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

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. 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. 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.