Opposing microbiome-mediated axes link modifiable lifestyles to health and chronic diseases

Analyses disentangling the role of the gut microbiome in linking lifestyle factors to health outcomes remain limited. Here, using fecal shotgun metagenomics from 6,803 adults in the Japanese 4D cohort, we identified two opposing microbiome-mediated axes linking lifestyle to health and 15 diseases. A health-associated axis enriched in microbial metabolism of dietary components was linked to plant-based, soy and dairy intake. In contrast, a disease-associated axis, enriched in oral-derived bacteria and pathobionts, was linked to refined carbohydrates and sedentary behavior. Starter culture microorganisms used to ferment foods did not show statistically significant mediation of the observed health effects. Alcohol was associated with both health- and disease-oriented mediation patterns involving microbial host-glycan utilization. Microbiome-defined health- and disease-oriented mediator axes were supported by fecal short-chain fatty acids and plasma cytokines from >1,700 individuals, revealing butyrate-associated anti-inflammatory and pro-inflammatory host profiles, respectively. Microbiome-based prediction (MADE) scores captured lifestyle–microbiome–disease mediation patterns and distinguished individual diseases across 13 independent external cohorts from the United States, China, Sweden, Russia and Australia. We identify the gut microbiome as a key mediator linking lifestyle to health and disease, providing a framework for microbiome-based assessment to guide lifestyle interventions for health promotion and disease prevention. Fecal shotgun metagenomics from 6,803 adults in the Japanese 4D cohort and microbiome-based prediction scores validated across 13 independent and geographically diverse cohorts revealed two opposing microbiome-mediated axes linking lifestyle to health and 15 diseases.