Evidence that the effect of lifestyle on human cardiometabolic health is strongly mediated through the gut microbiome

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 microbiome in the links between lifestyle and phenomes. Analyzing 1,643 individuals from the Metacardis European study, we created a non-exhaustive composite lifestyle score (QASD score) incorporating diet quality and diversity, physical activity and smoking. This score shows higher explanatory power for microbiome composition variation compared to individual lifestyle variables. It positively associates with microbiome gene richness, butyrate-producing bacteria, and serum metabolites like Hippurate linked metabolic health. It inversely associates with Clostridium bolteae and Ruminococcus gnavus, serum branched-chain amino acids and dipeptides observed in chronic diseases. Causal inference analyses found 135 cases where the microbiome mediates >20% of QASD score effects on host metabolome. Microbiome gene richness also emerged as a strong mediator in the QASD scores impact on markers of host glucose metabolism (27.3% of the effect on HOMA- IR), despite bidirectional associations between the microbiome and 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 microbiome on the impact of lifestyle on host metabolic phenotypes and metabolomic profiles.