高原低氧致肠黏膜屏障应激损伤机制的研究进展

刘文青; 牛江涛; 付占磊

doi:10.11855/j.issn.0577-7402.0605.2025.1205

您当前的位置：

首页 >

文章列表页 >

高原低氧致肠黏膜屏障应激损伤机制的研究进展

解放军医学杂志 2025年页码：1-11

更新时间：2026-01-30

- 高原低氧致肠黏膜屏障应激损伤机制的研究进展
- Research progress on the mechanism of stress-induced damage to the intestinal mucosal barrier caused by high-altitude hypoxia
- 作者机构：
  
  1.青海大学医学院中医系，青海西宁　810000
  2.青海省糖脂代谢疾病防控中医药重点实验室，青海西宁　810000
- 作者简介：
  
  刘文青，硕士研究生，主要从事中药“四君子汤”对高原低氧胃肠应激损伤大鼠黏膜屏障保护作用方面的研究
  牛江涛，E-mail：2021990029@qhu.edu.cn
- 基金信息：
  
  青海省科技计划青年基金项目(2024-ZJ-947)
- DOI：10.11855/j.issn.0577-7402.0605.2025.1205
  中图分类号： R574
- 收稿：2025-03-31，
  
  录用：2025-06-20，
  
  网络出版：2025-12-05，
- 稿件说明：
移动端阅览
刘文青,牛江涛,付占磊.高原低氧致肠黏膜屏障应激损伤机制的研究进展[J].解放军医学杂志,

Liu Wen-Qing,Niu Jiang-Tao,Fu Zhan-Lei.Research progress on the mechanism of stress-induced damage to the intestinal mucosal barrier caused by high-altitude hypoxia[J].Medical Journal of Chinese People′s Liberation Army,
刘文青,牛江涛,付占磊.高原低氧致肠黏膜屏障应激损伤机制的研究进展[J].解放军医学杂志, DOI：10.11855/j.issn.0577-7402.0605.2025.1205.

Liu Wen-Qing,Niu Jiang-Tao,Fu Zhan-Lei.Research progress on the mechanism of stress-induced damage to the intestinal mucosal barrier caused by high-altitude hypoxia[J].Medical Journal of Chinese People′s Liberation Army, DOI：10.11855/j.issn.0577-7402.0605.2025.1205.

摘要

肠道屏障功能障碍与急性高原病、高原脑水肿及高原肺水肿等常见高原病的发生发展关系密切。肠道黏膜屏障是人体抵御外界病原体的重要防御屏障，但在高原低氧环境下易受到应激损伤，发生肠道通透性增加、细菌易位，继而激活炎症反应，影响健康。目前，高原低氧致肠道黏膜屏障损伤的具体机制广受关注但尚待完善。本文系统综述了高原低氧条件下肠道黏膜屏障应激损伤的机制，包括黏膜屏障结构破坏、紧密连接蛋白表达异常、氧化应激、肠道菌群失调等多方面因素，以期为高原低氧肠黏膜屏障应激损伤的防治提供理论依据和参考。

Abstract

Recent studies have increasingly indicated a close relationship between intestinal barrier dysfunction and the pathogenesis of various high-altitude illnesses

including acute mountain sickness

high-altitude cerebral edema

and high-altitude pulmonary edema. As a crucial defensive line against pathogens

the intestinal mucosal barrier is vulnerable to stress injury under high-altitude hypoxic conditions. This damage leads to increased intestinal permeability

bacterial translocation

and the activation of inflammatory responses

thereby affecting systemic health. Currently

the specific mechanisms by which high-altitude hypoxia induces intestinal mucosal barrier injury have garnered significant attention yet require further elucidation. This article systematically reviews the mechanisms of stress injury to the intestinal mucosal barrier under high-altitude hypoxia

encompassing aspects such as the disruption of the mucosal barrier structure

aberrant expression of tight junction proteins

oxidative stress

and gut microbiota dysbiosis. It aims to provide a theoretical basis and reference for the prevention and treatment of intestinal mucosal barrier stress injury in high-altitude hypoxic environments.

