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Accumulating evidence has provided new insights regarding potentially effective therapeutic options targeting modulation of HDL metabolism, resulting in the prevention of cardiovascular diseases. The gut microbiota has now been convincingly linked to host health, but its impact on host lipid metabolism, especially HDL metabolism, remains poorly understood. This review focuses on the recent progress in establishing associations between gut microbiota and host HDL metabolism. It also discusses causality and mechanisms, and how to translate the findings into clinical use.Recent human and animal studies have demonstrated that the gut microbiota composition can explain a substantial proportion of the individual variation in host blood lipid profiles. In addition, signaling molecules produced by gut microbiota have been shown to have potent effects on reverse cholesterol transport, a crucial atheroprotective function of HDL, which could subsequently influence the development of atherosclerosis. Ultimately, selective manipulation of gut microbiota may serve as an ideal therapeutic approach for improving HDL function and cardiovascular risk, although further studies are needed for a better understanding of which specific bacteria, or alternatively, which bacterial metabolites, are appropriate targets.We are just beginning to understand how the gut microbiota, a newly recognized endocrine organ system, influences HDL metabolism and atherosclerotic diseases. From recent experimental and clinical perspectives, it can be targeted for therapeutic benefit with respect to HDL function and cardiovascular diseases.