Distinct transcriptional signatures in purified circulating immune cells drive heterogeneity in disease location in IBD

Abstract

ObjectiveTo infer potential mechanisms driving disease subtypes among patients with inflammatory bowel disease (IBD), we profiled the transcriptome of purified circulating monocytes and CD4 T-cells.DesignRNA extracted from purified monocytes and CD4 T-cells derived from the peripheral blood of 125 endoscopically active patients with IBD was sequenced using Illumina HiSeq 4000NGS. We used complementary supervised and unsupervised analytical methods to infer gene expression signatures associated with demographic/clinical features. Expression differences and specificity were validated by comparison with publicly available single cell datasets, tissue-specific expression and meta-analyses. Drug target information, druggability and adverse reaction records were used to prioritise disease subtype-specific therapeutic targets.ResultsUnsupervised/supervised methods identified significant differences in the expression profiles of CD4 T-cells between patients with ileal Crohn’s disease (CD) and ulcerative colitis (UC). Following a pathway-based classification (Area Under Receiver Operating Characteristic - AUROC=86%) between ileal-CD and UC patients, we identified MAPK and FOXO pathways to be downregulated in UC. Coexpression module/regulatory network analysis using systems-biology approaches revealed mediatory core transcription factors. We independently confirmed that a subset of the disease location-associated signature is characterised by T-cell-specific and location-specific expression. Integration of drug-target information resulted in the discovery of several new (BCL6,GPR183,TNFAIP3) and repurposable drug targets (TUBB2A,PRKCQ) for ileal CD as well as novel targets (NAPEPLD,SLC35A1) for UC.ConclusionsTranscriptomic profiling of circulating CD4 T-cells in patients with IBD demonstrated marked molecular differences between the IBD-spectrum extremities (UC and predominantly ileal CD, sandwiching colonic CD), which could help in prioritising particular drug targets for IBD subtypes.

Identification of PPARG as key gene to link coronary atherosclerosis disease and rheumatoid arthritis via microarray data analysis

“…Tubulin beta class IIa (TUBB2A) is encoded in the 10q24.2 locus, which plays a crucial role in cell division, cell motility, intracellular transport, and immunomodulatory processes [ 29 ]. Increased TUBB2A expression has been reported in intestinal cells during inflammation-associated bowel disease, thus highlighting its potential as a therapeutic target in immune modulation [ 30 ]. Peroxisome proliferator-activated receptor gamma (PPARG) is a transcription factor located on 3p25.2 [ 31 ] that is involved in regulating macrophage polarization, lipid metabolism and inflammation [ 32 ].…”

Investigating the Crime Scene—Molecular Signatures in Inflammatory Bowel Disease

“…In addition, biomarker-based dietary intervention could offer an additional non-immunosuppressive treatment option for patients [ 21 , 22 ]. Consequently, a currently unmet need is to identify, evaluate and implement promising IBD biomarkers in personalised medicine [ 16 , 17 , 18 ].…”

“…Since 2019, cutting-edge research has demonstrated that the effects of diet depend on patient factors and gut microbial activity. Furthermore, a range of biomarker candidates have been identified that need evaluation for clinical translational potential [ 16 , 17 , 18 ]. This review synthesises the newest published research and provides the latest understanding of the relationship between diet, gut microbes and the immune system of the gut barrier ( Box 1 ).…”

“…In addition, biomarkerbased dietary intervention could offer an additional non-immunosuppressive treatment option for patients [21,22]. Consequently, a currently unmet need is to identify, evaluate and implement promising IBD biomarkers in personalised medicine [16][17][18]. Although accumulating evidence points to interactions among diet, gut microbes and immune factors on the gut barrier as key elements controlling IBD, many studies have only individually characterised the environmental, gut microbial and patient factors, with interactions between these factors remaining unclear [23].…”

Discovery of a Highly Potent Oxysterol Receptor GPR183 Antagonist Bearing the Benzo[d]thiazole Structural Motif for the Treatment of Inflammatory Bowel Disease (IBD)

“…The Epstein–Barr-virus-induced gene 2 (EBI2, also known as GPR183) is a rhodopsin-like G protein-coupled receptor consisting of 361 amino acid residues . It is exclusively coupled to the Gα i protein, and the cholesterol oxidative metabolite, 7α,25-dihydroxycholesterol (7α,25-OHC), has been found as its most potent endogenous ligand. , GPR183 acts as a chemotactic GPCR highly expressed in immune cells, including B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and innate lymphoid cells. − Due to the significance of cholesterol and its metabolites in many fundamental physiological processes, especially as important signaling molecules in the innate and adaptive immune system, the axis of GPR183/7α,25-OHC has been closely implicated in the pathogenesis of many inflammatory and autoimmune diseases, including inflammatory bowel disease (IBD). − …”