The Gut Microbiome Study In Patients With Idiopathic Pulmonary Arterial Hypertension

BackgroundIdiopathic pulmonary arterial hypertension(IPAH)is an important subtype of pulmonary arterial hypertension,characterized by progressive pulmonary vascular resistance of unknown causes,eventually leading to right heart failure and even death.The unclear pathogenesis of IPAH has led to a bottleneck in clinical treatment and targeted drug development.Pulmonary arterial hypertension has been reported to be closely related to gut microbiome alterations.Microbial-derived metabolites such as short-chain fatty acids and trimethylamine N-oxide may be involved in the pathological process of pulmonary arterial hypertension.Studies on the gut microbiome of this specific subtype of pulmonary arterial hypertension,IPAH,are still lacking.However,studying IPAH from the perspective of the gut microbiome may help to explore the pathogenesis of IPAH and may facilitates the identification of key molecular targets for the diagnosis and treatment of IPAH.ObjectivesThe primary objectives of this study were to describe the characteristic alterations in gut microbiome of the patients with IPAH and to explore the role and mechanism of changes in gut microbiome and its derived metabolites in the pathogenesis of IPAH.MethodsIn the first part,a high-quality human gut microbiome research cohort was established,and high-throughput sequencing technology was used to identify key microbial taxa associated with IPAH.The functional characteristics of the gut microbiome in patients with IPAH were evaluated based on functional annotation information.The correlation between the gut microbiome and the clinical phenotype of patients with IPAH was evaluated using bioinformatics and statical methods subsequently.The panoramic features of the gut microbiome in patients with IPAH were comprehensively described in terms of composition and function.In the second part,multiple human plasma non-targeted metabolomics research cohorts were integrated to screen for host plasma differential metabolites related to microbiome alterations in patients with IPAH,and to explain the possible mechanism of gut microbiome involvement in the development of IPAH from a metabolic perspective.A monocrotaline-induced rat model of pulmonary arterial hypertension was used to evaluate the effects of microbial-derived metabolites on the pulmonary arterial hypertension phenotype and to explore the mechanisms.ResultsIn the first part,this study identified a significant imbalance of gut microbiome in patients with IPAH.Compared with the healthy control group,bacteria such as Clostridium citroniae that produce trimethylamine N-oxide were significantly enriched in the IPAH cohort;bacteria that produce short-chain fatty acids,such as Roseburia intestinalis and Roseburia inulinivorans were less abundant in the IPAH cohort.Bacteria related with tryptophan metabolism,such as Bacteroides thetaiotaomicron,Alistipes onderdonkii,were relatively enriched in the IPAH cohort,while Bifidobacterium longum were less abundant in the IPAH cohort.Veillonella dispar and Veillonella parvula were positively correlated with the severity of IPAH,while Roseburia inulinivorans were negatively correlated with the severity of IPAH.Futher analysis showed that changes in gut microbiome composition were accompanied by the enrichment of virulence factor genes and changes in metabolic functions such as energy metabolism,carbohydrate metabolism,and amino acid metabolism.In the second part,this study found that patients with IPAH had plasma non-targeted metabolic disturbances represented by abnormalities in histidine,arginine and energy metabolism.Changes in metabolites such as L-histidine,histamine and 3-methylhistidine in the histidine metabolism pathway were closely related to the severity of IPAH.The functional changes in gut microbiome may exacerbate the disorder of histidine metabolism in patients with IPAH and promote the development of IPAH.The results of this study suggest that additional supplementation of histidine from the gut significantly reduced the right ventricular systolic pressure,right ventricular hypertrophy and pulmonary vascular remodeling in a monocrotaline-induced rat model of pulmonary arterial hypertension.In addition,histamine H2 receptor antagonists antagonized the biological effect of additional histidine supplementation,while histamine H1 receptor antagonists had no significant effect.Therefore,this study indicates that histidine may play a protective role in IPAH by activating the histamine H2 receptor.ConclusionsThe gut microbiome of patients with IPAH undergoes significant alterations and is closely related to the development of the disease.Changes in gut microbiome result in impaired histidine metabolism,which exacerbates the disorder of histidine metabolism in patients with IPAH.This metabolic disorder affects the concentration of histamine and the activation of the H2 receptor,which may play an important role in the occurrence and development of IPAH.This study reveals the correlation between changes in gut microbiome and IPAH,providing a theoretical basis for clinical diagnosis,the search for therapeutic molecular targets,and the development of new drugs for IPAH.