关键词

Keywords

references

Wu Z , Wang Y , Gao R , et al . Potential therapeutic effects of traditional Chinese medicine in acute mountain sickness: pathogenesis, mechanisms and future directions [J ] . Front Pharmacol , 2024 , 15 : 1393209 .

Richalet JP , Hermand E , Lhuissier FJ . Cardiovascular physiology and pathophysiology at high altitude [J ] . Nat Rev Cardiol , 2024 , 21 ( 2 ): 75 - 88 .

范勇 , 史玉玲 , 刘杰 . 高原肺水肿发病机制及防治研究进展 [J ] . 河南中医 , 2023 , 43 ( 9 ): 1435 - 1444 .

Khanna K , Mishra KP , Ganju L , et al . High-altitude-induced alterations in gut-immune axis: a review [J ] . Int Rev Immunol , 2018 , 37 ( 2 ): 119 - 126 .

王永春 , 李嘉翔 . 高原习服的训练方法及其在军事中的应用 [J ] . 陆军军医大学学报 , 2025 , 47 ( 1 ): 1 - 9 .

张月文 , 王甜 , 姜璐瑶 , 等 . 高原低氧环境对机体损伤的研究进展 [J ] . 联勤军事医学 , 2024 , 38 ( 9 ): 813 - 817 .

Mckenna ZJ , Gorini Pereira F , Gillum TL , et al . High-altitude exposures and intestinal barrier dysfunction [J ] . Am J Physiol Regul Integr Comp Physiol , 2022 , 322 ( 3 ): R192 - R203 .

汪冬 , 周其全 . 高原缺氧环境下肠道菌群紊乱与急性重症高原病 [J ] . 胃肠病学和肝病学杂志 , 2017 , 26 ( 2 ): 222 - 226 .

Taylor CT , Colgan SP . Regulation of immunity and inflammation by hypoxia in immunological niches [J ] . Nat Rev Immunol , 2017 , 17 ( 12 ): 774 - 785 .

Su Q , Zhuang DH , Li YC , et al . Gut microbiota contributes to high-altitude hypoxia acclimatization of human populations [J ] . Genome Biol , 2024 , 25 ( 1 ): 232 .

Liu D , Chen D , Xiao J , et al . High-altitude-induced alterations in intestinal microbiota [J ] . Front Microbiol , 2024 , 15 : 1369627 .

杨志华 , 王鲲 , 哈小琴 , 等 . 构建急进高海拔地区急性应激性胃肠道损伤大鼠模型 [J ] . 中国组织工程研究 , 2015 , 19 ( 40 ): 6475 - 6479 .

周静 , 许琴 , 刘江伟 , 等 . 不同海拔高原低压缺氧环境下大鼠肠道病理损伤特点 [J ] . 现代生物医学进展 , 2017 , 17 ( 27 ): 5238 - 5241, 5250 .

Qi P , Lv J , Bai LH , et al . Effects of Hypoxemia by acute high-altitude exposure on human intestinal flora and metabolism [J ] . Microorganisms , 2023 , 11 ( 9 ): 2189 .

Li X , Li Q , Xiong B , et al . Discoidin domain receptor 1 (DDR1) promote intestinal barrier disruption in ulcerative colitis through tight junction proteins degradation and epithelium apoptosis [J ] . Pharmacol Res , 2022 , 183 : 106368 .

Chen Z , Luo J , Li J , et al . Foxo1 controls gut homeostasis and commensalism by regulating mucus secretion [J ] . J Exp Med , 2021 , 218 ( 9 ): e20201685 .

Hiippala K , Jouhten H , Ronkainen A , et al . The potential of gut commensals in reinforcing intestinal barrier function and alleviating inflammation [J ] . Nutrients , 2018 , 10 ( 8 ): 1077 .

Matute JD , Duan J , Flak MB , et al . Intelectin-1 binds and alters the localization of the mucus barrier-modifying bacterium Akkermansia muciniphila [J ] . J Exp Med , 2023 , 220 ( 1 ): e20221645 .

Cheng H , Li H , Li Z , et al . The role of glycosylated mucins in maintaining intestinal homeostasis and gut health [J ] . Anim Nutr , 2025 , 21 : 439 - 446 .

