Xie Huichao, Zeng Xiong, Wang Wensheng, Wang Wei, Han Ben, Tan QianShan, Hu Qiu, Liu Xingyu, Chen Shuaishuai, Chen Jun, Sun Lihua, Chen Yihui, Xiao Weidong
Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
Department of Nutrition, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
Mol Biomed. 2023 Oct 2;4(1):31. doi: 10.1186/s43556-023-00143-1.
Damage to the intestinal epithelial barrier (IEB) has been reported under high-altitude (HA) conditions and may be responsible for HA-associated gastrointestinal (GI) disorders. However, this pathogenetic mechanism does not fully explain the GI stress symptoms, such as flatulence and motility diarrhea, which accompany the IEB damage under HA conditions, especially for the people exposed to HA acutely. In the present study, we collected the blood samples from the people who lived at HA and found the concentration of enteric glial cells (EGCs)-associated biomarkers increased significantly. HA mouse model was then established and the results revealed that EGCs were involved in IEB damage. Zona occludens (ZO)-1, occludin, and claudin-1 expression was negatively correlated with that of glial fibrillary acidic protein (GFAP) and S100β under HA conditions. In order to learn more about how EGCs influence IEB, the in vitro EGC and MODE-K hypoxia experiments that used hypoxic stimulation for simulating in vivo exposure to HA was performed. We found that hypoxia increased S100β secretion in EGCs. And MODE-K cells cultured in medium conditioned by hypoxic EGCs showed low ZO-1, occludin, and claudin-1 levels of expression. Furthermore, treatment of MODE-K cells with recombinant mouse S100β resulted in diminished levels of ZO-1, occludin, and claudin-1 expression. Thus, HA exposure induces greater S100β secretion by EGCs, which aggravates the damage to the IEB. This study has revealed a novel mechanism of IEB damage under HA conditions, and suggest that EGCs may constitute a fresh avenue for the avoidance of GI disorders at HA.
据报道，在高海拔（HA）条件下肠道上皮屏障（IEB）会受到损伤，这可能是HA相关胃肠道（GI）疾病的病因。然而，这种发病机制并不能完全解释HA条件下伴随IEB损伤出现的GI应激症状，如肠胃胀气和动力性腹泻，尤其是对于急性暴露于HA的人群。在本研究中，我们采集了生活在HA地区人群的血液样本，发现与肠胶质细胞（EGCs）相关的生物标志物浓度显著增加。随后建立了HA小鼠模型，结果显示EGCs参与了IEB损伤。在HA条件下，紧密连接蛋白（ZO）-1、闭合蛋白和Claudin-1的表达与胶质纤维酸性蛋白（GFAP）和S100β的表达呈负相关。为了进一步了解EGCs如何影响IEB，我们进行了体外EGC和MODE-K细胞缺氧实验，通过缺氧刺激模拟体内HA暴露。我们发现缺氧会增加EGCs中S100β的分泌。在由缺氧EGCs条件培养基培养的MODE-K细胞中，ZO-1、闭合蛋白和Claudin-1的表达水平较低。此外，用重组小鼠S100β处理MODE-K细胞会导致ZO-1、闭合蛋白和Claudin-1的表达水平降低。因此，HA暴露会诱导EGCs分泌更多的S100β，从而加重对IEB的损伤。本研究揭示了HA条件下IEB损伤的新机制，并表明EGCs可能为预防HA地区的GI疾病提供新途径。
