State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China.
Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang province, China.
Gut Microbes. 2022 Jan-Dec;14(1):2096994. doi: 10.1080/19490976.2022.2096994.
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 in the gut of mice after hypoxia significantly decreased, while the abundance of significantly increased. Furthermore, -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 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.
胃肠道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 细胞在肠道疾病中发挥着关键作用。然而，微生物群和 γδ T 细胞在低氧诱导的肠道损伤中的机制联系尚不清楚。在这里，我们表明，用抗生素耗尽微生物群后，低氧诱导的肠道损伤明显减轻。低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组成。低氧后小鼠肠道中 的丰度明显降低，而 的丰度明显增加。此外，γδ T 细胞的激活由 -衍生的磷脂酰乙醇胺和磷脂酰胆碱促进。在 CD1d 缺陷型小鼠中，与野生型小鼠相比，低氧下上皮内 IL-17A 和 γδ T 细胞的水平以及肠道损伤明显降低。在机制上，来自 的磷脂代谢物由肠上皮细胞 CD1d 呈递，以诱导产生 IL-17A 的 γδ T 细胞的增殖，从而加重肠道损伤。肠道微生物衍生的代谢物通过 CD1d 依赖性 γδ T 细胞促进低氧诱导的肠道损伤，表明磷脂代谢物和 γδ T 细胞可能是 AMS 治疗的靶点。
