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Individual lifestyle factors moderately impact the gut microbiome and host biology. This study explores whether their combined influence significantly alters the gut microbiome and determines the mediating role of the gut microbiota in the relationship between lifestyle and phenomes. Analyzing 1,643 individuals from the Metacardis European cross-sectional study, we created a non-exhaustive composite lifestyle score (QASD score) incorporating diet quality and diversity, physical activity, and smoking.The QASD score shows substantial explanatory power for microbiome composition variation compared to individual lifestyle variables. It positively associates with microbiome genetic richness, butyrate-producing bacteria, and serum metabolites like Hippurate linked to genetic richness and metabolic health. Conversely, it inversely associates with Clostridium bolteae and Ruminococcus gnavus, as well as serum branched-chain amino acids and dipeptides observed in chronic diseases.Causal inference analyses identify 135 cases where the gut microbiome mediates >20% of QASD score effects on the host metabolome. Microbial gene richness emerges as a strong mediator in the QASD score's impact on markers of host glucose metabolism (e.g. 27.3% of the effect on HOMA-IR), despite bidirectional associations between the microbiome and host clinical phenotypes. This study emphasizes the importance of combining lifestyle factors to understand their collective contribution to the gut microbiota and the mediating effects of the gut microbiota on the impact of lifestyle on host metabolic phenotype and metabolomic profiles.