The human gut is a highly diverse microbial ecosystem. Although showing a well-defined core of dominant taxa, an interindividual variability exists in microbiome arrangement patterns, and the presence and proportion of specific species, determining individual metabolic features-metabotypes-which govern the health effects of dietary interventions (i.e. polyphenol consumption). Starting with a 19-volunteer human intervention study, divided into low, medium, and high wine-polyphenol-metabolizers, we detected interindividual discrepancies on the effect of wine consumption in gut bacterial alpha-diversity, but a significant homogenization of beta-diversity among moderate wine consumers, independently of their metabotype. In addition, the abundance of key health-related taxa such as Akkermansia sp. increased after moderate wine intake in the group of high polyphenol-metabolizers. Regarding the metabolic activity, significant (p < 0.05) positive correlations in the production of SCFAs were observed after wine intake. Finally, we were able to correlate the microbiome and the metabolome of the three metabotypes, and to identify some metabolites-biomarker species, highlighting the genera Phascolarctobacterium, Pelotomaculum and Prevotella, as positively correlated with polyphenol concentration, and Prevotella, Zymophilus and Eubacterium as positively correlated with SCFAs concentration in faeces. Our results contribute to the evidence of the need of including the microbiome variable in personalized nutrition programs, as different metabotyes respond differently to dietary interventions.