BACKGROUND: Although majority of patients with PSC have colitis (PSC-IBD) this is phenotypically different from UC. We sought to define further the pathophysiologic differences in PSC-IBD and UC, by applying a comparative and integrative approach in this pilot study. METHODS: Colonic biopsies were collected from patients with PSC-IBD (n=10), UC (n=10) and healthy controls (HC; n=10). Shotgun RNA-sequencing for differentially expressed colonic mucosal genes (DEGs), 16S rRNA analysis for microbial profiling and immunophenotyping were performed followed by multi-omic integration. RESULTS: The colonic transcriptome differed significantly between groups (P=0.01). Colonic transcriptomes from HC were different from both UC (1343 DEGs) and PSC-IBD (4312 DEGs). Of these genes, only 939 had shared differential gene expression in both UC and PSC-IBD compared to HC. Imputed pathways were predominantly associated with upregulation of immune response and microbial defence in both disease cohorts compared to HC. There were 1692 DEGs between PSC-IBD and UC. Bile acid signalling pathways were upregulated in PSC-IBD compared to UC (P=0.02). Microbiota profiles were different between the three groups (P=0.01); with inferred function in PSC-IBD also being consistent with dysregulation of bile acid metabolism. Th17 cells and IL17 producing CD4 cells were increased in both PSC-IBD and UC when compared to HC (P<0.05). Multi-omic integration revealed networks involved in bile acid homeostasis and cancer regulation in PSC-IBD. CONCLUSIONS: Colonic transcriptomic and microbiota analysis in PSC-IBD points toward dysregulation of colonic bile acid homeostasis compared to UC. This highlights important mechanisms and suggests the possibility of novel approaches in treating PSC-IBD.