Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease of the gastrointestinal tract that is categorized into two main subtypes: Crohn's disease (CD) and ulcerative colitis (UC), depending on the damaged part of the gastrointestinal tract. Although IBD is commonly diagnosed among adolescents and young adults, a rising occurrence in pediatric patients has also been reported. As such, the complexity of phenotypes along the IBD continuum as well as the age of onset raises the need for customized targets.
Here, we performed multi-omics review of IBD, i.e. a meta-analysis of publicly available IBD datasets on CDIAM (Table 1). CDIAM is a multi-omics analytical software platform that offers custom tools to identify new therapeutic targets for different IBD subtypes via the combination of different types of -omics data.
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Targets currently being trialed or extensively used were identified for general IBD.
To identify potential targets for IBD, i.e. for both CD and UC, Pathway2Targets (P2T) results generated from significant differential metabolites (metabolomics) and genes with mutations affecting IBD (mutationDNA) were combined. A default target weighting was chosen for this combination. Among the top five potential targets, one is currently in clinical trials for IBD and another target is extensively used for the treatment of IBD.
The target in trials as a therapeutic for IBD is a pro-inflammatory cytokine produced by both hematopoietic and non-hematopoietic cells. Despite various clinical trials of this target for the treatment of IBD, these agents still present with adverse effect, possibly arising from excessive immunosuppression. Recently, a new inhibitor for this target has been developed with no physiologic and host defense activity related to classic target signaling. Its potential in the phase 2a trial was reported when being translated from mouse models into patients.
Currently, another target is extensively used as first-line treatment of IBD. Targeting this protein is a breakthrough in the treatment of IBD patients. However, as 30% of patients are reported not to respond to this therapy and half of patients experience secondary loss of response within the first year, new targets should also be identified and developed.
Table 1. Summary of dataset used in the study.
Targets for pediatric CD could be used in combination with current first-line treatments.
Predicted targets for the treatment of pediatric CD were identified via the combination of P2T results from scRNA and bulk RNA of pediatric patients.
Two notable potential targets include a transcription factor involved in host defense against viral or bacterial infections and an interferon-induced protein regulating inhibition of proliferation and invasion of endothelial cells. The increased expression of these two proteins in CD patients was documented. Particularly, the former target established a relationship with the first-line treatment of IBD identified in the previous section. Blocking the feedback loop between this protein and the first-line treatment could be a beneficial strategy for IBD therapy. This target has also been shown to be involved in enriched pathways relating to the target trialed in the previous section, suggesting a combination treatment of these two targets. Meanwhile, the interferon-induced protein was identified as a pharmacogenomic biomarker of early response to the first-line treatment in children with IBD.
Different targets identified from different cell types.
We also examined the potential targets from the three major cell types composing the intestine: stromal cells, epithelial cells, and immune cells.
In stromal cells, the potential target is involved in the genetic regulation of a protein whose dysregulation contributes to immune homeostasis in mice models of dextran sulfate sodium -induced colitis as well as human IBD. The inhibition of this protein could be a potential therapeutic strategy to restore a “healthier” state in immune-related homeostatic regulation in CD patients.
In epithelial cells, a protein belonging to the family of anti-apoptotic/pro-apoptotic proteins was identified. The increased ratio of anti-apoptotic/pro-apoptotic proteins recorded in lamina propria mononuclear cells of CD patients and in peripheral blood mononuclear cells of IBD patients was found to be correlated with the efficacy of IBD first-line treatment, suggesting this ratio as a clinical biomarker of primary response.
In immune cells, we found two notable potential targets. The expression of the first target was found in both inflamed mucosa and peripheral blood CD4+ T cells of IBD patients, facilitating Th1 cell differentiation. Meanwhile, the increased expression of the second target was proposed to accelerate the development and rehabilitation of the innate immune response and inflammatory response, ultimately promoting IBD treatment.
In conclusion, our analysis provides a functional outlook on how the powerful workflows provided within the CDIAM software platform can facilitate multi-omics data integration analysis and interpretation. Particularly, depending on the biological question, we demonstrated that our computational workflow can robustly and effectively identify potential targets for different IBD phenotypes via a combination of different types of “-omics” datasets.
NFα (first line treatment)-induced intestinal epithelial cells shedding and mucosal inflammation, a characteristic feature of IBD
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