Altered Lung Microbiome and Metabolome Profile in Children With Pulmonary Arterial Hypertension Associated With Congenital Heart Disease

Abstract

BackgroundsPulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular functional and structural changes, resulting in increased pulmonary vascular resistance and eventually right heart failure and death. Congenital Left-to-Right shunts (LTRS) is one type of congenital heart disease (CHD) and PAH associated with the congenital Left-to-Right shunt (PAH-LTRS) is a severe disease in children. However, changes in the lung microbiome and their potential impact on PAH-LTRS have not been not fully studied. We hypothesized that lung microbiota and their derived metabolites have been disturbed in children with PAH-LTRS, which might contribute to the progression and outcomes of PAH-LTRS.MethodsIn this study, 68 age- and sex-matched children of three different groups (patients with PAH-LTRS cohort, patients with LTRS but have no pathologic features of PAH cohort, and healthy reference cohort) were enrolled in the current study. Bronchoalveolar lavage fluid samples from these participants were conducted for multi-omics analysis, including 16S rRNA sequencing and metabolomic profiling. Data progressing and integration analysis were performed to identify pulmonary microbial and metabolic characteristics of PAH-LTRS in children.ResultsWe found that microbial community density was not significantly altered in PAH-LTRS based on α-diversity analysis. Microbial composition analysis indicated phylum of Bacteroidetes was that less abundant while Lactobacillus, Alicycliphilus, and Parapusillimonas were significantly altered and might contribute to PAH in children with LTRS. Moreover, metabolome profiling data showed that metabolites involved in Purine metabolism, Glycerophospholipid metabolism, Galactose metabolism, and Pyrimidine metabolism were also significantly disturbed in the PAH-LTRS cohort. Correlation analysis between microbes and metabolites indicated that alterations in the microbial composition from the lung microbiota could eventually result in the disturbance in certain metabolites, and might finally contribute to the pathology of PAH-LTRS.ConclusionLung microbial density was not significantly altered in patients with PAH-LTRS. Composition analysis results showed that the relative microbiome abundance was different between groups. Metabolome profiling and correlation analysis with microbiota showed that metabolome also altered in children with PAH-LTRS. This study indicated that pulmonary microbes and metabolites disturbed in PAH-LTRS could be potentially effective biomarkers and provides valuable perspectives on clinical diagnosis, treatment, and prognosis of pediatric PAH-LTRS.

Genetic association and bidirectional Mendelian randomization for causality between gut microbiota and six lung diseases

“…Mounting evidence suggests that the gut-dwelling Lactobacillus and its components play a key role in modulating the immune system through stimulating immunological signaling between the gastrointestinal tract and distant organs (58). Consistently, Ma et al have also demonstrated that the increased abundance of Lactobacillus is associated with PAH compared with healthy volunteers and congenital left to right shunt heart diseases (59).…”

Microbiota and pulmonary hypertension: a systematic review on human studies

“…The design of all studies was case-control (Table 1). Two articles were focused on pediatric and adolescent populations (15,16), while the rest of the studies were undertaken on adults (17)(18)(19)(20)(21)(22). In the majority of studies, females were more prevalent than men among PH cases (18)(19)(20)(21)(22).…”

“…Endotoxin level was increased among PH patients due to chronic thromboembolism (18), while, there was no signi cant difference between PH patients due to different etiologies compared to healthy controls in another study (21). Also, different metabolite levels were reported to be changed among PH patients such as short-chain fatty acid (SCFA) and bile acid (BA) (15,21). Interestingly, only one study reported alterations in trimethylamine N-oxide (TMAO) levels and there was no difference between PH and control samples, however, it was signi cantly increased among patients with higher REVEAL scores (21) (Table 3).…”

Pulmonary arterial hypertension associated with congenital heart disease: An omics study

“…In addition, three predictors (based on plasma concentrations of DBH, ANPEP, and ADIO) were detected in patients with congenital ventricular septal defect PH. Ma et al (95) performed 16 S rRNA sequencing and metabolomics analysis on bronchoalveolar lavage fluid of PAH associated with the congenital Left-to-Right shunts (LTRS), patients with LTRS but no PAH, and the healthy group. The integration of multi-omics showed that the pulmonary microbes and metabolites may be potentially effective biomarkers.…”