Poster Presentation Hunter Cell Biology Meeting 2025

Distinct topography of the primary sclerosing cholangitis colonic mucosa defined through paired microbial and single-cell RNA sequencing (#111)

Jacqueline LE Tearle 1 2 , Fan Zhang 3 , Katherine JL Jackson 4 , Pratibha Malhotra 1 2 , Paris Tavakoli 3 , Sabrina Koentgen 3 , Joanna Warren 5 , Cameron Williams 6 , Ashraful Haque 6 7 , Arteen Arzivian 8 , Nicodemus Tedla 1 , Andrew Kim 8 , Hamish W King 7 9 , Georgina L Hold 3 , Simon Ghaly 8 , Kylie R James 1 2
  1. School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
  2. Translational Genomics Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  3. School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
  4. Immune Biotherapies Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  5. Cellular Genomics Platform, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  6. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  7. University of Melbourne, Melbourne, Victoria, Australia
  8. St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
  9. Genetics and Gene Regulation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

For reasons unknown, 80% of patients with primary sclerosing cholangitis (PSC; a chronic, progressing cholestatic disease) will also develop inflammatory bowel disease (IBD). PSC-IBD most commonly affects the colon and is likened clinically to ulcerative colitis (UC). However, differences include a right colon dominance, less severe inflammatory presentation, and a greater lifetime risk of developing colorectal cancer in individuals with PSC. The unique clinical presentation of PSC-IBD has led to the postulation of PSC-IBD as a distinct disease entity to IBD, but little is known about the underlying biology of colitis in PSC patients. To address this, we performed single-cell mRNA and antigen receptor sequencing, 16S ribosomal RNA gene analysis, and spatial transcriptomics on mucosal biopsies from four regions of the colon in PSC-IBD and UC patients. This revealed that PSC-IBD patients harbour a unique cellular makeup in the right colon, defined by reduced microbial diversity and enrichment of active CD8 T, γδ T, and natural killer cells, even during symptomatic remission. In contrast, we identified a shared, inflammation-associated mast cell state in both diseases characterised by the expression of colorectal cancer-associated cation channel TMEM176B. These results highlight that the PSC-IBD and UC colonic mucosa are fundamentally different, with shared cell programs during active disease, providing insights to guide tailored clinical management and precision therapies.