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ORIGINAL RESEARCH article

Front. Neurosci.

Sec. Gut-Brain Axis

Volume 19 - 2025 | doi: 10.3389/fnins.2025.1600069

This article is part of the Research TopicPhysiological and Pathological Responses to Hypoxia and High Altitude, Volume IIIView all 12 articles

Research on the Correlation between Gut Microbiota and Brain Cognitive Function under Chronic Hypoxia at High Altitude

Provisionally accepted
Feng  ZengFeng ZengHanxue  LiHanxue LiYan  MaYan MaShuang  MaShuang Ma*
  • Qinghai University, Xining, China

The final, formatted version of the article will be published soon.

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/6J 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 Xi'ning, 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 Morganella and Klebsiella abundance and positively correlated with Prevotella, Bifidobacterium and Lactobacillus. 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.

Keywords: High altitude hypoxia, Microbiota-gut-brain axis, Gut Microbiota, Metabolome, cognitive impairment

Received: 25 Mar 2025; Accepted: 02 Jun 2025.

Copyright: © 2025 Zeng, Li, Ma and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Shuang Ma, Qinghai University, Xining, China

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