Project Summary: Pulmonary hypertension (PH) is a devastating disease that leads to right heart failure and death. Despite recent advances in drug therapy and improvements in patient care, PH remains a fatal disease. Thus, a mechanism-based breakthrough is imperative to identify novel targets and discover innovative strategies to control and potentially cure PH. Our findings suggest that a dysfunctional gut-angiotensin converting enzyme 2 (ACE2)-lung interaction represents this breakthrough. ACE2 is a key gut epithelial cell enzyme of the renin-angiotensin system (RAS), produces angiotensin-(1-7) and together constitutes the vasoprotective axis of the RAS and opposes the fibrotic, proliferative, and inflammatory effects of angiotensin II. We propose that risk factors for PH exert profound influences on the gut resulting in a decrease in gut ACE2. This initiates a series of events key in the establishment of PH. They include increases in gut permeability, inflammation, and microbial dysbiosis. Collectively, they contribute to inflammation, endothelial dysfunction and microvascular pathophysiology. Therefore, we hypothesize that PH is caused by gut ACE2 deficiency-mediated increases in High-Mobility Group Protein B1 (HMGB1) signaling and microbial dysbiosis. Hence, increases in gut ACE2 would decrease HMGB1, reestablish eubiosis and attenuate/reverse PH pathophysiology. This innovative hypothesis is supported by our data and evidence from the literature. However, many questions remain: Are changes in gut permeability and dysbiosis prevalent in PH patients? What is the mechanism of ACE2-mediated gut dysbiosis? How do gut dysbiosis-induced changes impact PH? We propose following aims to address these issues: 1) Investigate the hypothesis that a decrease in intestinal ACE2 results in increased gut permeability, inflammation and dysbiosis, which leads to the development of PH; 2) Investigate the hypothesis that ACE2-induced changes in the gut are mediated by HMGB1; 3) Evaluate the hypothesis that oral ACE2 feeding improves gut barrier properties and rebalances microbial community to protect against PH; 4) Test the impact of gut dysbiosis in PH patients. Results of this study will support our concept that ACE2-mediated dysfunctional gut-lung communication is critical in PH and provide clinical validity for our hypothesis. Thus, the outcome will be valuable for the development of ?paradigm-changing? approaches involving oral supplementation of ACE2 for PH.