The regulatory effects of specific polyphenols on Akkermansia are dependent on uridine

•The regulatory effects of CA, PA, and Pue on microbiota and metabolites are different from Res.•CA, PA, and Pue supplement promoted Akkermansia growth by uridine.•The regulatory effect of Res on microbiota is dependent on petroselinic acid.•The regulatory effect of four polyphenol on Alistipes and Eubacterium xylanophilum are related to 4-methylphenol and 2,2′-methylenebis(4-methyl-6-tert-butylphenol). We examined the microbial regulatory capacity of four polyphenols with different structure in healthy mice and explore the mechanism according to exogenous metabolites and microbial metabolites. Oral administration of four polyphenols, including caffeic acid (CA), procyanidin (PA), puerarin (Pue), and resveratrol (Res), did not lead to metabolic disorder in healthy mice. Gut microbiota analysis revealed that CA, PA, and Pue administration significantly enhanced the abundance of Akkermansia and Ruminococcaceae UCG-014 while Res supplement mainly promoted the growth of Lactobacillus and Bacteroides. Furthermore, correlation analysis and exogenous metabolite prediction revealed that the effects of polyphenols, including CA, PA, and Pue, on Akkermansia have strong relationship with uridine while the regulation of Res on microbiota might be dependent on the decrease on petroselinic acid. These investigations considerably suggest the importance of exploration of exogenous metabolites and reveal the similarity of effects of polyphenols on microbiota and metabolites.