Microbiome–Metabolome Axis in BALF Reveals Novel Diagnostic Biomarkers for Congenital Heart Disease-Associated Pulmonary Arterial Hypertension

<b>Background:</b> Early identification of irreversible pulmonary vascular remodeling in congenital heart disease-associated pulmonary arterial hypertension (C-PAH) is critical for optimizing surgical timing. Current noninvasive diagnostic methods are inadequate, and the lung microbiome and metabolome may provide novel insights into disease progression. <b>Methods:</b> We analyzed bronchoalveolar lavage fluid (BALF) from 47 children, including those with C-PAH (n = 15), CHD without PAH (C-NPAH, n = 16), and healthy controls (n = 16), using 16S rRNA gene sequencing and untargeted metabolomics. Differential microbial taxa and metabolites were identified, and their interactions with clinical indicators were assessed via Random Forest (RF) and Mediation Analysis. <b>Results:</b> C-PAH patients exhibited airway microbial dysbiosis, characterized by an elevated Firmicutes/Bacteroidetes (F/B) ratio and increased abundance of <i>g_Lactobacillus</i>. Metabolomic profiling revealed 88 differential metabolites between C-PAH and controls, and 3 between C-PAH and C-NPAH. N1-methylnicotinamide (MNAM) and 2-piperidone emerged as potential biomarkers. Mediation analysis showed that <i>g_Eikenella</i> influenced PAH indirectly through 2-piperidone (β = -0.376, <i>p</i> = 0.026), indicating a microbe-metabolite-host interaction. <b>Conclusions:</b> Integrative microbiome-metabolome profiling of BALF reveals potential biomarkers for C-PAH. These findings provide exploratory evidence that microbial and metabolic biomarkers, particularly 2-piperidone and MNAM, hold potential for the early, noninvasive identification of irreversible pulmonary vascular remodeling, but require further validation in independent cohorts.