Pulmonary Arterial Hypertension Patients Have a Proinflammatory Gut Microbiome and Altered Circulating Microbial Metabolites

Inflammation drives pulmonary arterial hypertension (PAH). Gut dysbiosis causes immune dysregulation and systemic inflammation by altering circulating microbial metabolites; however, little is known about gut dysbiosis and microbial metabolites in PAH.To characterize the gut microbiome and microbial metabolites in PAH patients.We performed 16S ribosomal ribonucleic acid gene and shotgun metagenomics sequencing on stool from PAH patients, family controls, and healthy controls. We measured markers of inflammation, gut permeability, and microbial metabolites in plasma from PAH patients, family controls, and healthy controls.The gut microbiome was less diverse in PAH patients. Shannon diversity index correlated with measures of pulmonary vascular disease but not with right ventricular function. PAH patients had a distinct gut microbial signature at the phylogenetic level with lower copies of gut microbial genes that produce anti-inflammatory short-chain fatty acids (SCFAs) and secondary bile acids and lower relative abundances of species encoding these genes. Consistent with the gut microbial changes, PAH patients had relatively lower plasma levels of SCFAs and secondary bile acids. PAH patients also had enrichment of species with the microbial genes that encoded the proinflammatory microbial metabolite trimethylamine. The changes in the gut microbiome and circulating microbial metabolites between PAH patients and family controls were not as substantial as the differences between PAH patients and healthy controls.PAH patients have proinflammatory gut dysbiosis in which lower circulating SCFAs and secondary bile acids may facilitate pulmonary vascular disease. These findings support investigating modulation of the gut microbiome as a potential treatment for PAH.