Tissue-dependent transcriptomic and bacterial associations in primary sclerosing cholangitis-associated IBD

Background: Primary sclerosing cholangitis (PSC) is primarily a disease of the bile duct and liver. However, patients frequently have co-occurring diseases including inflammatory bowel disease (IBD) and colorectal cancer. Indeed, colorectal cancer risk in patients with PSC-associated IBD is elevated relative to patients with IBD alone, reasons for which remain obscure. Understanding the molecular and/or microbial basis for differences in cancer risk between these two patient groups will be important for the development of therapies to prevent colorectal cancer development in at-risk individuals. Methods: We employed RNA-sequencing analysis of biopsy samples across three intestinal tissue locations (ileum, caecum and rectum) in patients with PSC-associated ulcerative colitis (PSC/UC n = 8), ulcerative colitis (UC; n = 10) and healthy controls (n = 12) to determine tissue-dependent transcriptional alterations in PSC/UC. We also performed 16S rRNA amplicon sequencing of the same tissue sites to determine bacterial associations with PSC/UC and host-microbiome associations.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. Finally, through integrating host transcriptomic and bacterial amplicon sequencing data we were able to identify clear tissue-dependent host-microbiome correlations that may be important for tissue-dependent immune responses.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.