<i>N</i>6,<i>N</i>6‐Dimethyl‐<scp>l</scp>‐Lysine: An Anti‐Obesity Metabolite of <i>Lactiplantibacillus plantarum</i> R2‐5 From Longevity Area Revealed by Multi‐Omics Analysis

ABSTRACT Lactobacilli bacteria, as probiotics, show significant potential for lipid reduction. Current research into their lipid‐lowering effects is in the early stages, with mechanisms largely unexplored. In this study, mice were induced with a high‐fat diet (HFD) and treated with Lactiplantibacillus plantarum R2‐5 (LPR2‐5) via oral gavage. After 12 weeks, the LPR2‐5‐treated group exhibited substantial improvements in body weight and lipid abnormalities, with significant reductions in liver and abdominal fat accumulation. (LPR2‐5 can reduce serum total cholesterol [TC] by 25.7%, lower triglycerides [TG] by 45%, decrease low‐density lipoprotein cholesterol [LDL‐C] by 30%, and double high‐density lipoprotein cholesterol [HDL‐C].) Analysis of gut microbiota diversity demonstrated that LPR2‐5 intervention altered the gut microbiome, increasing the abundance of short‐chain fatty acid (SCFA)‐producing bacteria ( Lactobacillus , Roseburia ) and potentially beneficial microbes (Turicibacter , Christensenella ), while inhibiting obesity‐associated bacteria ( Alistipes , Bilophila ), thus altering metabolic activity in the gut. Using multi‐omics techniques, key metabolic pathways and metabolites were identified. The lipid‐lowering mechanism involved a notable increase in N 6, N 6‐dimethyl‐ l ‐lysine, a precursor for carnitine synthesis, enhancing carnitine production in the liver and promoting β‐oxidation of long‐chain fatty acids, thereby effectively reducing early stage adipose accumulation.