Abstract
BACKGROUND: Research into the "gut-lung" axis links gut microbiota to pulmonary artery hypertension (PAH). However, the mechanisms by which gut microbiota influence PAH remain unclear. We aimed to investigate the causal relationship between the gut microbiota and PAH using Mendelian randomization analysis, identify key microbiota and metabolites, and explore the regulatory role of associated genes in PAH pathogenesis. METHODS AND RESULTS: We examined the association between gut microbiota taxa and PAH using inverse variance weighted 2-sample Mendelian randomization analysis, Mendelian randomization-Egger, weighted median, and weighted mode methods. Additionally, we identified PAH-regulating genes in the intestinal microbiome using bioinformatics tools and validated their expression levels in the lung tissue of hypoxia-induced PAH mice models by quantitative reverse transcription polymerase chain reaction. Eleven gut microbiota taxa were associated with PAH. The order Clostridiales and genera Eubacterium fissicatena group, Lachnospiraceae UCG004, and Ruminococcaceae UCG002 were positively associated with PAH, whereas the order Bifidobacteriales; family Bifidobacteriaceae; and genera Eubacterium eligens group, Sutterella, Methanobrevibacter, Sellimonas, and Tyzzerella3 were negatively associated with PAH, with some exhibiting bidirectional causality. These microbiota modulate 24 metabolites, including palmitoylcholine, oleoylcholine, and 3,7-dimethylurate, to influence PAH. Hypoxia-induced PAH mice had significantly downregulated 1,4,5-trisphosphate receptor type 2, degrading enzyme, nuclear receptor-interacting protein 1, and growth factor-binding protein 1 in lung tissues, indicating their potential role in PAH regulation. CONCLUSIONS: These findings suggest that gut microbiota composition and associated metabolites contribute to PAH development by regulating lung tissue gene expression. Our findings have implications for advancing gut microbiota-based PAH diagnostic technologies and targeted therapies.