Gut opportunistic pathogens contribute to high-altitude pulmonary edema by elevating lysophosphatidylcholines and inducing inflammation.

UNLABELLED

Gut microbiota have been found to promote hypoxia-induced intestinal injury. However, the role of gut microbiota in high-altitude pulmonary edema (HAPE), the preventive effect of synbiotic on HAPE, and the mechanisms by which they might work remain unknown. In this study, we aimed to investigate the role of gut microbiota in the pathogenesis of HAPE and to explore the underlying mechanisms involved. We performed a fecal microbiome analysis and found a significant decrease in intestinal and , along with a notable increase in intestinal and , as volunteers recovered from acute mountain sickness (AMS). Gavage colonization with and induced plasma inflammation, increased plasma lysophosphatidylcholine (LPC) levels, and contributed to HAPE in rats at a simulated altitude of 6,500 m. Conversely, a synbiotic containing , , fructooligosaccharides, and isomaltose-oligosaccharides significantly reduced the severity of HAPE. Cellular experiments and molecular dynamics simulations revealed that LPCs can cause damage and permeability to human pulmonary microvascular endothelial cell (HPMEC) and human pulmonary alveolar epithelial cell (HPAEpiC) monolayers under hypoxic conditions by disrupting cell membrane integrity. In addition, tail vein injection of LPCs promoted HAPE in mice at a simulated altitude of 6,500 m. In conclusion, this study describes a gut microbiota-LPCs/inflammation-HAPE axis, an important new insight into HAPE that will help open avenues for prevention and treatment approaches.

IMPORTANCE

The role of the gut microbiota in high-altitude pulmonary edema (HAPE) is currently unknown. This study found that intestinal and contribute to HAPE by inducing inflammation and increasing lysophosphatidylcholine (LPC) levels under hypoxic conditions. Conversely, a synbiotic containing , , fructooligosaccharides, and isomaltose-oligosaccharides significantly reduced the severity of HAPE. Further investigation revealed that LPCs can cause damage and permeability to human pulmonary microvascular endothelial cell (HPMEC) and human pulmonary alveolar epithelial cell (HPAEpiC) monolayers under hypoxic conditions by disrupting cell membrane integrity. These findings contribute to the understanding of the pathogenesis of HAPE and will benefit populations living at high altitude or traveling from low to high altitude.