Gastrointestinal exposure to silica nanoparticles induced Alzheimer's disease-like neurotoxicity in mice relying on gut microbiota and modulation through TLR4/NF-κB and HDAC.

Background: Silica nanoparticles (SiO₂ 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 SiO₂ 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 SiO₂ NPs to C57BL/6 J mice.

Results: After 14 weeks administration, we comprehensively discovered that gastrointestinal exposure to SiO₂ 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 SiO₂ 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.

Conclusions: We showed for the first time that gastrointestinal exposure to SiO₂ 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 SiO₂ NPs-induced neurotoxicity. The health risks of exposure to SiO₂ NPs should be recognised, and addressing strategies should be extensively reconsidered.