Inflammatory Bowel Disease in patients with Primary Sclerosing Cholangitis: a distinct form of colitis

Background and aims Primary sclerosing cholangitis (PSC) is an inflammatory disorder of the bile ducts, often accompanied by inflammatory bowel disease (PSC-IBD). Substantial differences in clinical presentation are observed between PSC-IBD and ulcerative colitis (UC). In this study we aim to find distinct pathomechanisms for PSC-IBD using single-cell mRNA sequencing. Methods Forty-seven colonic mucosal biopsies of PSC-IBD (n=24), UC (n=18) (where possible matched inflamed (I) non-inflamed (NI)), and non-IBD subjects (n=5) were collected and dissociated. Library preparation and processing for sequencing was followed by differential abundance, differential expression, and cell-cell-interaction analyses. Stainings for DUOX2 and HLA-DR were applied on tissue sections. Results In total, 71,798 cells comprised 54 distinct cell types, including a new cell type: the DUOX2+ enterocyte, mainly present in inflamed colon and acting as antigen presenting cells (HLA-DR+). Stem cells exhibited increased abundances in PSC-NI but not in UC-NI. Additionally, we found distinct gene expression profiles in PSC and UC which were related to inflammation: while mainly inflammatory monocytes were activated in PSC inflammation, and inflammatory fibroblasts were activated in UC inflammation. Conclusion Our study found a new cell type, the DUOX2+ enterocyte that is primarily present in inflamed conditions, and based on their expression profile, potentially perform antigen presentation. Moreover, we highlight that PSC-IBD, but not UC, is characterized by the activation of inflammatory HLA-DRB1+ monocytes, which are likely involved in the activation of CD4+ T cells. Notably, we observed an increased abundance of stem cells in non-inflamed PSC-IBD, possibly linked to the elevated risk of colorectal cancer in PSC-IBD.