Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF2

Abstract

Aim To assess the pathobiological and translational importance of whole blood transcriptomic analysis in inflammatory bowel disease (IBD). Methods We analyzed whole blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn’s disease [CD, n = 156], ulcerative colitis [UC, n = 167], and controls [n = 267]), exploring differential expression (DESeq2), co-expression networks (WGCNA), and transcription factor involvement (EPEE, ChEA, DoRothEA). Findings were validated by analysis of an independent replication cohort (99 CD, 100 UC, and 95 controls). In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure. Results Disease-specific transcriptomes were defined in IBD (8697 transcripts), CD (7152), and UC (8521), with the most highly significant changes in single genes, including CD177 (log2-fold change [LFC] = 4.63, p = 4.05 × 10 -118), MCEMP1 (LFC = 2.45, p = 7.37 × 10 -109), and S100A12 (LFC = 2.31, p = 2.15 × 10 -93). Significantly over-represented pathways included IL-1 (p = 1.58 × 10 -11), IL-4, and IL-13 (p = 8.96 × 10 -9). Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 (PU.1), CEBPB, and IRF2, all regulators of cytokine signaling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% CI 5.3–102.0). Conclusion Transcriptomic analysis has allowed for a detailed characterization of IBD pathobiology, with important potential translational implications.

Immune cell-specific smoking-related expression characteristics are revealed by re-analysis of transcriptomes from the CEDAR cohort

“…Since GPR15 is a homing receptor for lymphocytes into the colon, it is of special importance in the context of the protective influence of smoking against ulcerative colitis. We showed that GPr15 expression in whole blood is associated with smoking in a cohort of patients with IBD (IBD-Character) [13]. A context for the interpretation of this finding was provided by Xiong et al In their experiments AHR activation could increase GPr15 expression in regulatory T lymphocytes, in cooperation with FOXP3, leading to inflow of immunosuppressive GPR15 + T reg cells into the colon [14].…”

Dynamic Changes in Gut Microbiome of Ulcerative Colitis: Initial Study from Animal Model

“…Studies have shown that IL-4 in UC could induce monocytes and eosinophils to participate in inflammatory response and stimulate mast cell proliferation, thus promoting inflammatory response and aggravating the degree of UC. 78 , 79 The level of peripheral 5-HT, a pro-inflammatory factor, which could regulate cellular immune function, promote emission of IFN-γ and other inflammatory factors, 80 and also aggravate inflammatory response of UC, was positively correlated with the severity of UC, 80 , 81 Taken together, DSS could increase the abundance of Clostridium_sensu_stricto_1 relative pro-inflammatory factors, promotes the release of IL-4, 5-HT, TNF-α and IFN-γ, which could promote intestinal inflammation, leading to ulcerative colitis.…”

Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion

“…SNP-dependent putative transcription factor binding sites were identified by motif analysis. Thirty one TF factors were identified ( Supplemental Table 1 ) of which 50% have been associated with differential gene expression in whole blood from CD compared to non-IBD subjects ( 37 ). All TFs were analyzed for trans eQTL association of expression with RNASET2 disease risk genetic variation carriage.…”