Gut Microbiota Alterations and Hypoxic Pulmonary Hypertension in Rats Under Antibiotics Intervention

Hypoxia-induced pulmonary hypertension (HPH) represents a severe threat to the life and health of high-altitude populations, and effective therapeutic modalities capable of reversing pulmonary vascular remodeling remain lacking. Although hypoxia is known to induce gut microbiota dysbiosis, the specific role of the microbiota in HPH remains poorly understood. Therefore, this study aimed to investigate the development and progression of HPH under altered gut microbiota states by employing two distinct hypoxic environments: normobaric and hypobaric hypoxia combined with antibiotic intervention strategies, thereby clarifying the precise role played by the gut microbiota in HPH. Sprague-Dawley (SD) rats were used, with 6 rats initially assigned to each group. They were then exposed to chronic hypoxia and divided into two intervention groups, normobaric hypoxia with antibiotic pretreatment (AP) and hypobaric hypoxia with full antibiotic intervention (HA). Baseline physiological status was assessed via body weight and hematological parameters. Right ventricular function was evaluated using echocardiography. Pulmonary vascular remodeling was analyzed via Hematoxylin and eosin (HE) staining, immunohistochemistry (IHC), and Western blotting (WB). Inflammatory responses in the lung and gut tissues were quantified using ELISA. Furthermore, gut microbiota composition and metabolic alterations were profiled using 16S rRNA sequencing, KEGG functional prediction, and fecal targeted metabolomics. 16S rRNA sequencing confirmed that the gut microbiota was significantly altered in the AP group compared with the NH group, whereas there was a profound change in the gut microbiota in the HA group compared with the HH group. In the AP group, echocardiography, lung tissue HE staining, immunohistochemistry, and WB analyses revealed a trend toward improvement compared with the NH group; however, hematological Parameters along with ELISA indicated an exacerbated systemic inflammatory response compared with the NH group. In the HA group, right ventricular function in rats was significantly improved, pulmonary vascular remodeling was markedly attenuated, and inflammatory responses showed a decreasing trend compared with the HH group. This study suggests that the gut microbiota is an important participant in the HPH. Both antibiotic intervention strategies consistently indicate that gut microbiota are associated with HPH. This validation further reinforces the critical standing of the gut-lung axis theory in HPH pathogenesis, providing a novel theoretical foundation and promising clinical strategies for targeting the gut microbiota in the prevention and treatment of HPH.