Identification of Diagnostic Biomarkers Causally Associated With Gut Microbiota and Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a pulmonary disease associated with alterations in gut microbiota. We aimed to identify potential diagnostic genes causally associated with gut microbiota and PAH. Mendelian randomization (MR) was performed to screen gut microbiota causally associated with PAH and to identify gut microbiota-related genes. A regulatory network was constructed to reveal the relationships among genes, gut microbiota and PAH. Diagnostic genes were screened and used to construct a diagnostic model for PAH. Characteristics of immune infiltration and diagnostic gene expression in each cell type were evaluated at the transcriptome and single-cell levels. Family. Porphyromonadaceae and genus. Eubacteriumfissicatena were risk factors for PAH, whereas phylum. Actinobacteria, class. Bacilli, genus. Erysipelatoclostridium, and genus. Ruminococcaceae were protective factors for PAH. The gene-gut microbiota-PAH network showed causal associations among six gut microbiota taxa, 13 PAH-associated genes and PAH. Copper metabolism MURR1 domain (COMMD) containing 10 (COMMD10), FES proto-oncogene, tyrosine kinase (FES), nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1), solute carrier family 22 member 4 (SLC22A4), and synaptogyrin 1 (SYNGR1) were identified as diagnostic genes, with Area Under Curve (AUC) values ranging from 0.79 to 0.99. The abundances of activated B cells, activated CD8 T cells, eosinophils, mast cells, and T helper cells were increased, whereas the abundances of activated dendritic cells (DCs), gamma delta T cells, MDSCs, macrophages, neutrophils, plasmacytoid DCs, and regulatory T cells were decreased in PAH. NUCKS1 was expressed in each cell type and was lower in T/NK and NK cells. The study deepens the understanding of PAH pathogenesis, and may provide diagnostic targets for PAH.