFAs in the airway microbiome, inflammation, and mucus plugging in type 2-dominant obstructive airway diseases remains unclear.

Objective: Our aim was to investigate associations between sputum SCFAs and the relative abundance of anaerobic bacteria, neutrophil and eosinophil counts in sputum, and mucus plug scores on computed tomography images in patients with obstructive airway diseases.

Methods: Sputum samples and chest computed tomography images were prospectively collected in stable patients with asthma with fixed airflow limitation, chronic obstructive pulmonary disease, and asthma-chronic obstructive pulmonary disease overlap (ACO). Sputum samples were analyzed for concentrations of SCFA, including n-butyrate, acetate, and propionate; microbiome composition using 16S rRNA sequencing; and inflammatory cell differentials.

Results: In 46 patients, enriched for ACO with relatively high levels of type 2 markers, higher SCFA levels were associated with higher relative abundance of bacteria of the phylum Bacteroidetes and lower relative abundance of bacteria of the phylum Proteobacteria. Hierarchic clustering identified a severe eosinophil-dominant inflammation cluster characterized by lower SCFAs levels and higher mucus plug scores. In the 2 neutrophilic clusters, one characterized by higher SCFAs levels and the other by lower SCFAs levels, lower butyrate levels were significantly associated with higher mucus plug scores.

Conclusion: Local SCFA concentrations may be closely associated with the airway microbiome and influence mucus plugging in ACO-enriched populations. Understanding these interactions could inform therapeutic strategies targeting SCFAs or the microbiome to manage type 2-dominant obstructive airway diseases.

Keywords: COPD; Short-chain fatty acid; airway inflammation; asthma; asthma-COPD overlap; computed tomography; imaging; microbiome; mucus.