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Transcriptomic profiling of collagenous colitis identifies hallmarks of non-destructive inflammatory bowel disease [Microdissected IEC]

ABSTRACT: Background and Aims: The pathophysiology of the diarrhoea-predominant inflammatory bowel disease collagenous colitis (CC) is poorly described. Our aim was to use RNA sequencing of colonic biopsies from patients with active CC, CC in remission, refractory CC, ulcerative colitis (UC), and controls to gain insight into CC pathophysiology, identify additional genetic signatures linked to CC, and uncover targets for future therapeutic agents. Methods: We performed whole transcriptome sequencing of CC colonic samples from patients before and during treatment with the corticosteroid drug budesonide, steroid-refractory patients, UC and healthy controls (n=9-13). Bulk mucosa and laser-captured microdissected intestinal epithelial cell gene expression was functionally analyzed by gene-set enrichment and gene-set variation analyses to identify statistically significant pathways and cells, respectively, that change in CC. Leading genes and cells were validated using reverse transcription quantitative PCR and/or immunohistochemistry. Finally, we compared CC transcriptome with that from UC samples. Results: We identified an activation of the adaptive immune response to bacteria in active CC compared to that in remission that could be mediated by dendritic cells. However, a unique signature of genes related to the immune response and DNA transcription remain dysregulated after achieving remission. Budesonide-refractory CC patients fail to restore normal gene expression, which results in a transcriptomic profile close to UC. Intestinal epithelial CC cells displayed an impaired cell proliferation and increased antigen presentation. Conclusion: Our study confirmed previous findings from GWAS and immunological studies related to CC pathogenesis and describes novel genes, pathways and cells that might contribute to the pathophysiology of CC, ongoing epithelial damage, and complications associated with CC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159007 | GEO | 2021/05/03

REPOSITORIES: GEO

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Project description:Objective: Ulcerative colitis (UC) is a chronic disease with rising incidence and unclear etiology. The application of mass spectrometry-based post-genomic analysis methods shall support the development of molecular biomarker signatures providing status information with regard to UC pathomechanisms. Design: Pathomechanisms characteristic for UC were assessed by proteome profiling of human tissue specimen, obtained from five distinct colon locations each of 12 patients. Systemic disease-associated alterations were investigated by mass spectrometry-based multi-omics analyses comprising proteins, metabolites and eicosanoids of plasma obtained from UC patients during disease and upon remission in comparison to healthy controls. Results: Proteome profiling results identified colitis-associated activation of neutrophils, macrophages, B- and T-cells, platelets, fibroblasts and endothelial cells and indicated hypoxic stress, as well as a general reduction of mitochondrial proteins accompanying the establishment of apparent healing-promoting activities as well as scar formation. While the immune cells mainly contributed pro-inflammatory proteins, the colitis-associated epithelial cells, fibroblasts, endothelial cells and platelets predominantly formed anti-inflammatory and healing-promoting proteins. Blood plasma proteomics indicated chronic inflammation and platelet activation, whereas plasma metabolomics identified disease-associated deregulation of bile acids, eicosanoids and gut microbiome-derived metabolites. Upon remission, several, but not all, molecular candidate biomarker levels recovered to normal levels. These findings may indicate that pathomechanisms related to gut functions, gut microbiome status, microvascular damage and metabolic dysregulation associated with hypoxia may do not resolve uniformly upon remission. Conclusions: The establishment of disease-associated biomarker profiles related to molecular UC pathomechanisms may support the establishment of bioassays with improved prognostic power aiding individualized therapy.

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Transcriptomic profiling of collagenous colitis identifies hallmarks of non-destructive inflammatory bowel disease [Microdissected IEC]

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