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

In 6,803 adults from the Japanese 4D cohort, fecal shotgun metagenomics identified two opposing gut-microbiome mediator axes linking lifestyle to health and 15 diseases, including a butyrate-linked anti-inflammatory profile.

• Why it matters: It remains unclear how the gut microbiome mediates lifestyle–health links and whether distinct microbial pathways correspond to health versus disease outcomes.
• What they did: The study used fecal shotgun metagenomics to define lifestyle–microbiome–disease axes, tested mediation by starter culture microbes, and validated mediator signatures with fecal short-chain fatty acids and plasma cytokines from >1,700 individuals.
• The result: Microbiome-defined health- and disease-oriented axes were supported by butyrate-associated host cytokine profiles, and MADE scores predicted lifestyle–microbiome–disease patterns and distinguished individual diseases across 13 external cohorts.

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