Leonurine alleviates HFD-induced inflammation and dyslipidemia via modulating gut microbiota-derived indole-3-propionic acid signaling.

High-fat diet (HFD) induces metabolic disturbances, in which gut microbiota and metabolites play a critical role. Although leonurine (LE) has demonstrated lipid-lowering effects, whether it ameliorates metabolic disorders through gut microbiota modulation remains unclear. Using 16S rRNA sequencing and untargeted metabolomics, we systematically evaluated the effects of LE on metabolic phenotypes, organ inflammation, intestinal barrier integrity, and the microbiota-metabolite axis in HFD-fed mice. Our results showed that LE significantly suppressed HFD-induced weight gain, dyslipidemia, and elevations in serum pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), while alleviating tissue inflammation and damage in the heart, liver, and kidneys. Furthermore, LE ameliorated HFD-related colon shortening, jejunal villus blunting, and decreased expression of tight junction proteins (ZO-1, Occludin), thereby enhancing intestinal barrier function. Gut microbiota analysis revealed that LE reversed HFD-induced dysbiosis, reduced the Firmicutes/Bacteroidetes ratio, and increased the abundance of beneficial genera such as Bifidobacterium. Metabolomic analysis further indicated that LE reduced intestinal levels of lipid metabolites (fatty acids, glycerides, glycerophospholipids) and markedly increased the content of the microbiota-derived metabolite indole-3-propionic acid (IPA). Correlation network analysis suggested that IPA levels were closely associated with beneficial bacterial abundance and improvements in lipid profiles and inflammatory markers. Mechanistically, LE elevated both serum and intestinal IPA levels, increased expression of the aryl hydrocarbon receptor (AhR), and decreased phosphorylation of NF-κB. Collectively, this study elucidates a novel association in which LE ameliorates HFD-induced metabolic inflammation and organ damage by remodeling the gut microbiota-metabolite axis, with the IPA-AhR pathway potentially playing a central role.