Du Lisha, Wang Benjie, Wang Xinyi, Wang Longxing, Wang Renjun, Zhang Yuanyuan, Hong Zemei, Han Xiaofei, Wang Yadong
College of Life and Health of Dalian University, Affiliated Zhongshan Hospital of Dalian University, Key Laboratory of Saccharide and Lipid Metabolism Research in Liaoning Province, Affiliated Xinhua Hospital of Dalian University, Dalian, 116622, Liaoning, China.
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, Liaoning, China.
J Nanobiotechnology. 2025 Jun 2;23(1):406. doi: 10.1186/s12951-025-03481-0.
Silica nanoparticles (SiO NPs) are widely used in the food and pharmaceutical industries and dramatically increase the health risks associated with gastrointestinal exposure. However, the neurotoxicological effects and mechanisms of exposure to SiO NPs and their relationship with the gut microbiome require further in-depth investigation. Here, we performed a systematic assessment of the toxicity of gavage containing 20 nm SiO NPs to C57BL/6 J mice.
After 14 weeks administration, we comprehensively discovered that gastrointestinal exposure to SiO NPs led to mice Alzheimer's disease (AD)-like neurotoxicity, including Aβ accumulation, cognitive impairment, oxidative stress burden, and neuroinflammation, which was microbiota-gut-brain axis-dependent and proven using a low-load gut-bacteria experiment and antibiotic treatment. Mechanistically, gastrointestinal exposure to SiO NPs disrupted intestinal homeostasis. Specifically, the total faecal short-chain fatty acid (SCFA) levels were reduced as analysed by 16S rRNA gene sequencing and liquid chromatography mass-spectrometry (LC-MS) analysis. The reduced SCFA content damaged the integrity of gut-brain axis by increasing gut permeability, which may have caused metabolite redistribution, brain basement membrane dissolution, activated the neuroinflammation signalling pathway TLR4/NF-κB, and interfered with HDAC3 and HDAC1/OGG1 pathways.
We showed for the first time that gastrointestinal exposure to SiO NPs depends on the gut microbiome and causes neurological and cognitive impairment via gut-brain axis information transmission. These findings suggest that the gut microbiota, as a mediator between intestinal and brain information communications, contributes to gastrointestinal exposure to SiO NPs-induced neurotoxicity. The health risks of exposure to SiO NPs should be recognised, and addressing strategies should be extensively reconsidered.
二氧化硅纳米颗粒（SiO NPs）广泛应用于食品和制药行业，显著增加了胃肠道暴露相关的健康风险。然而，SiO NPs暴露的神经毒理学效应及机制以及它们与肠道微生物群的关系需要进一步深入研究。在此，我们对经口灌胃给予20 nm SiO NPs对C57BL/6 J小鼠的毒性进行了系统评估。
给药14周后，我们全面发现胃肠道暴露于SiO NPs会导致小鼠出现类似阿尔茨海默病（AD）的神经毒性，包括Aβ积累、认知障碍、氧化应激负担和神经炎症，这依赖于微生物群-肠-脑轴，并通过低负荷肠道细菌实验和抗生素治疗得到证实。机制上，胃肠道暴露于SiO NPs会破坏肠道内环境稳态。具体而言，通过16S rRNA基因测序和液相色谱-质谱联用（LC-MS）分析发现，粪便中总短链脂肪酸（SCFA）水平降低。SCFA含量降低通过增加肠道通透性破坏了肠-脑轴的完整性，这可能导致代谢物重新分布、脑基底膜溶解，激活神经炎症信号通路TLR4/NF-κB，并干扰HDAC3和HDAC1/OGG1通路。
我们首次表明胃肠道暴露于SiO NPs依赖于肠道微生物群，并通过肠-脑轴信息传递导致神经和认知障碍。这些发现表明，肠道微生物群作为肠道和大脑信息交流之间的介质，促成了胃肠道暴露于SiO NPs诱导的神经毒性。应认识到SiO NPs暴露的健康风险，并广泛重新考虑应对策略。
