Palmatine protects against atherosclerosis by gut microbiota and phenylalanine metabolism

Accumulating evidence illuminated that gut microbiota directly modulates the development of atherosclerosis (AS) through interactions with metaflammation. The natural bioactive isoquinoline alkaloid palmatine (PAL), which is extracted from one of the herbs (Coptis chinensis) of the anti-AS formular, is of particular interest due to its pharmacological properties. ApoE-/- mice were administered PAL or vehicle; plaque areas, and stability were assessed by histopathological and immunohistochemistry analysis, serum glycolysis and lipid levels, and inflammation levels were also evaluated. 16S rRNA sequencing and metabolomics analysis were employed to evaluate microbial composition and serum metabolites. Microbial culture experiments were designed to reveal the target microbiota and associated metabolites. Cell culture and transcriptome were performed to elucidate the function of microbial metabolites on THP-1. PAL reduced the area of plaque and necrotic core, improving inflammatory infiltration within plaques, improving glycolipid metabolism, and reducing the levels of serum inflammatory cytokines in a dose-dependent manner. PAL treatment reshaped the composition of the gut microbiota, especially, reducing the relative abundance of Desulfovibrio piger (D. piger) in a dose-dependent manner and serum level of hippuric acid (HA). D. piger was able to convert phenylalanine into 3-phenylpropionic acid (precursor of HA). Finally, we verified HA accelerated the progression of AS and increased the secretions of inflammatory cytokines in vivo and in vitro. In conclusion, PAL exhibited anti-AS effects by regulating the gut microbiota-phenylalanine metabolism axis.