Exploring the Causal Relationship Between Gut Microbiota and Pulmonary Artery Hypertension: Insights From Mendelian Randomization

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: 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.