Gut Microbiota-Derived Leucine Promotes Cold-Induced Atherosclerosis by Inhibiting Macrophage Efferocytosis

Cold exposure has been shown to impact the development of atherosclerotic cardiovascular disease (ASCVD) and is associated with dysbiosis in the gut microbiota. In our study, we found that cold exposure increased both plaque area and plaque instability in ApoE−/− mice. Further analysis revealed that gut microbiota and microbial metabolites play a crucial role in cold-related atherosclerosis. Specifically, following cold exposure, there was a notable decrease in the abundance of Lactobacillus. johnsonii (L. johnsonii) in the intestinal tract and an increase in plasma leucine levels. Supplementation with L. johnsonii alleviated cold-related atherosclerosis in ApoE−/− mice. Importantly, our in vivo and in vitro studies demonstrated that leucine reduces efferocytosis by decreasing the expression of Gas6 in macrophages, thereby promoting the progression of cold-related atherosclerosis. These findings highlight the central role of gut microbiota and microbial metabolites in modulating efferocytosis during cold-related atherosclerosis. The L. johnsonii-leucine-Gas6 pathway holds promise as a potential therapeutic target for addressing cold-related atherosclerosis.