OWE-014 Whole transcriptome shotgun sequencing reveals significant upregulation of colonic mucosal immune-mediated anti-microbial mechanisms in psc-uc

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Abstract

Introduction

Primary sclerosing cholangitis is a hepatobiliary disorder of unknown aetiology that is commonly associated with ulcerative colitis (PSC-UC). We have previously demonstrated that patients with PSC-UC have significant alterations in their gut microbiota compared to patients with UC alone and healthy controls. The mechanisms by which these alterations influence pathogenesis is unclear.

Methods

Shotgun sequencing was performed on whole transcriptomic libraries of colon biopsies obtained from 10 patients with PSC-UC and 10 healthy controls. Differential gene expression analysis with false discovery rate correction was performed with limma and edgeR. In addition lamina propria mononuclear cells were analysed by multicolour flow cytometry.

Results

The colonic transcriptome of patients with PSC-UC demonstrated 6774 significantly differentially expressed genes compared to healthy controls. Gene expression in PSC-UC clustered separate to healthy controls on multidimensional scaling (p=0.006). Gene enrichment analysis revealed 280 significantly altered biological processes. PSC-UC was characterised by an overexpression of processes associated with regulation of anti-microbial immune responses compared to healthy controls (p<0.0001). These immunological responses were enriched with pathways associated with innate, cell-mediated and humoral immunity, autophagy, complement activation and chemokine signalling (p<0.0001). Expression of genes associated with microbial handling including defensins, mannose receptors and anti-microbial peptides were significantly upregulated in PSC-UC. Paired CD4 T cell immunophenotyping of colon biopsies revealed a significant increase in the population of Th17 cells and IL-17 producing cells in PSC-UC in comparison to healthy controls (18.6% vs 8.5%; p=0.0007 8.5% vs 5.6%; p=0.005 respectively).

Conclusion

We have for the first time demonstrated the colonic mucosal transcriptional response in PSC-UC. In comparison to healthy controls, patients with PSC-UC have highly significant expression of genes associated with over-representation of multiple immunological processes, many of which are directed against bacteria. Consistently patients with PSC-UC have a significant increase in colonic mucosal Th17 and IL-17 cell population compared to healthy controls.

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