崇洁 , 马继登 , 张进威 , 等 . SCFAs对肠道免疫调控的研究进展 [J ] . 生命科学 , 2023 , 35 ( 5 ): 663 - 670 .

Pietrzak B , Tomela K , Olejnik-Schmidt A , et al . Secretory IgA in intestinal mucosal secretions as an adaptive barrier against microbial cells [J ] . Int J Mol Sci , 2020 , 21 ( 23 ): 9080 .

Fabisiak A , Murawska N , Fichna J . LL-37: cathelicidin-related antimicrobial peptide with pleiotropic activity [J ] . Pharmacol Rep , 2016 , 68 ( 4 ): 802 - 808 .

韩菲菲 , 杨莎莎 , 赵霞 , 等 . 抗菌肽LL-37对患结肠炎小鼠肠黏膜屏障的保护功能 [J ] . 中国食品学报 , 2020 , 20 ( 9 ): 67 - 73 .

Li GQ , Xia J , Zeng W , et al . The intestinal γδ T cells: functions in the gut and in the distant organs [J ] . Front Immunol , 2023 , 14 : 1206299 .

Jr Sabatino JJ , Pröbstel AK , Zamvil SS . B cells in autoimmune and neurodegenerative central nervous system diseases [J ] . Nat Rev Neurosci , 2019 , 20 ( 12 ): 728 - 745 .

Meyer F , Wendling D , Demougeot C , et al . Cytokines and intestinal epithelial permeability: a systematic review [J ] . Autoimmun Rev , 2023 , 22 ( 6 ): 103331 .

闫聪 , 王琪格 , 战丽彬 . 肠黏膜屏障在2型糖尿病中的作用机制及中医药干预研究进展 [J ] . 四川大学学报(医学版) , 2025 , 56 ( 3 ): 619 - 626 .

Kim SE . Importance of nutritional therapy in the management of intestinal diseases: beyond energy and nutrient supply [J ] . Intest Res , 2019 , 17 ( 4 ): 443 - 454 .

张维进 , 马亚琪 , 李璐 , 等 . CKD患者肠道菌群及其代谢产物短链脂肪酸的研究进展 [J ] . 宁夏医学杂志 , 2025 , 47 ( 1 ): 84 - 87 .

Bedford A , Gong J . Implications of butyrate and its derivatives for gut health and animal production [J ] . Anim Nutr , 2018 , 4 ( 2 ): 151 - 159 .

Gadde U , Kim WH , Oh ST , et al . Alternatives to antibiotics for maximizing growth performance and feed efficiency in poultry: a review [J ] . Anim Health Res Rev , 2017 , 18 ( 1 ): 26 - 45 .

Sun M , Wu W , Liu Z , et al . Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases [J ] . J Gastroenterol , 2017 , 52 ( 1 ): 1 - 8 .

Tremblay JC , Ainslie PN . Global and country-level estimates of human population at high altitude [J ] . Proc Natl Acad Sci U S A , 2021 , 118 ( 18 ): e2100712118 .

Lankford HV . The death zone: lessons from history [J ] . Wilderness Environ Med , 2021 , 32 ( 1 ): 114 - 120 .

Burtscher M . Effects of living at higher altitudes on mortality: a narrative review [J ] . Aging Dis , 2014 , 5 ( 4 ): 274 - 280 .

赵海涛 , 马力天 , 林强 , 等 . 高原胃肠应激反应的病理变化与肠道菌群调控作用的研究进展 [J ] . 山西医科大学学报 , 2024 , 55 ( 7 ): 936 - 941 .

Li M , Han T , Zhang W , et al . Simulated altitude exercise training damages small intestinal mucosa barrier in the rats [J ] . J Exerc Rehabil , 2018 , 14 ( 3 ): 341 - 348 .

Sies H . Oxidative stress: concept and some practical aspects [J ] . Antioxidants (Basel) , 2020 , 9 ( 9 ): 856 .

迟阳 , 孙倩 , 肖玉伟 , 等 . 低温和CO 2 对缺氧性脑损伤的影响 [J ] . 创伤与急危重病医学 , 2025 , 13 ( 3 ): 210 - 215 .

