Highlights from

ECCO 2019

European Crohn's and Colitis Organisation's 14th congress

Copenhagen 6-9 March 2019

Immune cells and microbes: a happy marriage?

A coordinated cellular network of innate as well as adaptive immune cell types are implicated in inflammatory bowel disease (IBD). This was concluded from a comprehensive analysis of the cell composition in intestinal biopsies from IBD patients across all major immune lineages simultaneously, using high-dimensional mass cytometry [1].

In patients with a clinical suspicion of IBD, paired biopsies from ileum and colon were taken, as well as blood samples in 23 IBD patients and 15 controls with a normal colonoscopy. A total of 309 distinct cell clusters from the collective intestinal dataset were identified containing 3.4 million cells. Affected samples from the different subgroups of IBD (Crohn’s disease, ulcerative colitis, and indeterminate colitis) were mostly intermixed, suggesting similarities in the immune profiles. Also noted, was a large interindividual variation in the immune cell composition, which was indicative of unique individual ‘immune fingerprints’ in the intestinal tract. Comparing affected-IBD samples and unaffected-IBD samples, 19 subsets were significantly different. Several CD4+ T cell clusters correlated with innate lymphoid cells (ILC) and myeloid cell clusters and were up-regulated in IBD-affected segments (see Figure, top-left network). In particular, T cell receptor (TCR) γδ cell clusters (see Figure, top-right network) and a group of ILC clusters (see Figure, bottom network) were up-regulated in unaffected samples of patients and controls.

Together with the evidence for the unique individual-specific composition of the intestinal immune system, these findings may aid in the development of more (cost-)effective and personalised treatments.

Figure 1: Network representation of immune cell cluster correlations [1] Network representation of immune cell cluster correlations

CD, Crohn’s disease; IBD, inflammatory bowel disease; ILC, innate lymphoid cells.

In another study, scientists from Oxford, United Kingdom, assessed host-microbial functions in primary sclerosing cholangitis-inflammatory bowel disease (PSC-IBD) and evaluated whether PSC-IBD-associated pathways affect epithelial transformation [2]. A distinct transcriptomic profile in the caecal biopsies of patients with PSC-IBD compared with ulcerative colitis and haemorrhagic colitis was identified, with 890 genes being regulated in PSC-IBD. This profile in the colonic mucosa of patients with PSC-IBD showed altered regulation of pathways, previously associated with IL-22 and TGFβ signalling. Both these cytokines have been implicated in cancer pathogenesis. PSC-IBD-associated Th1 responses may result in increased epithelial IL-22 responsiveness. Higher expression of the cancer stemness genes OLFM4 and POU5F1 (both associated with pluripotency and early stages of neoplastic transformation) was triggered by bacteria and IL-22 via STAT3 activation. This suggests that microbial-driven IL-22 responses may contribute to epithelial transformation.

Further, emergent date suggest IL-33 and its receptor, ST, might provide a critical contribution to inflammation-driven tumorigenesis, which can lead to colorectal cancer (CRC) [3]. This was the incentive for Dr Loris Lopetuso (Catholic University of the Sacred Heart, Italy) et al. to study the precise contribution of IL-33/ST2 axis in the azoxymethane (AOM)/dextran sodium sulphate (DSS) model of colitis-associated CRC. The results showed that the IL-33/ST2 axis promotes tumorigenesis in colitis-associated CRC through the activation of CD73.

IL-33, ST2L, and sST2 mRNA transcripts were dramatically elevated in AOM/DSS-treated wild-type mice vs knock-out control mice. Localisation of IL-33 to the colonic epithelium and to cells within the lamina propria was morphologically consistent with tissue macrophages in treated wild-type mice. ST2 staining was localised to the intestinal epithelium in tissues immediately adjacent to tumours; within the tumours themselves, ST2+ cells displayed a spindle/fibroblast-like morphology, with a unique distribution throughout the polyps. Little or no staining for both IL-33 and ST2 was present in controls. FACS analysis showed a distinct population of CD45+ haematopoietic cells, consisting of CD3/CD8+ cytotoxic T cells (CTLs), CD19+ B lymphocytes, CD11b+CD11c- and CD11b+CD11c+ myeloid cells. CD45-ST2+ and CD45+ST2+ expressed significantly elevated levels of CD73 compared with ST2-cells. AOM/DSS treatment in IL-33, ST2 knock-out, and CD73 knock-out mice resulted in a significant decreased polyp number and size vs wild-type mice.

Keywords: Crohn’s disease, ulcerative colitis, interleukin

  1. Van Unen V, et al. ECCO 2019, OP27.
  2. Neyaz M, et al. ECCO 2019, OP28.
  3. Lopetuso LR, et al. ECCO 2019, OP29.

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.