Saccharin Supplementation Aggravates High-Fat-Diet-Induced Atherosclerosis through Lipid Metabolism Disorder and Intestinal-Impairment-Induced Endothelial Dysfunction in ApoE–/– Mice

Non-nutritive sweetener (NNS) administration has been proven to be likely related to cardiovascular disease (CVD) risk. However, the effect of saccharin (SA), a major daily consumed NNS, on atherosclerosis (AS) progression remains insufficiently elucidated. In this study, free drinking water plus 0.1 mg/mL SA for 3 mouths significantly aggravated high-fat-diet-induced AS in apolipoprotein-E-deficient ( ApoE –/– ) mice. SA exposure was found to exacerbate lipid metabolism dysregulation by facilitating intestinal cholesterol absorption while impairing hepatic cholesterol excretion, concomitant with a marked elevation in circulating trimethylamine oxide (TMAO) levels. Moreover, SA intake induced depletion of goblet cells and compromised the intestinal structure, resulting in increased colonic permeability. These effects led to endothelial dysfunction and synergistically enhanced atherosclerotic plaque formation and their instability. In summary, this is the first study to alert the potential pro-atherosclerotic role of SA and emphasize the need for reevaluating food additive safety in public cardiovascular health.