Korbecki J , Simińska D , Gąssowska-Dobrowolska M , et al . Chronic and cycling hypoxia: drivers of cancer chronic inflammation through HIF-1 and NF-κB activation: a review of the molecular mechanisms [J ] . Int J Mol Sci , 2021 , 22 ( 19 ): 10449 .

Hwang J , Jin J , Jeon S , et al . SOD1 suppresses pro-inflammatory immune responses by protecting against oxidative stress in colitis [J ] . Redox Biol , 2020 , 37 : 101760 .

Dvornikova KA , Platonova ON , Bystrova EY . Hypoxia and intestinal inflammation: common molecular mechanisms and signaling pathways [J ] . Int J Mol Sci , 2023 , 24 ( 3 ): 2595 .

Tu W , Wang H , Li S , et al . The anti-inflammatory and anti-oxidant mechanisms of the Keap1/Nrf2/ARE signaling pathway in chronic diseases [J ] . Aging Dis , 2019 , 10 ( 3 ): 637 - 651 .

李杰 , 谢海玲 , 李昭辉 , 等 . 氧化应激在炎症性肠病和结肠炎相关结直肠癌疾病中的研究进展 [J ] . 胃肠病学和肝病学杂志 , 2022 , 31 ( 7 ): 836 - 840 .

Yan H , Hu Y , Liang J , et al . Yinchenhao decoction mitigates intestinal impairment induced by high carbohydrate diet in largemouth bass (micropterus salmoides): insights from inflammation, apoptosis, oxidative stress, tight junctions, and microbiota homeostasis [J ] . Fish Physiol Biochem , 2024 , 50 ( 6 ): 2207 - 2223 .

黄雨薇 , 叶元土 , 蔡春芳 , 等 . 饲料氧化鱼油引起草鱼肠道黏膜结构屏障损伤 [J ] . 水产学报 , 2015 , 39 ( 10 ): 1511 - 1520 .

Shi XC , Jin A , Sun J , et al . α-lipoic acid ameliorates n-3 highly-unsaturated fatty acids induced lipid peroxidation via regulating antioxidant defenses in grass carp (ctenopharyngodon idellus) [J ] . Fish Shellfish Immunol , 2017 , 67 : 359 - 367 .

Li K , He C . Gastric mucosal lesions in tibetans with high-altitude polycythemia show increased HIF-1A expression and ROS production [J ] . Biomed Res Int , 2019 , 2019 : 6317015 .

Bao LL , Yu YQ , González-Acera M , et al . Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease [J ] . Sci Transl Med , 2025 , 17 ( 781 ): eadn8699 .

Garcia JG , Cruz MD , Rollan CM , et al . Superoxide dismutase (SOD) and neutrophil infiltration in intestinal ischaemia-revascularization [J ] . Int Surg , 1995 , 80 ( 1 ): 95 - 97 .

Pral LP , Fachi JL , Corrêa RO , et al . Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions [J ] . Trends Immunol , 2021 , 42 ( 7 ): 604 - 621 .

严海新 , Wyesen K , 刘志丹 . HIF-1α/BNIP3信号通路调控低氧诱导下细胞自噬及凋亡的研究进展 [J ] . 江苏大学学报(医学版) , 2025 , 35 ( 5 ): 455 - 460 .

Anitha RE , Janani R , Peethambaran D , et al . Lactucaxanthin protects retinal pigment epithelium from hyperglycemia-regulated hypoxia/ER stress/VEGF pathway mediated angiogenesis in ARPE-19 cell and rat model [J ] . Eur J Pharmacol , 2021 , 899 : 174014 .

Thanas C , Ziros PG , Chartoumpekis DV , et al . The Keap1/Nrf2 signaling pathway in the thyroid-2020 update [J ] . Antioxidants (Basel) , 2020 , 9 ( 11 ): 1073 .

娄文静 . 高氧抑制肠道紧密连接蛋白和肠道干细胞标记物的表达 [D ] . 沈阳 : 中国医科大学 , 2019 .

Kim S , Eun HS , Jo EK . Roles of autophagy-related genes in the pathogenesis of inflammatory bowel disease [J ] . Cells , 2019 , 8 ( 1 ): 30 .

