Danik Martirosyan
The gut–lung axis represents a bidirectional communication network linking intestinal and pulmonary immunity through microbial metabolites, immune cell trafficking, and systemic signaling. Short-chain fatty acids (SCFAs) — acetate, propionate, and butyrate — produced through colonic bacterial fermentation of dietary fiber, have emerged as critical immunomodulatory mediators in this axis with significant therapeutic potential for respiratory diseases. SCFAs exert anti-inflammatory effects in the lungs through two principal mechanisms: activation of G protein-coupled receptors FFAR2 (GPR43) and FFAR3 (GPR41) in alveolar macrophages, dendritic cells, and epithelial cells, suppressing pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β) and modulating neutrophil trafficking; and inhibition of histone deacetylases (HDACs), driving epigenetic reprogramming that promotes regulatory T cell (Treg) differentiation, enhances epithelial barrier integrity, and reduces Th2-driven eosinophilia. Preclinical evidence shows that SCFA supplementation or high-fiber diets reduce airway hyperresponsiveness, eosinophilia, and mucus production in murine asthma models, with propionate acting via GPR41 signaling. In acute respiratory distress syndrome (ARDS) models, acetate and butyrate reduce neutrophil infiltration and alveolar-capillary barrier disruption. In chronic obstructive pulmonary disease (COPD), butyrate inhibits IL-13-producing innate lymphoid cells (ILC2) and modulates the NLRP3 inflammasome via GPR43. Limited clinical data associate reduced fecal SCFA levels with increased asthma risk in children, while early-life propionate exposure correlates with protection against atopy. Therapeutic strategies include dietary fiber supplementation, prebiotics (inulin, fructooligosaccharides), probiotics (Faecalibacterium prausnitzii, Bifidobacterium spp., Roseburia spp.), and direct SCFA administration. Postbiotics — bioactive compounds produced during microbial fermentation — represent an emerging approach that bypasses live microbial colonization. Context-dependent effects related to dose, route, disease stage, and baseline microbiome composition necessitate personalized approaches. Translation to clinical practice requires well-designed human trials addressing optimal dosing, delivery routes, patient stratification, and long-term safety. Novelty of the Study: This review highlights short-chain fatty acids as central mediators of the gut–lung axis, integrating receptor-mediated and epigenetic mechanisms with emerging translational strategies such as postbiotics. It emphasizes the role of SCFAs in modulating pulmonary inflammation across multiple respiratory diseases and identifies key gaps for clinical application, particularly in personalized nutrition, dosage, and targeted delivery approaches. Keywords: Short-chain fatty acids; gut–lung axis; pulmonary inflammation; microbiota; FFAR2; FFAR3; histone deacetylase; asthma; COPD; ARDS