Strain-specific variation in Cutibacterium acnes shapes its role in human skin

Cutibacterium acnes dominates sebaceous skin sites, yet its role in health and disease remains elusive. Distinct strains coexist across different skin regions, but their metabolic diversity and niche adaptations are poorly characterized. Here we combined pan-genomics, metabolic models, and experimental assays to explore variation in strain-specific metabolism in health- and acne-associated context. Using 172 curated genome-scale metabolic models, we predicted phenotypes across 972 nutrient conditions, uncovering phylogroup-specific capabilities, including shared and strain-specific amino acid auxotrophies. Nutrient utilization patterns distinguish acne- from health-associated strains and a decision tree identified key classifiers such as D-gluconate and 1-O-methyl-beta-D-glucuronate. Experimental validation with skin isolates confirmed these classifiers with high predictive accuracy and sensitivity. We further demonstrate that C. acnes strains can metabolize skin-associated substrates, including long-chain fatty acids, when co-utilized with other nutrients, a prediction validated experimentally. These findings establish a functional framework for predicting C. acnes metabolism and its strain-specific roles in human skin.