Dietary titanium dioxide particles (E171) promote diet-induced atherosclerosis through reprogramming gut microbiota-mediated choline metabolism in APOE-/- mice

Food-grade titanium dioxide (E171) has been reported to induce changes in some intestinal metabolites related to development of atherosclerosis (AS). However, little is known about the effects of chronic dietary intake of E171 on AS development, particularly in AS-prone populations with high-choline western diet (HCD). Herein, we disclosed that E171 obviously exacerbated HCD-induced AS through increasing production of trimethylamine (TMA) and pro-atherogenic trimethylamine-N-oxide (TMAO) via remodeling gut microbiota structure in APOE-/- mice. Oral administration of 40 mg/kg E171 daily for 4 months significantly increased the atherosclerotic lesion area, especially in the HCD group. Mechanistic studies revealed that E171 induced much more TMAO production by increasing the gut microbial expression of choline TMA lyases (CutC/D), which converted dietary choline to TMA by a glycyl radical reaction. The 16S rDNA sequencing analysis demonstrated that bacterial strains expressing CutC/D were enriched by E171 in HCD-fed mice. In contrast, gut microbiota depletion eliminated the impact of E171 on choline/TMA/TMAO pathway and AS progression, indicating gut flora shifts were responsible for the exacerbation effects of E171 ingestion on HCD-induced AS. All the results emphasized the alarming role of E171 on AS progression and stated the importance of reevaluating the impact of food additives on the development of chronic diseases.