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

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 Klebsiella and Escherichia-Shigella, along with a notable increase in intestinal Bifidobacterium and Lactobacillus as volunteers recovered from acute mountain sickness (AMS). Gavage colonization with Klebsiella pneumoniae and Escherichia coli induced plasma inflammation, increased plasma lysophosphatidylcholine (LPC) levels, and contributed to HAPE in rats at a simulated altitude of 6500 metres. Conversely, a synbiotic containing Bifidobacterium, Lactiplantibacillus, 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 cells (HPMECs) and human pulmonary alveolar epithelial cells (HPAEpiCs) 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 6500 metres. 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.