Food-grade TiO2 impairs intestinal mucus barrier via disrupting the gut microbiota-ILA-mucin sulfation axis: novel insights and dietary intervention strategies

The use of titanium dioxide (TiO 2 ) as a food additive has persistently elicited concerns about its potential toxicity, primarily attributed to the significant presence of nanoparticles. Studies have recently demonstrated that nano- or micro-sized food-grade TiO 2 (fg-TiO 2 ) particles can disrupt gut microbial balance and weaken the intestinal barrier; however, the underlying mechanisms remain poorly understood. Furthermore, research on dietary interventions for repairing fg-TiO 2 -induced intestinal injury is limited. This study delved into the role of the interactions among gut microbes, indole-3-lactic acid (ILA) and mucin sulfation in fg-TiO 2 -induced intestinal mucosal barrier damage through multi-omics analysis, and revealed the protective effects of quercetin. Prolonged oral administration of fg-TiO 2 at doses pertinent to human exposure resulted in notable intestinal inflammation and mucosal barrier damage through diminishing mucin sulfation. Further analysis demonstrated that fg-TiO 2 caused significant gut microbiota dysbiosis and metabolite changes. It was found that Lactobacillus and its metabolite ILA, an aryl hydrocarbon receptor (AHR) agonist, was significantly downregulated following oral ingestion of fg-TiO 2 , which decreased the activation of AHR and ultimately led to a loss in mucin sulfation in colon tissues. Notably, experiments involving fecal microbiota transplantation (FMT) and ILA supplementation indicated gut microbial shifts and the consequent decrease in colonic ILA levels were accountable for the detrimental effects of fg-TiO 2 on mucin sulfation and intestinal barrier integrity. Moreover, this study found that dietary intervention with quercetin could effectively reverse the damage to the intestinal mucosal barrier induced by fg-TiO 2 through targeting gut microbiota-ILA-mucin sulfation axis. This research uncovered the adverse impacts of fg-TiO 2 on gut homeostasis and indicates the potential of quercetin to combat the intestinal toxicity of fg-TiO 2 . These findings enhanced our comprehension of the safety profile of fg-TiO 2 and proposed a nutritional approach to mitigate the health risks associated with fg-TiO 2 exposure.