The synergistic effects of lotus seed resistant starch (LRS3) and sodium lactate (SL; a postbiotics of RS3) on hypolipidemic function and serum nontargeted metabolites of hyperlipidemia rats were investegated. Rats fed a high-fat diet were orally administered with LRS3 (HLRS group) or SL (HSL group) either alone or in combination (HLRSSL group) for consecutive 4 weeks. HLRSSL was found to control weight gain, regulate blood lipid levels, reduce accumulation of fat in liver cells, and improve lesions in rat cardiac arteries, liver, small intestine, and colon tissues more effectively compared to HLRS or HSL group alone. Compared to the high-fat control group (HMC), l-phenylalanine and LysoPC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)) in serum were upregulated in HLRSSL rats, while aconitic acid and suberic acid were decreased. Correlation analysis showed that SM(d18:0/16:1(9Z)), taurochenodeoxycholic acid, LysoPC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)), oleic acid, and retinol were negatively correlated with total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) and positively correlated with high-density lipoprotein cholesterol (HDL-C). Moreover, glutamic acid and serine showed a significant positive correlation with LDL-C and negative correlation with HDL-C. These differential metabolites were associated with reducing serum lipid levels in hyperlipidemia rats potentially through metabolic pathways such as linoleic acid, glutamine and glutamate, pyruvate, citric acid cycle, and glycerophospholipid.
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