Gut Dysbiosis and Altered Circulating Microbial Metabolites in Patients with Pulmonary Arterial Hypertension

Introduction: Inflammation plays a mechanistic role in pulmonary arterial hypertension (PAH); however, what triggers inflammation remains unclear. Hypothesis: PAH is characterized by gut dysbiosis and barrier dysfunction, leading to an altered burden of circulating microbial metabolic products, promoting disease. We aimed to characterize the gut microbiome and circulating microbial metabolic products in healthy controls and PAH patients. Methods: The V4 hypervariable region of the 16S rRNA gene was analyzed from fecal samples of 40 healthy controls and 57 PAH patients. Plasma was analyzed for interleukin (IL)-6, claudin-3, trimethylamine N-oxide (TMAO), short chain fatty acids, and secondary bile acids. Results: PAH patients had elevated plasma IL-6 (Fig 1A, P =.02), claudin-3, a measure of intestinal permeability (Fig 1B, P =.04), and TMAO (Fig 1C, P =.04), and reduced taurolithocholic acid (Fig 1D, P =.02). Short chain fatty acid levels were not significantly different (data not shown). Principal component analysis (PCOA) of pairwise Bray-Curtis dissimilarity showed distinct microbiome compositions (Fig 1E, P <.001). The Shannon diversity index (Fig 1F, P <.001) and species richness (Fig 1G, P =0.005) were lower in PAH patients. Linear discriminant analysis (LDA) of effect size revealed that PAH patients had increased relative abundances of Bacteroidetes and Proteobacteria and decreased relative abundances of Ruminococcaceae and Lachnospiraceae (Fig 1H). There was no difference in gut microbiome richness and Shannon diversity between patients with low, intermediate, and high-risk REVEAL scores (data not shown). Conclusions: PAH patients have distinct gut dysbiosis, increased intestinal permeability (claudin-3), and circulating microbial metabolic products. These findings support our hypothesis that microbiome-driven, pro-inflammatory signals may contribute to PAH pathogenesis.