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Infection with parasitic helminths has been reported to improve insulin sensitivity and glucose homeostasis, lowering the risk for type 2 diabetes. However, little is known about its impact on whole-body lipid homeostasis, especially in obese individuals. For this purpose, a cross-sectional study was carried out in lean and overweight/obese adults residing in the Lambaréné region of Gabon, an area endemic for Schistosoma haematobium. Helminth infection status, peripheral blood immune cell counts, and serum metabolic and lipid/lipoprotein levels were analyzed. We found that urine S. haematobium egg-positive individuals exhibited lower serum total cholesterol (TC; 4.42 vs 4.01 mmol/L, adjusted mean difference [95%CI] -0.30 [-0.68,-0.06]; P = 0.109), high-density lipoprotein (HDL)-C (1.44 vs 1.12 mmol/L, -0.24 [-0.43,-0.06]; P = 0.009) and triglyceride (TG; 0.93 vs 0.72 mmol/L, -0.20 [-0.39,-0.03]; P = 0.022) levels than egg-negative individuals. However, when stratified according to body mass index, these effects were only observed in overweight/obese infected individuals. Similarly, significant negative correlations between the intensity of infection, assessed by serum circulating anodic antigen (CAA) concentrations, and TC (r = -0.555; P<0.001), HDL-C (r = -0.327; P = 0.068), LDL-C (r = -0.396; P = 0.025) and TG (r = -0.381; P = 0.032) levels were found in overweight/obese individuals but not in lean subjects. Quantitative lipidomic analysis showed that circulating levels of some lipid species associated with cholesterol-rich lipoprotein particles were also significantly reduced in overweight/obese infected individuals in an intensity-dependent manner. In conclusion, we reported that infection with S. haematobium is associated with improved lipid profile in overweight/obese individuals, a feature that might contribute reducing the risk of cardiometabolic diseases in such population. Author summary: Infection with parasitic helminths has been reported to be beneficial for metabolic homeostasis by improving insulin sensitivity and lowering the risk for developing type 2 diabetes. Elevated circulating cholesterol and triglyceride levels associated with obesity are also risk factors for cardiometabolic diseases. In the framework of a cross-sectional study conducted in an endemic rural area, we have investigated the impact of infection with Schistosoma hematobium on serum lipid homeostasis in adult individuals with a broad range of body weight. We found that helminth infection is associated with a lower serum total cholesterol (TC), high-density lipoprotein (HDL)-C and triglyceride (TG) levels, especially in overweight/obese individuals. Furthermore, significant negative correlations between the intensity of infection and TC, HDL-C, LDL-C and TG levels were also found in overweight/obese individuals but not in lean subjects. Altogether our study show for the first time that infection with Schistosoma hematobium is associated with an improved serum lipid profile in overweight/obese humans, a feature that may contribute to protection against cardiometabolic diseases in such population. Further investigation is however required to elucidate the underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]