Gut Microbiota-Derived Indole-3-propionic Acid Attenuates Titanium Dioxide Nanoparticle-Induced Liver Injury by Targeting Kupffer Cells via the Gut–Liver Axis

Abstract Nanotitanium dioxide (nTiO2) is widely used as a food additive, leading to chronic dietary exposure and rising health concerns. Although adverse effects on the liver and gut microbiota have been individually investigated, whether gut microbiota mediates nTiO2-induced liver injury remains unclear, especially given the well-established role of the gut–liver axis in hepatic physiology and pathology. Herein, we explored the long-term hepatotoxic effects of oral nTiO2 in mice and the underlying mechanisms through the lens of gut–liver axis crosstalk. Our results showed that chronic exposure to nTiO2 induced dose-dependent liver injury and the disorder of the gut microbiota. Spearman correlation analysis suggested the reduced abundance of beneficial taxa, notably g_Lactobacillus and g_Bacteroides, was strongly associated with elevated intestinal inflammation markers, impaired liver function indicators, and altered hepatic metabolite profiles. Fecal microbiota transplantation demonstrated that nTiO2-perturbed microbiota directly caused liver injury, while colonization with Lactobacillus intestinalis reversed this toxic phenotype, confirming the important role of gut microbiota in the liver injury mediated by nTiO2. More importantly, we found the administration of indole-3-propionic acid (IPA), one of the Lactobacillus-derived indole compounds, restored microbiota homeostasis and alleviated liver toxicity. Mechanistically, IPA increased the expression of MERTK receptor in Kupffer cells, enhancing their phagocytic capacity to redirect nTiO2 accumulation from hepatocytes to Kupffer cells, thereby reducing hepatic oxidative stress and inflammation. Collectively, these findings establish gut microbiota as a critical mediator of nTiO2-induced liver injury, highlight the hepatoprotective role of microbiota-derived IPA, and provide effective strategies for risk intervention against foodborne nanomaterials.