Gut Microbiota in Pulmonary Arterial Hypertension: Murine Models and Human Microbial Signatures, Pathogenic Mechanisms, and Emerging Therapeutic Avenues

Pulmonary arterial hypertension (PAH) is a chronic, severe cardiopulmonary disease characterized by the progressive increase in pulmonary vascular resistance (PVR) because of the proliferation and fibrosis of the pulmonary arterioles. Although the disease originates in the pulmonary vasculature, it ultimately leads to right heart failure and death. PAH is associated with high mortality rates and poor prognosis, with no therapies currently available to reverse pulmonary vascular remodeling, imposing substantial socioeconomic burdens. Growing interest in the gut-lung axis has highlighted the role of gut microbiota and their metabolites in the occurrence and development of PAH. Evidence showed that gut dysbiosis and metabolite imbalances, involving reduced short-chain fatty acids (SCFAs), increased trimethylamine-N-oxide (TMAO), and dysregulated tryptophan metabolism, contributed to pulmonary vascular remodeling. This review systematically compares gut microbiota and metabolites across PAH murine models (including chronic hypoxia, SU5416/hypoxia [SuHx], monocrotaline [MCT], and non-classical models) and patients (adults and children). The analysis aims to identify disease-specific microbial and metabolic signatures. It is also discussed how the microbiota and their metabolites may influence inflammation around the pulmonary vasculature. Furthermore, the potential of probiotic therapy, fecal microbiota transplantation (FMT), and mesenchymal stem cells (MSCs) therapies as novel treatment strategies for PAH is discussed.