Detailed Transcriptional Landscape of Peripheral Blood Points to Increased Neutrophil Activation in Treatment-Naïve Inflammatory Bowel Disease

Abstract

Background and Aims Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn’s disease (CD) or ulcerative colitis (UC). These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and thus, common immune regulatory pathways. Methods Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve (n=110) and treatment-exposed (n=177) IBD patients as well as symptomatic- (n=65) and healthy controls (n=95). Results Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, the IL1B was identified as the central gene. The co-expression levels among IL1B and chemosensing receptor (CXCR1/2 and FPR1/2) genes were reduced in the blood of IBD patients when compared with healthy controls. Conclusions Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.

Differences in Whole-Blood Transcriptional Profiles in Inflammatory Bowel Disease Patients Responding to Vedolizumab Compared with Non-Responders

“…Our observation of there being no DEGs between UC and CD is in agreement with some reports [ 18 ], although it is in contrast with others [ 19 ]. However, in the gene-by-gene comparisons, the transcriptional dynamics were strikingly different between responders and non-responders following treatment.…”

“…Therefore, it has been suggested that α 4 β 7 -directed therapy alone may leave additional compensatory homing mechanisms active [ 39 , 40 ], which merits further investigation. Blood-based transcriptomic profiling of treatment-naïve as well as treated IBD patients has shown an enrichment of pathways of “innate immunity”, and especially of myeloid-mediated immunity such as “neutrophil mediated immunity”, as well as the activation of “oxidative phosphorylation” when compared with healthy controls [ 18 ].…”

Inverse and Concordant Mucosal Pathway Gene Expressions in Inflamed and Non-Inflamed Ulcerative Colitis Patients: Potential Relevance to Aetiology and Pathogenesis

“…Thus far, 241 risk loci have been associated with IBD via genome-wide association study (GWAS) approaches, and two thirds of these loci impart susceptibility to both diseases [3]. In addition, studies have examined the IBD transcriptome in the intestinal mucosa [4,5], in isolated epithelial cells [6] and in peripheral blood [7] and tried to define gene expression signatures for disease subtypes [8,9] and for the prediction of disease course and clinical response to drug treatment [4,10]. In spite of these advances, the pathophysiology of IBD is not fully explained, which justifies additional investigations and approaches to dissect the etiological and pathogenic factors involved.…”

Whole blood RNA sequencing identifies transcriptional differences between primary sclerosing cholangitis and ulcerative colitis

“…For UC, we further observed an upregulation of genes of general cellular metabolism, like genes coding for ribosomal proteins, mitochondrial genes and genes of the oxidative phosphorylation process, which has partly been shown by others. 12 , 39 We showed that although PSC and UC are both characterized by strong upregulation of genes like S100A12, S100A9 and C19orf59 in module M14 (“neutrophil-S100A12”) from WGCNA compared to controls, their transcriptomes are quite different. Random forest classification models can easily distinguish PSC and UC, but most coexpression modules are unevenly expressed in the two diagnoses.…”

“…First, we replicated the well-known upregulation of neutrophil-associated transcripts for patients with UC. 12 , 39 For patients with PSC, we are only aware of one other publication providing transcriptomic data from peripheral blood 20 although we were unable to replicate their differentially expressed gene sets or validate our findings in their expression data. For UC, we further observed an upregulation of genes of general cellular metabolism, like genes coding for ribosomal proteins, mitochondrial genes and genes of the oxidative phosphorylation process, which has partly been shown by others.…”