Cutibacterium acnes is the most abundant bacterium of the human skin microbiome since adolescence, participating in both skin homeostasis and diseases. Here, we demonstrate individual and niche heterogeneity of C. acnes from 1,234 isolate genomes. Skin disease (atopic dermatitis and acne) and body site shape genomic differences of C. acnes, stemming from horizontal gene transfer and selection pressure. C. acnes harbors characteristic metabolic functions, fewer antibiotic resistance genes and virulence factors, and a more stable genome compared with Staphylococcus epidermidis. Integrated genome, transcriptome, and metabolome analysis at the strain level unveils the functional characteristics of C. acnes. Consistent with the transcriptome signature, C. acnes in a sebum-rich environment induces toxic and pro-inflammatory effects on keratinocytes. L-carnosine, an anti-oxidative stress metabolite, is up-regulated in the C. acnes metabolome from atopic dermatitis and attenuates skin inflammation. Collectively, our study reveals the joint impact of genes and the microenvironment on C. acnes function.

痤疮皮肤杆菌是自青春期以来人类皮肤微生物组中最丰富的细菌，参与皮肤稳态和疾病。在这里，我们展示了 1,234 个分离基因组中痤疮丙酸杆菌的个体和生态位异质性。皮肤病（特应性皮炎和痤疮）和痤疮丙酸杆菌的身体部位形状基因组差异，源于水平基因转移和选择压力。与表皮葡萄球菌相比，痤疮丙酸杆菌具有特有的代谢功能，抗生素耐药基因和毒力因子较少，基因组更稳定。菌株水平的综合基因组、转录组和代谢组分析揭示了痤疮丙酸杆菌的功能特征。与转录组特征一致，痤疮丙酸杆菌在富含皮脂的环境中会对角质形成细胞产生毒性和促炎作用。 L-肌肽是一种抗氧化应激代谢物，在特应性皮炎的痤疮丙酸杆菌代谢组中上调，并减轻皮肤炎症。总的来说，我们的研究揭示了基因和微环境对痤疮丙酸杆菌功能的共同影响。