Reduction in microbiota-derived short-chain fatty acids contributes to the pathogenesis of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive and fatal cardiopulmonary disorder, with growing evidence implicating proinflammatory gut dysbiosis in its pathogenesis. Fast growing broiler chickens (Gallus gallus) spontaneously develop PAH with histopathological features that closely resemble those of the human disease, providing a robust translational model. Gut microbiota composition in PAH-afflicted broilers was compared to that of healthy controls to identify disease-associated microbial alterations. Microbiota depletion was achieved using a broad-spectrum antibiotic cocktail, and oral supplementation with calcium acetate, a short-chain fatty acid (SCFA) salt, was administered to assess therapeutic potential. Pulmonary cytokine expression was measured to evaluate inflammation. PAH-afflicted broilers exhibited gut microbial alterations similar to those observed in human patients, characterized by a reduction in bacterial genera involved in the production of anti-inflammatory metabolites, particularly SCFAs, and an increase in arginine- and tryptophan-producing taxa. Microbiota depletion selectively enriched SCFA-producing bacteria and prevented the onset of PAH. Calcium acetate supplementation significantly mitigated disease progression and reduced pulmonary expression of proinflammatory cytokines. These findings establish a causal relationship between microbiome-derived metabolites and pulmonary vascular remodeling, supporting SCFA-based interventions as a promising therapeutic strategy for PAH.