Immunomodulatory effects of short-chain fatty acids in chronic obstructive pulmonary disease: rebalancing Th17/Treg axis and enhancing epithelial repair.

The imbalance of T helper 17 (Th17)/regulatory T (Treg) is pivotal in the development of chronic obstructive pulmonary disease (COPD). This study focused on evaluating the regulatory effects of short-chain fatty acids (SCFAs) on Th17/Treg balance in COPD. A COPD mouse model was induced by exposure to cigarette smoke (CS) and intranasal lipopolysaccharide (LPS) instillation. Mice were administered sodium acetate (NaA), sodium propionate (NaP), or sodium butyrate (NaB) via oral gavage. Lung function, histopathological changes, cytokine levels, and the distribution of Th17 and Treg cells were then evaluated. Epithelial cell injury induced by cigarette smoke extract (CSE) was assessed using the Cell Counting Kit-8 (CCK-8) assay, wound healing assay, and flow cytometry for apoptosis and T cell subset analysis. SCFAs treatment attenuated pathological damage in lung tissue, including reduced inflammatory cell infiltration and pulmonary fibrosis. SCFAs suppressed apoptosis and increased peak inspiratory flow (PIF) and peak expiratory flow (PEF). SCFAs effectively rebalanced the Th17/Treg axis by suppressing Th17 differentiation while promoting Treg cell expansion, which was accompanied by reduced levels of inflammatory signaling factors (IL-17, IL-6, IL-2, and TNF-α). Moreover, SCFAs enhanced CSE-induced MLE-12 cell viability and migration, and suppressed apoptosis. SCFAs blocked the differentiation of naïve CD4⁺ T cells into Th17 cells while facilitating their differentiation into Treg cells. SCFAs alleviate the pathological features of COPD by restoring the Th17/Treg balance and enhancing epithelial resilience, suggesting their promise as a therapeutic strategy for CS-related COPD.