Phase-dependent hepatotoxicity of Aluminum oxide nanoparticles mediated through the intestinal microbiota

Aluminum oxide (Al₂O₃) nanoparticles (NPs) are extensively utilized in the food industry for applications such as food packaging, antimicrobial coatings, food processing equipment, and additives. Despite their widespread use, the mechanisms underlying Al₂O₃ NP-induced hepatotoxicity and the relationship between their physicochemical properties and toxicity remain inadequately understood. In this study, we explored the hepatotoxic effects of α-Al₂O₃ and γ-Al₂O₃ NPs in rats subjected to oral exposure for 28 days. Employing an integrated metabolomics and microbiome approach, we aimed to elucidate the potential mechanisms involved. Our findings revealed distinct hepatotoxic profiles for α-Al₂O₃ and γ-Al₂O₃ NPs, potentially mediated by differential interactions with the intestinal microbiome. α-Al₂O₃ NPs exhibited reduced hepatotoxicity, as evidenced by minimal liver oxidative stress, which may be associated with the upregulation of digestion-related intestinal flora such as Peptococcaceae and Romboutsia, potentially influencing Al₂O₃ accumulation in the liver. Conversely, γ-Al₂O₃ NPs demonstrated pronounced hepatotoxicity, characterized by liver histopathological changes and elevated levels of alanine aminotransferase, malondialdehyde, and glutathione. This increased toxicity was correlated with alterations in intestinal flora, including Ruminococcaceae and Exiguobacterium, which affected metabolites like L-phenylalanine and arachidonic acid, potentially contributing to hepatotoxicity. The results underscore the importance of the intestinal microbiome in mediating NP-induced toxicity and determining differences in toxicities of different NP phases. This study provides valuable insights into the differential toxicological impacts of Al₂O₃ NP phases, paving the way for safer nanomaterial design and application in the food industry.