Kim, Seungbum

Introduction: Pulmonary arterial hypertension (PAH) is a fatal disease and vasodilators are the mainstay for its therapy. However, they offer restricted advancement opportunities for the control and treatment of PAH. Thus, the PAH field needs a paradigm-shifting strategy for its successful management and control. Objective: To test the hypothesis that gut microbial dysbiosis and its increased permeability are associated with PAH. Methods: Healthy control subjects and patients with PAH were recruited from two hospitals in the Americas to ascertain the wider applicability of our hypothesis. Fecal samples of PAH patients (n=19) and control, reference subjects (n=16) were obtained at the Hospital de Clinicas de Porto Alegre, Brazil, for microbiota analysis. Plasma/serum samples were collected from PAH patients (n=22) and control, reference subjects (n=19) at the Mayo Clinic, Jacksonville, Florida, USA, for analysis of gut leakiness and inflammatory biomarkers. Results: In PAH patients, a significant decrease in abundance, diversity and evenness of gut microbial population was observed as measured by 16S ribosomal DNA analyses of fecal samples. Analysis of fecal bacteria populations also demonstrated significant increases in gram-positive, facultative-anaerobic genera, such as Actinomyces, Bifidobacterium Slackia, and Streptococcus in PAH patients. Further, plasma zonulin and iFABP, the biomarkers for gut leakiness increased by 40.3% (p=0.0018) and 81% (p=0.0012), respectively in PAH patients. High plasma LPS, HMGB1, and TIMP1 levels are involved in increased gut inflammation and gut mucosal injury. We also observed LPS, HMGB1, and TIMP1 levels were increased by 363% (p=0.0096), 20.5% (p=0.0027), and 213% (p<0.0001), respectively in PAH patients. Conclusions: PAH patients demonstrate profound gut microbial dysbiosis and increased permeability and inflammation. Further characterization of PAH specific microbial species holds novel management potential with the use of pre- and probiotics, designer antibiotics, appropriate fecal/bacterial transplantation, on top of background proven therapies.

Objectives: Pulmonary arterial hypertension (PAH) is a cardiopulmonary disease without effective cure. The objective of this study is to test the hypothesis that PAH patients have a distinct gut microbiome composition acting as a driving force for the increased PAH metabolic biomarkers, acyl carnitines and urate. Methods: Fecal samples from 18 type 1 PAH patients (mean pulmonary arterial pressure [mPAP] 57.4±16.7 mmHg) and 13 reference subjects in Brazil were collected for comparison of microbiome using shotgun metagenomics. Plasma samples from 33 type I PAH patients (mPAP 51.7± 13.5 mmHg) and 19 reference subjects in the USA were used for untargeted metabolomic analysis. Results: More than 80 bacterial taxa were differentially enriched in the microbiomes of the PAH cohort. Random forest machine-learning algorithm predicted PAH patients with 82.4% accuracy from their gut microbiome composition. The most increased taxa in the PAH microbiome were trimethylamine (TMA) producing bacteria like Collinsella (P=0.0037). The PAH metabolome also showed increases of gut microbiome-derived short chain acyl carnitines like isubutyrylcarnitine (P=0.010) and valerylcarnitine (P=0.030), which are the precursors of TMA. In addition, increased urate (P=0.0004) and allantoin (P=0.027) in PAH plasma correlated with significantly increased enzymes producing urate in the PAH microbiome (purine metabolism (P=0.017) and xanthine oxidase (P<0.05)). Conclusion: These findings suggest that the random forest modeling of the gut microbiome composition can be used for prediction of PAH and that the unique gut microbiome of PAH influences acyl carnitines and urate metabolism to contribute to pathophysiology.