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

Abstract

AbstractBackground and aimsPrimary 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.MethodsForty-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.ResultsIn 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.ConclusionOur 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.What is known on the subject?Inflammatory Bowel Disease (IBD) presents in 60–80% of primary sclerosis cholangitis (PSC) patients, termed PSC-IBD. However, the clinical presentation is distinct: patients have 10 times increased risk of colorectal carcinoma as compared to ulcerative colitis (UC) patients, and the conventional IBD treatment regimen is not always effective. The underlying genetic predisposition is also different from general IBD, where PSC-IBD shows a very strong risk association in the HLA-DRB1 region, generally a hallmark of auto-immune disease.What this study addsThis study uncovers that PSC-IBD has more autoimmune and UC more inflammatory characteristics. This is supported by the interaction between inflammatory monocytes and CD4+/CD8+ T cells through HLA-DR in PSC-IBD. PSC-IBD patients have pronounced increased activity of inflammatory monocytes, not seen in UC. We find increased stem cell abundance in PSC-IBD. In addition, we show cellular-molecular mechanisms potentially driving the increased risk of carcinoma in PSC-IBD patients offering valuable foundations for targeted therapeutic strategies. In addition, we determined the new DUOX2+ enterocyte.How this research might affect research, practice, or policyThis study uncovers that PSC-IBD has more autoimmune characteristics whereas UC is an immune mediated inflammatory disease. This is supported by the specific interaction between inflammatory monocytes and CD4+/CD8+ T cells through HLA-DR in PSC-IBD, while in UC DUOX2+ enterocytes and inflammatory monocytes communicate with innate immune cells, Tregs and CD4+ T cells. Our findings may form new treatment targets for PSC-IBD and IBD in general.