P0161 The primary sclerosing cholangitis and ulcerative colitis colonic mucosa defined through paired microbial and single-cell RNA sequencing
J Tearle, F Zhang, K Jackson, P Malhotra, P Tavakoli, S Koentgen, J Warren, C Williams, A Haque, A Arzivian, N Tedla, A Kim, H King, G Hold, S Ghaly, K JamesAbstract
Background
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-UC) is likened clinically to ulcerative colitis (UC), however differences include a right colon dominance, less severe inflammatory presentation and a greater lifetime risk of colorectal cancer.
Methods
We combine single-cell mRNA and antigen receptor sequencing, 16S ribosomal RNA gene analysis and spatial transcriptomics to profile mucosal biopsies from four colon regions of PSC-UC and UC patients in remission or at the time of relapse.
Results
In contrast to UC, PSC-UC patients display an enrichment of CD8 T, γδ T and natural killer cells and reduced microbial diversity in the right colon, even in the absence of symptomatic inflammation. During flare, we demonstrate the expansion of a novel inflammatory mast cell state in both diseases and highlight the function of TMEM176B in sustaining this activated state.
Conclusion
These results highlight that the PSC-UC and UC colonic mucosa are fundamentally different with shared cell programs during active disease, providing insights to guide tailored clinical management and precision therapies.