Zeng Feng, Li Hanxue, Ma Yan, Ma Shuang
Department for Basic Medicine of Qinghai University, Xining, China.
Research Center for High Altitude Medicine of Qinghai University, Key Laboratory of the Ministry of High Altitude Medicine, Laboratory for High Altitude Medicine of Qinghai Province, Key Laboratory of Applied Fundamentals of High Altitude Medicine (Qinghai-Utah Joint Key Laboratory of Plateau Medicine), Xining, China.
Front Neurosci. 2025 Jun 19;19:1600069. doi: 10.3389/fnins.2025.1600069. eCollection 2025.
Long-term exposure to high-altitude hypoxia can lead to cognitive impairment, yet the role of the gut microbiota in this process remains unclear. This study investigated the contribution of gut microbiota to cognitive dysfunction induced by chronic hypoxia.
C57BL/6 J mice were assigned to four groups: control group (NC), control pseudo-germ-free group (CA), hypoxic group (HC), and hypoxic pseudo-germ-free group (HA). HC and HA groups were exposed to a hypobaric oxygen chamber simulating an altitude of 5,000 m (11% O₂) for 28 days. Control mice were housed Xining, 2,200 m altitude (16% O₂). All groups had free access to water; CA and HA groups received oral administration of a four-antibiotic cocktail in drinking water to deplete gut microbiota and establish pseudo-germ-free mouse models. Cognitive function was assessed by the Morris water maze, Expression levels of hippocampal BDNF, SYP, and PSD-95 were determined using Western blotting. H&E staining was used to observe morphological changes in colonic tissues. Gut microbiota composition and metabolic profiles were analyzed through 16S rRNA gene sequencing and metabolomics, respectively, followed by multi-omics correlation analyses.
Chronic hypoxia impaired learning and memory in mice, which was further exacerbated by gut microbiota depletion. This was evidenced by prolonged escape latency, and reduced expression of synaptic plasticity-related proteins. Although hypoxia induced colonic injury, pseudo-germ-free status did not aggravate colonic pathology. Hypoxia and microbiota depletion significantly altered gut microbial diversity, with cognitive impairment negatively correlated with and abundance and positively correlated with , and . Additionally, tryptophan metabolism and urea cycle were identified as critical pathways regulating chronic hypobaric hypoxia-induced cognitive dysfunction. S-adenosylhomocysteine and 2-isopropylmalic acid were pinpointed as potential biomarkers for hypoxia-induced cognitive impairment.
These findings highlight the regulatory role of the gut microbiota in cognitive dysfunction under chronic hypoxic conditions and suggest potential microbiota-targeted strategies for preventing hypoxia-related brain injury.
长期暴露于高原低氧环境可导致认知功能障碍，但肠道微生物群在此过程中的作用仍不清楚。本研究调查了肠道微生物群对慢性低氧诱导的认知功能障碍的影响。
将C57BL/6 J小鼠分为四组：对照组（NC）、对照无菌组（CA）、低氧组（HC）和低氧无菌组（HA）。HC组和HA组暴露于模拟海拔5000米（氧气含量11%）的低压氧舱中28天。对照小鼠饲养在海拔2200米的西宁（氧气含量16%）。所有组均可自由饮水；CA组和HA组通过在饮用水中口服四种抗生素混合物来清除肠道微生物群并建立无菌小鼠模型。通过莫里斯水迷宫评估认知功能，采用蛋白质免疫印迹法测定海马脑源性神经营养因子（BDNF）、突触素（SYP）和突触后致密蛋白95（PSD-95）的表达水平。采用苏木精-伊红（H&E）染色观察结肠组织的形态学变化。分别通过16S rRNA基因测序和代谢组学分析肠道微生物群组成和代谢谱，随后进行多组学相关性分析。
慢性低氧损害小鼠的学习和记忆能力，肠道微生物群的清除使其进一步恶化。这表现为逃避潜伏期延长以及突触可塑性相关蛋白表达降低。尽管低氧诱导了结肠损伤，但无菌状态并未加重结肠病理变化。低氧和微生物群清除显著改变了肠道微生物多样性，认知功能障碍与 和 的丰度呈负相关，与 、 和 呈正相关。此外，色氨酸代谢和尿素循环被确定为调节慢性低压低氧诱导的认知功能障碍的关键途径。S-腺苷同型半胱氨酸和2-异丙基苹果酸被确定为低氧诱导的认知障碍的潜在生物标志物。
这些发现突出了肠道微生物群在慢性低氧条件下对认知功能障碍的调节作用，并提出了针对微生物群的潜在策略以预防与低氧相关的脑损伤。
