Tissue-dependent transcriptional and bacterial associations in primary sclerosing cholangitis-associated inflammatory bowel disease

Nicholas E Ilott; Mastura Neyazi; Oxford Translational Gastroenterology Unit Investigators; Carolina V Arancibia-Cárcamo; Fiona Powrie; Alessandra Geremia

doi:10.12688/wellcomeopenres.16901.2

Tissue-dependent transcriptional and bacterial associations in primary sclerosing cholangitis-associated inflammatory bowel disease

Wellcome Open Res. 2022 Nov 4:6:199. doi: 10.12688/wellcomeopenres.16901.2. eCollection 2021.

Authors

Nicholas E Ilott¹, Mastura Neyazi²; Oxford Translational Gastroenterology Unit Investigators; Carolina V Arancibia-Cárcamo², Fiona Powrie^{1

2}, Alessandra Geremia²

Affiliations

¹ The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7FY, UK.
² Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.

Abstract

Background: Patients with primary sclerosing cholangitis (PSC) frequently have co-ocurring ulcerative colitis (UC) and develop colorectal cancer. Colorectal cancer risk in patients with PSC-associated ulcerative colitis (PSC/UC) is elevated relative to patients with ulcerative colitis (UC) alone, reasons for which remain obscure. Understanding the molecular and microbial basis for differences between these two patient groups and how these vary across intestinal sites is important for the development of therapies to prevent colorectal cancer development in at-risk individuals. Methods: We employed ribonucleic acid sequencing (RNA-seq) analysis of biopsy samples across three intestinal tissue locations (ileum, caecum and rectum) in patients with PSC/UC (ileum n = 7, caecum n = 7, rectum n = 7), UC (ileum n = 9, caecum n = 10, rectum n = 10) and healthy controls (ileum n = 11, caecum n = 9, rectum n = 12) to determine tissue-dependent transcriptional alterations in PSC/UC. We also performed 16S ribosomal RNA (rRNA) amplicon sequencing to determine bacterial associations with PSC/UC. Results: Tissue-defining transcriptional signatures revealed that the ileum was enriched for genes involved in lipid and drug metabolism, the caecum for activated immune cells and the rectum for enteric neurogenesis. Transcriptional alterations relative to healthy control samples were largely shared between patients with PSC/UC or UC although were distinct across tissue locations. Nevertheless, we observed reduced expression of gamma-glutamyl transferase 1 ( GGT1) specifically in the ileum and caecum of patients with PSC/UC. Analysis of the bacterial component of the microbiome revealed high inter-individual variability of microbiome composition and little evidence for tissue-dependency. We observed a reduction in Parabacteroides relative abundance in the rectum of patients with PSC/UC. Conclusions: The role of gamma-glutamyl transferase in maintaining the redox environment through the glutathione salvage pathway makes our observed alterations a potential pathway to PSC-associated colorectal cancer.

Keywords: IBD; Primary sclerosing cholangitis; microbiome; transcriptomics.

Associated data

figshare/10.6084/m9.figshare.c.5438892.v2

Grants and funding

This work was supported by the Wellcome Trust (101734, https://doi.org/10.35802/101734, 212240, https://doi.org/10.35802/212240), the National Institute for Health Research (RCF19/016) and the Kennedy Trust for Rheumatology Research.