ABSTRACT

Gastrointestinal dysfunction is a common symptom of acute mountain sickness (AMS). The gut microbiota and γδ T cells play critical roles in intestinal disease. However, the mechanistic link between the microbiota and γδ T cells in hypoxia-induced intestinal injury remains unclear. Here, we show that hypoxia-induced intestinal damage was significantly alleviated after microbiota depletion with antibiotics. Hypoxia modulated gut microbiota composition by promoting antimicrobial peptides angiogenin-4 secretions. The abundance of Clostridium in the gut of mice after hypoxia significantly decreased, while the abundance of Desulfovibrio significantly increased. Furthermore, Desulfovibrio-derived phosphatidylethanolamine and phosphatidylcholine promoted γδ T cell activation. In CD1d-deficient mice, the levels of intraepithelial IL-17A and γδ T cells and intestinal damage were significantly decreased compared with those in wild-type mice under hypoxia. Mechanistically, phospholipid metabolites from Desulfovibrio are presented by intestinal epithelial CD1d to induce the proliferation of IL-17A-producing γδ T cells, which aggravates intestinal injury. Gut microbiota-derived metabolites promote hypoxia-induced intestinal injury via CD1d-dependent γδ T cells, suggesting that phospholipid metabolites and γδ T cells can be targets for AMS therapy.

摘要

胃肠功能障碍是急性高山病（AMS）的常见症状。肠道微生物群和 γδ T 细胞在肠道疾病中起关键作用。然而，在缺氧诱导的肠道损伤中，微生物群和 γδ T 细胞之间的机制联系仍不清楚。在这里，我们表明在用抗生素消耗微生物群后，缺氧引起的肠道损伤得到了显着缓解。缺氧通过促进抗菌肽血管生成素 4 的分泌来调节肠道微生物群的组成。缺氧后小鼠肠道中梭菌丰度显着降低，而脱硫弧菌丰度显着增加。此外，脱硫弧菌-衍生的磷脂酰乙醇胺和磷脂酰胆碱促进γδT细胞活化。在CD1d缺陷小鼠中，上皮内IL-17A和γδT细胞的水平和肠损伤与缺氧下的野生型小鼠相比显着降低。从机制上讲，来自脱硫弧菌的磷脂代谢物由肠上皮 CD1d 呈递，以诱导产生 IL-17A 的 γδ T 细胞增殖，从而加重肠道损伤。肠道微生物群衍生的代谢物通过 CD1d 依赖性 γδ T 细胞促进缺氧诱导的肠道损伤，这表明磷脂代谢物和 γδ T 细胞可以成为 AMS 治疗的靶点。