Various diseases have been linked to the human microbiota, but the underlying molecular mechanisms of the human microbiota in disease pathogenesis are often poorly understood. Using acne as a disease model, my study aims to understand the functional capability changes and the molecular response of the skin microbiota to host metabolite signaling in disease pathogenesis. By metagenomic analysis, I found that the genes of a pathogenic gene island in the skin bacterium, Propionibacterium acnes, were significantly enriched in acne subjects. By metatranscriptomic analysis, I found that the transcriptional profiles of the skin microbiota separated acne patients from healthy individuals. The vitamin B12 biosynthesis pathway in P. acnes, was significantly down-regulated in acne patients. Through in-vivo and in-vitro experiments, I further demonstrated that host vitamin B12 modulates the activities of the skin microbiota and plays a signaling role in acne pathogenesis. To understand the molecular mechanism underlying the transcriptional regulation of P. acnes genes by vitamin B12, I analyzed ten putative regulatory elements in multiple P. acnes genomes and identified sequence variations among different strains. It suggests that the vitamin B12 modulation of P. acnes transcription is individual microbiome-dependent. My findings suggest a novel bacterial pathogenesis pathway in acne. My study also provides evidence that metabolite-mediated interactions between the host and the skin microbiota play essential roles in disease development. To further elucidate how the skin microbiota interacts with the host in disease pathogenesis, I have developed a protocol for enriching bacterial RNA from human skin biopsy samples, which lays a foundation for simultaneously analyzing the interactions between the skin microbiota and host cells at the transcriptional level.