Prominent mediatory role of gut microbiome in the effect of lifestyle on host metabolic phenotypes

Lifestyle factors influence both gut microbiome composition and host metabolism, yet their combined and mediating effects on host phenotypes remain poorly characterized in cardiometabolic populations. In 1,643 participants from the MetaCardis study, we developed a composite lifestyle score (QASD: dietary Quality, physical Activity, Smoking, and diet Diversity) that outperformed individual lifestyle variables in explaining microbial gene richness and exhibited a significant impact on gut microbiome composition. While bidirectional pathways linking the QASD score, host phenotypes, and microbiome composition were assessed, causal inference-based mediation analyses indicated stronger effects when the microbiome was modeled as the mediator variable, particularly in relation to insulin resistance–associated profile. Microbiome gene richness emerged as a key mediator explaining 27.8% of QASD score's effect on insulin resistance marker (HOMA-IR), whereas no significant mediation was observed on BMI. Extended mediation analyses on microbial species and serum metabololomics deconfounded for drug use and clinical profiles identified 47 microbial taxa mediating more than 20% of the effect of QASD score on serum metabolites associated to insulin resistance. Notably, several Faecalibacterium lineages enriched in individuals with high QASD score played a significant mediatory role in the rise of serum biomarkers of microbiome diversity (as cinnamoylglycine or 3-phenylpropionate). Conversely, elevated levels of secondary bile acids in individuals with low QASD scores were strongly mediated by high levels of Clostridium bolteae. These findings highlight distinct and clinically relevant microbiome pathways linking lifestyle behaviors to cardiometabolic risks.