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Poster presentations: Basic Science 2020

P005 Regulators of the guanylate cyclase pathway are potential novel markers of mucosal healing in IBD

L.E. Jeffery1, U.N. Shivaji1, D. Zardo2, A. Acharjee3, O.M. Nardone4, S.C. Smith4, G. Gkoutos3, S.S. Visweswariah5, S. Ghosh1, M. Iacucci1

1NIHR Birmingham Biomedical Research Centre, University of Birmingham, Gastroenterology, Birmingham, UK, 2University Hospitals Birmingham, Pathology, Birmingham, UK, 3Department of Gastroenterology, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK, 4Department of Gastroenterology, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK, 5Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India

Background

Intestinal guanylate cyclase C (GC-C) present in epithelial cells has been shown to have a role in gut homeostasis. The downstream effects of activation of GC-C are due to production of cyclic-GMP. GC-C is encoded by the gene GUCY2C, mutations in which are implicated in Familial Diarrhoea Syndrome and noted as risk factors for Crohn’s disease. GUCY2C and its activator, GUCA2A have been shown to be downregulated in IBD. We hypothesised that regulation of this pathway might be important in remission and response to therapy.

Methods

Forty-four patients with IBD and 7 patients with polyps (controls) at University Hospitals Birmingham, UK were recruited under ethical consent. Relevant demographic and clinical data were extracted from the hospital EMR. All patients had disease activity recorded on endoscopic examination of mucosa and intestinal biopsies collected for analysis. Mucosal healing was defined as MES = 0 (UC) and SES-CD <6 (CD). Of 44 patients, 14 had matched baseline and 12-week post-biologic therapy assessment and had tissues collected. Intestinal biopsies were analysed by 3’RNA-sequencing using the Illumina Nextseq sequencer. FASTQ files were generated through BaseSpace and reads de-multiplexed, trimmed, aligned, and quantified using the GeneGlobe (Qiagen) workflow. Expression was compared between groups using either Wilcoxon tests or Kruskal–Wallis with Dunn post-hoc analysis as appropriate.

Results

Expression of Guanylate cyclase activators GUCA2A and GUCA2B in patients who showed mucosal healing was equivalent to controls, but GUCA2A was down-regulated in those with active disease (non-healing) (p = 0.006). The same pattern was observed for transcriptional regulators of GUCY2C, including HNF4A (p = 0.0248) and CDX2 (0.0062). Correspondingly, GUCY2C was reduced in non-healing mucosa, although the difference was not significant (Figure 1). In patients who responded to biologic therapy, both GUCA2A (p = 0.0234) and GUCA2B (p = 0.0117) were increased at follow-up but no change was observed for those who did not respond. Change in GUCY2C expression did not reach statistical significance in either group, although an increase was observed for a large proportion of responders.

Conclusion

Our findings suggest that regulation of the Guanylate Cyclase pathway may be involved in the restoration of a stable mucosa in IBD and that expression of its regulators may be used to indicate response to treatment.