Hyodeoxycholic Acid and Cholesterol Sulfate as Key Modulators of Lipid Metabolism in Dyslipidemia based on Gut Microbiome and Metabolome Integrative Analysis

Dyslipidemia, a driver of atherosclerosis and fatty liver disease, burdens society and is associated with gut microbiota responses to dietary patterns. This study aimed to identify key intestinal metabolites involved in regulating lipid metabolism in dyslipidemia and to explore the underlying mechanisms. We performed a metabolome analysis of a humanized dyslipidemia mouse model. Then we screened out hyodeoxycholic acid (HDCA) and cholesterol sulfate (CSS) that potentially interact with farnesoid X receptor (FXR) based on molecular docking and cell culture. Oral administration demonstrated that the HDCA and CSS may ameliorate dyslipidemia via regulating bile acid metabolism, potentially mediated by activation of hepatic or intestinal FXR. Additionally, HDCA promoted the proliferation of <em>g_Roseburia</em> and <em>g_norank_Muribaculaceae</em>, and CSS enhanced the multiplication of <em>g_Alloprevotella</em>. These findings underscored that the intestinal steroid metabolites HDCA and CSS may be promising functional substances for regulating lipid metabolism.