Airway delivery of Streptococcus salivarius is sufficient to induce experimental pulmonary hypertension in rats

Background and Purpose The causal relationship between altered host microbiome composition, especially the respiratory tract microbiome, and the occurrence of pulmonary hypertension (PH) has not yet been studied. An increased abundance of airway streptococci is seen in patients with PH compared with healthy individuals. This study aimed to determine the causal link between elevated airway exposure to Streptococcus and PH. Experimental Approach The dose‐, time‐ and bacterium‐specific effects of Streptococcus salivarius ( S. salivarius ), a selective streptococci, on PH pathogenesis were investigated in a rat model established by intratracheal instillation. Key Results Exposure to S. salivarius successfully induced typical PH characteristics, such as elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy (Fulton's index) and pulmonary vascular remodelling, in a dose‐ and time‐dependent manner. Moreover, the S. salivarius ‐induced characteristics were absent in either the inactivated S. salivarius (inactivated bacteria control) treatment group or the Bacillus subtilis (active bacteria control) treatment group. Notably, S. salivarius ‐induced PH is characterized by elevated inflammatory infiltration in the lungs, in a pattern different from the classic hypoxia‐induced PH model. Moreover, in comparison with the SU5416/hypoxia‐induced PH model (SuHx‐PH), S. salivarius ‐induced PH causes similar histological changes (pulmonary vascular remodelling) but less severe haemodynamic changes (RVSP, Fulton's index). S. salivarius ‐induced PH is also associated with altered gut microbiome composition, suggesting potential communication of the lung‐gut axis. Conclusion and Implications This study provides the first evidence that the delivery of S. salivarius in the respiratory tract could cause experimental PH in rats.