Atorvastatin alleviates atherosclerosis by improving intestinal barrier function in mice and patients by modulating inflammation

BACKGROUND: Atherosclerosis (AS) is a chronic inflammatory disease caused by high cholesterol levels in the blood, leading to plaque deposition on the inside of arteries. Gastrointestinal dysfunction is a determining factor in the progression of AS by modulating inflammatory pathways. Atorvastatin (ATO) is a classic drug used to lower lipids levels, thus preventing AS. However, the underlying mechanism of ATO extends beyond lipid metabolism; it affects various pathophysiological processes, such as intestinal function. Therefore, this study attempted to measure the effect of ATO on AS and determine how it impacts mechanisms associated with gastrointestinal-vascular interaction. METHODS: ApoE-/- mice were fed a lipid and cholesterol-rich diet containing angiotensin II ad libitum for 12 weeks. Subsequently, ATO or phosphate-buffered saline solution was orally administered for another 4 weeks. Aorta, colon, and serum samples were obtained. Permeability tests were performed on human Caco-2 colon carcinoma cells using transepithelial electrical resistance. Twenty-seven patients with AS, 22 with AS treated with ATO (AS+ATO), and 17 healthy controls were enrolled in this study. Carotid artery narrowing was evaluated using carotid artery ultrasound, and blood samples were collected for enzyme-linked immunosorbent assays. RESULTS: ATO significantly alleviated aortic AS and improved blood lipid levels in mice. Simultaneously, ATO reduced intestinal permeability, inhibited immune activation inside the intestines of the mice, and decreased circulating endotoxin levels. The protective effects of ATO on intestinal barrier function were also demonstrated in an AS cell model. Clinical samples were obtained to determine the efficacy of ATO in humans, and the results primarily verified that ATO significantly decreased lipids in human serum. Moreover, a positive correlation between circulating endotoxin, inflammatory cytokines, and ZO-1 was also found in the serum of AS patients. The findings indicate the importance of intestine-vessel connections while treating stroke, providing novel therapeutic strategies for AS. CONCLUSIONS: ATO is a classic drug used for AS prevention. The findings of this study suggest that the anti-atherosclerotic effect of ATO may be mediated, at least in part, through its protective effects on intestinal barrier function and anti-inflammatory properties.