Background: Although a majority of patients with PSC have colitis [PSC-IBD; primary sclerosing cholangitis-inflammatory bowel disease], this is phenotypically different from ulcerative colitis [UC]. We sought to define further the pathophysiological differences between PSC-IBD and UC, by applying a comparative and integrative approach to colonic gene expression, gut microbiota and immune infiltration data. Methods: Colonic biopsies were collected from patients with PSC-IBD [n = 10], UC [n = 10], and healthy controls [HC; n = 10]. Shotgun RNA-sequencing for differentially expressed colonic mucosal genes [DEGs], 16S rRNA analysis for microbial profiling, and immunophenotyping were performed followed by multi-omic integration. Results: The colonic transcriptome differed significantly between groups [p = 0.01]. Colonic transcriptomes from HC were different from both UC [1343 DEGs] and PSC-IBD [4312 DEGs]. Of these genes, only 939 had shared differential gene expression in both UC and PSC-IBD compared with HC. Imputed pathways were predominantly associated with upregulation of immune response and microbial defense in both disease cohorts compared with HC. There were 1692 DEGs between PSC-IBD and UC. Bile acid signalling pathways were upregulated in PSC-IBD compared with UC [p = 0.02]. Microbiota profiles were different between the three groups [p = 0.01]; with inferred function in PSC-IBD also being consistent with dysregulation of bile acid metabolism. Th17 cells and IL17-producing CD4 cells were increased in both PSC-IBD and UC when compared with HC [p < 0.05]. Multi-omic integration revealed networks involved in bile acid homeostasis and cancer regulation in PSC-IBD. Conclusions: Colonic transcriptomic and microbiota analysis in PSC-IBD point toward dysregulation of colonic bile acid homeostasis compared with UC. This highlights important mechanisms and suggests the possibility of novel approaches in treating PSC-IBD.
Bibliographical noteFunding Information:
GMH has received educational grant support from Dr Falk and Gilead, and consultancy and speaker fees from Intercept, Cymabay, GSK, Dr Falk, and Gilead. JW has received consultancy fees from GE Healthcare, Enyo, Falk, Intercept, Metacrine, Novartis, Pendopharm, and Zealand pharmaceutical companies.
This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at UHB and University of Birmingham. The views expressed are those of the author[s] and not necessarily those of NHS, the NIHR, or Department of Health and Social Care. ADB acknowledges funding from the Wellcome Trust [102732/Z/13/Z], Cancer Research UK [C31641/ A23923], and the Medical Research Council [MR/M016587/1]. GMH is supported by the Lily and Terry Horner Chair in Autoimmune Liver Disease Research.
We would like to thank MRC-CLIMB for providing infrastructure to perform microbial bioinformatics [grant number MR/L015080/1] and the Gastroenterology Unit at University Hospitals Birmingham NHS Foundation Trust [UHB] for facilitating sample collection ADB acknowledge Cancer Research UK advanced clinician scientist award (Ref C41641/ A23933). GG and AA acknowledge support from Health Research (NIHR) Surgical Reconstruction and Microbiology Research Centre (SRMRC) and the MRC HDR UK (HDRUK/CFC/01), an initiative funded by UK Research and Innovation, Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the Medical Research Council or the Department of Health.
© European Crohn’s and Colitis Organisation 2020
- Autoimmune liver disease