赫玉宝 , 张方信 , 杜倩楠 , 等 . 高原缺氧与肠黏膜屏障损伤研究 [J ] . 中国微生态学杂志 , 2018 , 30 ( 12 ): 1470 - 1474 .

Mrakic-Sposta S , Biagini D , Bondi D , et al . Oxinflammation at high altitudes: a proof of concept from the himalayas [J ] . Antioxidants (Basel) , 2022 , 11 ( 2 ): 200 .

Yang S , Cui Y , Ma R , et al . Hypoxia regulates the proliferation and apoptosis of coronary artery smooth muscle cells through HIF-1α mediated autophagy in Yak [J ] . Biomolecules , 2025 , 15 ( 2 ): 305 .

Yu C , Liu S , Niu Y , et al . Exercise protects intestinal epithelial barrier from high fat diet- induced permeabilization through SESN2/AMPKα1/HIF-1α signaling [J ] . J Nutr Biochem , 2022 , 107 : 109059 .

陈嘉屿 , 刘德科 , 吴红梅 , 等 . 低压缺氧环境对大鼠胃肠运动影响机制及生白术的干预作用 [J ] . 中国中西医结合消化杂志 , 2015 , 23 ( 2 ): 79 - 82 .

宋亚芳 , 张晓梅 , 蒋诗媛 , 等 . HIF-1α介导针灸调节氧化应激修复肠易激综合征肠黏膜屏障策略与机制探讨 [J ] . 中国医药导报 , 2024 , 21 ( 26 ): 141 - 145 .

Wenzel UA , Magnusson MK , Rydström A , et al . Spontaneous colitis in Muc2-deficient mice reflects clinical and cellular features of active ulcerative colitis [J ] . PLoS One , 2014 , 9 ( 6 ): e100217 .

张美曦 , 隋欣 , 刘超男 , 等 . 双歧杆菌对雏鸡肠道杯状细胞数量及黏蛋白2含量的影响 [J ] . 中国兽医杂志 , 2016 , 52 ( 12 ): 24 - 27, 50 .

王晓娟 , 齐平 , 蒋贤森 , 等 . 基于肠道菌群探讨益生菌防治高原低氧肠道损伤的机制 [J ] . 兰州大学学报(医学版) , 2025 , 51 ( 5 ): 80 - 89 .

Liu W , Fan X , Jian B , et al . The signaling pathway of hypoxia inducible factor in regulating gut homeostasis [J ] . Front Microbiol , 2023 , 14 : 1289102 .

张雅兰 , 干意 , 张舰涛 , 等 . 微生态与黏膜免疫:共生与防御的平衡 [J/OL ] . 中国免疫学杂志 , 2020 , 11 ( 4 ): 1 - 16 .

Ozcan A , Vicanolo T , Angeli V , et al . Structural immunity: immune cells as architects of tissue barriers [J ] . Nat Rev Immunol , 2025 .

杨春敏 , 陈英 , 毛高平 , 等 . 急性低压低氧对大鼠胃排空和小肠推进运动的影响 [J ] . 空军总医院学报 , 2009 , 25 ( 3 ): 145 - 147 .

林启运 , 候鹏飞 , 郎和东 , 等 . 复合因素急性应激诱导肠道屏障功能障碍及其作用机制研究 [J ] . 陆军军医大学学报 , 2024 , 46 ( 1 ): 73 - 83 .

陈秋宇 , 王烨 , 张国梁 . 佛手柑对克罗恩病样结肠炎小鼠模型肠道屏障及Th17/Treg平衡的影响 [J ] . 西部医学 , 2025 , 37 ( 6 ): 800 - 805 .

Mantis NJ , Forbes SJ . Secretory IgA: arresting microbial pathogens at epithelial borders [J ] . Immunol Invest , 2010 , 39 ( 4-5 ): 383 - 406 .

寇娜 , 周义玲 , 纪巧荣 , 等 . 短期低压低氧对小鼠肠道黏膜免疫功能的影响 [J ] . 中国高原医学与生物学杂志 , 2019 , 40 ( 1 ): 15 - 19 .

