The role of the intestinal microbiome in Crohn's disease (CD) treatment remains poorly understood. This study investigates microbe-host interactions in CD patients undergoing ustekinumab (UST) therapy. Fecal metagenome, metabolome, and host transcriptome data from 85 CD patients were analyzed using multi-omics integration and mediation analysis. Our findings reveal significant microbiome-metabolite-host interactions. Specifically, Faecalibacterium prausnitzii was linked to altered L-ornithine biosynthesis, resulting in higher L-ornithine levels in patients before UST therapy. In vivo and in vitro studies demonstrated that microbiome-derived L-ornithine enhances UST treatment sensitivity in CD by disrupting the host IL-23 receptor signaling and inhibiting Th17 cell stabilization through the IL-12RB1/TYK2/STAT3 axis. L-ornithine significantly enhances the therapeutic efficacy of UST in CD patients, as demonstrated in a prospective clinical trial. These findings suggest that targeting specific microbe-host metabolic pathways may improve the efficacy of inflammatory bowel disease (IBD) treatments.