Intestinal toxicity of micro- and nano-particles of foodborne titanium dioxide in juvenile mice: Disorders of gut microbiota-host co-metabolites and intestinal barrier damage

Abstract

The wide use of TiO₂ particles in food and the high exposure risk to children have prompted research into the health risks of TiO₂. We used the microbiome and targeted metabolomics to explore the potential mechanism of intestinal toxicity of foodborne TiO₂ micro-/nanoparticles after oral exposure for 28 days in juvenile mice. Results showed that the gut microbiota-including the abundance of Bacteroides, Bifidobacterium, Lactobacillus, and Prevotella-changed dynamically during exposure. The organic inflammatory response was activated, and lipopolysaccharide levels increased. Intestinal toxicity manifested as increased mucosal permeability, impaired intestinal barrier, immune damage, and pathological changes. The expression of antimicrobial peptides, occludin, and ZO-1 significantly reduced, while that of JNK2 and Src/pSrc increased. Compared with micro-TiO₂ particles, the nano-TiO₂ particles had strong toxicity. Fecal microbiota transplant confirmed the key role of gut microbiota in intestinal toxicity. The levels of gut microbiota-host co-metabolites, including pyroglutamic acid, L-glutamic acid, phenylacetic acid, and 3-hydroxyphenylacetic acid, changed significantly. Significant changes were observed in the glutathione and propanoate metabolic pathways. There was a significant correlation between the changes in gut microbiota, metabolites, and intestinal cytokine levels. These, together with the intestinal barrier damage signaling pathway, constitute the network mechanism of the intestinal toxicity of TiO₂ particles.

Keywords: Biomarker; Correlation; Fecal transplant; Gut microbiome; TiO(2) microparticle; TiO(2) nanoparticle.