Park D , Kim CH , Park DY , et al . Intermittent hypoxia induces Th17/Treg imbalance in a murine model of obstructive sleep apnea [J ] . PLoS One , 2024 , 19 ( 6 ): e0305230 .

曾文静 . 长链菊粉对抗生素处理模型小鼠肠道菌群和肠粘膜免疫功能的影响 [D ] . 广州 : 广东药科大学 , 2021 .

Stolfi C , Maresca C , Monteleone G , et al . Implication of intestinal barrier dysfunction in gut dysbiosis and diseases [J ] . Biomedicines , 2022 , 10 ( 2 ): 218 .

段坤坤 , 王亚峰 . 高原低氧环境下肠道微生态失调及防治的研究现状 [J ] . 中国高原医学与生物学杂志 , 2021 , 42 ( 2 ): 142 - 144 .

金其贯 , 胡要娟 , 金爱娜 , 等 . 不同模式的低氧运动训练对大鼠肠道体液免疫功能的影响 [J ] . 中国运动医学杂志 , 2015 , 34 ( 8 ): 764 - 769 .

Cheng J , Sun Y , Zhao Y , et al . Research progress on the mechanism of intestinal barrier damage and drug therapy in a high altitude environment [J ] . Curr Drug Deliv , 2024 , 21 ( 6 ): 807 - 816 .

刘淑月 , 秦超 . 肠道微生态对老年脓毒症患者预后影响的研究进展 [J ] . 中国现代医生 , 2025 , 63 ( 12 ): 113 - 116 .

陆松翠 , 郑楠 , 王加启 , 等 . 短链脂肪酸的生物学功能研究进展 [J ] . 动物营养学报 , 2024 , 36 ( 6 ): 3514 - 2524 .

Ibrahim I , Syamala S , Ayariga JA , et al . Modulatory effect of gut microbiota on the gut-brain, gut-bone axes, and the impact of cannabinoids [J ] . Metabolites , 2022 , 12 ( 12 ): 1217 .

程俊飞 , 赵安鹏 , 赵以览 , 等 . 高原低氧环境影响胃肠道功能的因素及药物保护作用研究进展 [J ] . 药学实践与服务 , 2023 , 41 ( 11 ): 648 - 653 .

王昱昊 , 施艺 , 李文豪 , 等 . 肠道菌群在高原低氧肠道损伤中的作用研究 [J ] . 中国临床解剖学杂志 , 2021 , 39 ( 6 ): 666 - 672 .

仝永娟 , 束华 , 马刚 , 等 . 模拟高原环境对小鼠肠道微生物菌群的影响 [J ] . 实验动物科学 , 2022 , 39 ( 2 ): 31 - 37 .

王珍 , 周亚洲 , 王立坤 , 等 . 持续低氧条件下大鼠肠道微生物变化及其与心肌损伤的关联研究 [J ] . 微生物学报 , 2023 , 63 ( 8 ): 3054 - 3067 .

Cong J , Zhou P , Zhang R . Intestinal microbiota-derived short chain fatty acids in host health and disease [J ] . Nutrients , 2022 , 14 ( 9 ): 1929 .

Lu ZY , Feng L , Jiang WD , et al . An antioxidant supplement function exploration: rescue of intestinal structure injury by mannan oligosaccharides after aeromonas hydrophila infection in grass carp (ctenopharyngodon idella) [J ] . Antioxidants (Basel) , 2022 , 11 ( 5 ): 885 .

Ren D , Ding M , Su J , et al . Stachyose in combination with L. rhamnosus GG ameliorates acute hypobaric hypoxia-induced intestinal barrier dysfunction through alleviating inflammatory response and oxidative stress [J ] . Free Radic Biol Med , 2024 , 212 : 505 - 519 .

赵海涛 . 高原缺氧条件对人体肠黏膜屏障与肠道菌群的影响及其干预的研究 [D ] . 西安 : 解放军空军军医大学 , 2025 .

Hou K , Wu ZX , Chen XY , et al . Microbiota in health and diseases [J ] . Signal Transduct Target Ther , 2022 , 7 ( 1 ): 135 .

浏览量

下载量

CSCD

CNKI被引量

文章被引用时，请邮件提醒。

提交

关联资源

暂无数据