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

Background: 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. Methods: 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. Results: C-PAH patients exhibited airway microbial dysbiosis, characterized by an elevated Firmicutes/Bacteroidetes (F/B) ratio and increased abundance of g_Lactobacillus. 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 g_Eikenella influenced PAH indirectly through 2-piperidone (β = −0.376, p = 0.026), indicating a microbe–metabolite–host interaction. Conclusions: 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.