Gan Baoxing, Zhang Xufei, Xin Jinge, Duan Lixiao, Sun Ning, Chen Yu, Zeng Junqi, Lian Yueying, Li Hao, Wang Hesong, Ni Xueqin, Ma Hailin
Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, No. 211 Huimin Road, Wenjiang District, Chengdu, Sichuan, China.
Plateau Brain Science Research Center, Tibet University, Lhasa, 850000, Tibet, China.
AMB Express. 2025 Jun 19;15(1):96. doi: 10.1186/s13568-025-01898-2.
Plateau environment represents a common terrestrial characterized by multistress conditions including hypobaric hypoxia, low temperature, and intense radiation, yet sustain over 100 million permanent or transient inhabitants. While this extreme environment exerts profound impacts on cerebral architecture and gut microbiota homeostasis, precipitating cognitive deficits and microbiome-derived intestinal pathologies, the mechanistic interplay between plateau environment adaptation and microbial dynamics remains contentious. Here, we employ a microbiota-gut-brain axis framework to investigate whether probiotic intervention can ameliorate hippocampal impairments induced by simulated plateau environment exposure (3500-4000 m) in mice. Through simulated plateau environment exposure experiments, we revealed that extreme high-altitude conditions induced hippocampal memory dysfunction in mice, exacerbated oxidative stress damage in hippocampal tissues, and altered synaptic plasticity-related biomarkers including CREB transcription factor, BDNF protein levels, and electrophysiological power spectra. Administration of HL79 alleviated these burdens, including memory dysfunction and tissue damage, though complete reversal was not achieved. Combined hippocampal transcriptomic analyses suggested that HL79's beneficial effects primarily involved modulation of lipid-related gene expression in the hippocampus, consistent with prior reports of plateau environmental impacts on gene expression. Serum metabolomic results further reinforced this inference that differential metabolites regulated by HL79 are mainly enriched in bile secretion, taurine and hypotaurine metabolism, linoleic acid metabolism, and PPAR signaling pathways, though the precise regulatory mechanisms require further elucidation. This research provides a novel microbiota-gut-brain axis-based regulatory strategy for adaptation to extreme plateau environments and offers new evidence for understanding the relationship between gut microbiota and plateau environment adaptation at high elevations.
高原环境是一种常见的陆地环境，其特点是存在多种应激条件，包括低压缺氧、低温和强辐射，但仍有超过1亿的常住人口或流动人口。虽然这种极端环境对大脑结构和肠道微生物群稳态产生深远影响，引发认知缺陷和微生物群衍生的肠道疾病，但高原环境适应与微生物动态之间的机制相互作用仍存在争议。在这里，我们采用微生物群-肠道-大脑轴框架来研究益生菌干预是否可以改善小鼠模拟高原环境暴露（3500-4000米）所诱导的海马损伤。通过模拟高原环境暴露实验，我们发现极端高海拔条件会诱导小鼠海马记忆功能障碍加剧海马组织中的氧化应激损伤，并改变与突触可塑性相关的生物标志物，包括CREB转录因子、BDNF蛋白水平和电生理功率谱。给予HL79减轻了这些负担，包括记忆功能障碍和组织损伤，尽管未完全逆转。联合海马转录组分析表明，HL79的有益作用主要涉及调节海马中与脂质相关的基因表达，这与之前关于高原环境对基因表达影响的报道一致。血清代谢组学结果进一步强化了这一推断，即HL79调节的差异代谢物主要富集在胆汁分泌、牛磺酸和低牛磺酸代谢、亚油酸代谢和PPAR信号通路中，尽管确切的调节机制需要进一步阐明。本研究为适应极端高原环境提供了一种基于微生物群-肠道-大脑轴的新型调节策略，并为理解肠道微生物群与高海拔高原环境适应之间的关系提供了新证据。
