Impact of smoking on gut microbiota and short-chain fatty acids in human and mice: Implications for COPD

•Cigarette smoke exposure reduces short-chain FA levels by altering gut microbiota.•A high-fiber diet counteract smoking-induced gut microbiota changes.•Diet-induced gut microbiota change mitigate lung inflammation and emphysema in COPD.•Targeting gut microbiota may alleviate COPD symptoms alongside traditional treatments.•Dietary interventions can be a part of comprehensive COPD management. We aimed to elucidate the dynamic changes in short-chain fatty acids (SCFA) produced by the gut microbiota following smoking exposure and their role in chronic obstructive pulmonary disease (COPD) pathogenesis. SCFA concentrations were measured in human plasma, comparing non-smokers (n = 6) and smokers (n = 12). Using a mouse COPD model induced by cigarette smoke exposure or elastase-induced emphysema, we modulated SCFA levels through dietary interventions and antibiotics to evaluate their effects on inflammation and alveolar destruction. Human smokers showed lower plasma SCFA concentrations than non-smokers, with plasma propionic acid positively correlating with forced expiratory volume in 1 s/forced vital capacity. Three-month smoking-exposed mice demonstrated altered gut microbiota and significantly reduced fecal SCFA concentrations compared to air-exposed controls. In these mice, a high-fiber diet increased fecal SCFAs and mitigated inflammation and alveolar destruction, while antibiotics decreased fecal SCFAs and exacerbated disease features. However, in the elastase-induced model, fecal SCFA concentration remained unchanged, and high-fiber diet or antibiotic interventions had no significant effect. These findings suggest that smoking exposure alters gut microbiota and SCFA production through its systemic effects. The anti-inflammatory properties of SCFAs may play a role in COPD pathogenesis, highlighting their potential as therapeutic targets.