Ulcerative colitis immune cell landscapes and differentially expressed gene signatures determine novel regulators and predict clinical response to biologic therapy

Abstract

The heterogeneous pathobiology underlying Ulcerative Colitis (UC) is not fully understood. Using publicly available transcriptomes from adult UC patients, we identified the immune cell landscape, molecular pathways, and differentially expressed genes (DEGs) across patient cohorts and their association with treatment outcomes. The global immune cell landscape of UC tissue included increased neutrophils, T CD4 memory activated cells, active dendritic cells (DC), and M0 macrophages, as well as reduced trends in T CD8, Tregs, B memory, resting DC, and M2 macrophages. Pathway analysis of DEGs across UC cohorts demonstrated activated bacterial, inflammatory, growth, and cellular signaling. We identified a specific transcriptional signature of one hundred DEGs (UC100) that distinctly separated UC inflamed from uninflamed transcriptomes. Several UC100 DEGs, with unidentified roles in UC, were validated in primary tissue. Additionally, non-responders to anti-TNFα and anti-α4β7 therapy displayed distinct profiles of immune cells and pathways pertaining to inflammation, growth, and metabolism. We identified twenty resistant DEGs in UC non-responders to both therapies of which four had significant predictive power to treatment outcome. We demonstrated the global immune landscape and pathways in UC tissue, highlighting a unique UC signature across cohorts and a UC resistant signature with predictive performance to biologic therapy outcome.

Identification of useful genes from multiple microarrays for ulcerative colitis diagnosis based on machine learning methods

“…The regulation of T cells for UC patients based on Bcl-6 and IL-21 could help to avoid the occurrence and development of IBD 39 . In a previous survey that included a global immune cell landscape of UC patients’ tissue, the results identified the increasing number of neutrophils, T CD4 memory-activated cells, active dendritic cells, and M0 macrophages, and decreasing number of T CD8, Tregs, B memory, and M2 macrophages 40 .…”

Immune Cells and Transcriptional Signatures Revealed Novel Regulators and Predict Clinical Response to Biologic Therapy in Ulcerative Colitis

“…This proceeds to aberrant immune cells presence and function in the affected tissue, activation of signaling pathways, and expression of regulators that subsequently drive inflammation [ 2 , 4 - 7 ]. Using publicly available transcriptomes obtained from large number of UC patients from European and the US cohorts [ 8 - 16 ], we identified systemic immune cell landscape, pathways, and transcriptional signatures specific for UC as well as those determining outcome of biologic therapy [ 17 ].…”

“…Several cell subsets were noticeably reduced such as T CD8, Tregs, B memory, and M2 macrophages. In addition, both resting DC and resting mast cells were lowered, while their active forms were elevated in UC tissue [ 17 ]. Relative abundances of other cell subsets in UC tissue were also altered but did not meet significant threshold with applied criteria.…”

“…Using Ingenuity Pathway Analysis, we discovered signaling pathways associated with differentially expressed genes (DEGs) in UC tissue compared to controls across different cohorts [ 17 ]. These systemic pathways are linked to bacterial response, inflammation, and intracellular signaling.…”

“…These systemic pathways are linked to bacterial response, inflammation, and intracellular signaling. Further, we identified a transcriptional signature consisting of the top hundred DEGs (UC 100 ) that are common across three different cohorts [ 17 ]. In an independent cohort, the UC 100 distinctly separated inflamed from non-inflamed samples via hierarchical clustering.…”