Primary sclerosing cholangitis displays distinct colonic mucosa topography yet a shared mast cell state with ulcerative colitis.

Primary sclerosing cholangitis (PSC) is a chronic, progressing cholestatic disease that often co-occurs with inflammatory bowel disease (PSC-IBD). PSC-IBD affecting the colon (PSC-ulcerative colitis or PSC-UC) resembles clinical UC, but is characterised by less severe disease flares, right-colon predominance, and a greater lifetime risk of colorectal cancer than UC alone. To elucidate differences in the underlying biology between PSC-UC and UC, here we combine single-cell mRNA and antigen receptor sequencing, 16S ribosomal RNA gene analysis and spatial transcriptomics on biopsies from four colon regions of patients with PSC-UC and UC during endoscopic remission or at the time of relapse. We show that the PSC-UC colon, compared to healthy control (HC) or UC colon, harbours distinct and region-specific mucosal-adherent microbial communities and an enrichment of activated CD8 T and γδ T cells at the right colon, even in the absence of histological inflammation. By contrast, a TMEM176B+ mast cell population that may be pro-tumourigenic is enriched in the colon during disease relapse in both PSC-UC and UC colon. These results highlight that the PSC-UC and UC colonic mucosa are fundamentally different while sharing similar cell programmes during active disease. Our data thus provide insights to guide tailored clinical management and precision therapies.