Genome-wide transcriptional analysis in intestinal biopsies from Crohn's disease (CD) patients.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE83448 | GEO | 2020/06/08
REPOSITORIES: GEO
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Project description:Perianal Fistulizing Crohn’s Disease (perianal-CD) is a debilitating form of CD typically associated with prolonged periods of morbidity. Leveraging single-cell RNA sequencing, rectal mucosal tissue was sequenced from individuals following anti-TNF biologic therapy having either active perianal-CD and inflamed rectal mucosa or healed perianal-CD but non-inflamed mucosa. Single cell transcriptomic profiles of the inflamed and non-inflamed tissue were contrasted to test for specific cellular subsets of rectal epithelial and immune cell compartments associated with inflamed perianal disease. We identified eight broad classes of epithelial, six of immune, and a small population of stromal cells in the rectal mucosa. There was an increase in colonocytes in the non-inflamed tissue compared to the inflamed tissue, and an increase of naïve b cells and plasma cells associated with inflamed tissue. The cell type proportions of immune cells, highlighted patient heterogeneity of cell type abundance and potential dysregulation of both the immune and epithelial compartment. We also note enrichment of IgG plasma cells in inflamed tissue of two donors and expansion of IgA plasma cells of non-inflamed tissue in two donors. Differential gene expression analysis of goblet cells revealed enrichment of inflammatory pathways, such as IL6 and interferon gamma signaling, in inflamed tissue. These inflammatory pathways might affect tight junctions between epithelial cells leading to increased permeability and potentially affect fistula formation. Our findings suggest dysregulation of crypt maturation during persistent inflammation and over-abundance of goblet cells and colonocyte precursors in inflamed tissue of perianal-CD.
2023-02-20 | GSE225199 | GEO
Project description:To investigate the gene expression profile of inflamed and non-inflamed mucosa in patients with Crohn's disease. To investigate TCR repertoires in the intestinal mucosa, the expression profile of the TCR repertoire gene was analyzed.
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Project description:In this study, we investigated miRNA expression profiles in ileal mucosa from CD patients in different settings (post-operative recurrent (POR) CD, newly diagnosed CD and late stage CD)) and controls.
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Project description:Inflammatory bowel diseases are associated with dysregulated immune responses in the intestinal tissue. Four molecularly identified macrophage subsets control immune homeostasis in healthy gut. However, the specific roles and transcriptomic profiles of the phenotypically heterogeneous CD14+ macrophage-like population in inflamed gut remain to be investigated in Crohn’s disease (CD). Here we identified two phenotypically, morphologically and functionally distinct colonic HLADR+SIRPα+CD14+ subpopulations that were further characterized using single-cell RNA-sequencing (scRNAseq) in CD. Frequencies of CD64hiCD163−/dim cells selectively augmented in inflamed colon and correlated with endoscopic score of disease severity. IL-1β and IL-23-producing CD64hiCD163−/dim cells predominated over TNF-α-producing CD64hiCD163hi cells in lesions. Purified “inflammatory monocyte-like” CD163−, but not “macrophage-like” CD163hi cells, through IL-1β, promoted Th17/Th1 but not Th1 responses in tissue memory CD4+T cells. Unsupervised scRNAseq analysis that captures the entire HLADR+SIRPα+ population revealed six clusters, two of which were enriched in either CD163− or CD163hi cells, and best defined by TREM1/FCAR/FCN1/IL1RN or CD209/MERTK/MRCI/CD163L1 genes, respectively. Selected newly identified discriminating markers were used beyond CD163 to isolate cells that shared pro-Th17/Th1 function with CD163− cells. In conclusion, a molecularly distinct pro-inflammatory CD14+ subpopulation accumulates in inflamed colon, drives intestinal inflammatory T-cell responses, and thus, might contribute to CD disease severity.
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Project description:In this study, we investigated gene expression profiles in ileal mucosa from CD patients in different settings (post-operative CD (Rutgeerts score i0); post-operative recurrent CD (i1), post-operative recurrent CD (≥i2b), newly diagnosed CD and late stage CD)) and controls.
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Project description:Anti-TNFα therapy induces mucosal healing in a large proportion of Crohn’s disease (CD) patients, but the mechanisms underlying this process are not fully elucidated. To this end we examined molecular effects of adalimumab treatment in CD. CD patients (n=10) underwent ileocolonoscopy were sampled for mucosal biopsies before and after three months of adalimumab treatment. Collected material was analyzed using transcriptome microarray analysis. All patients were responders and eight patients reached clinical remission. Mucosal transcriptome analyses demonstrated that anti-inflammatory and tissue-repair gene-sets were upregulated in inflamed mucosa, in addition to proinflammatory and tissue-destruction-related genes. After treatment, genes promoting inflammation or tissue-destruction were downregulated. , and these genes are primarily expressed in innate leukocytes and stromal cells. Expression of anti-inflammatory and tissue-repair-related genes was also downregulated, but to a lesser degree. Of note, various parts of the colon displayed distinct gene-expression profiles. Adalimumab operates by down-shifting several proinflammatory arms of both the innate and adaptive immune-system, but does not disturb regulatory T-cells. Anti-inflammatory and tissue-repair machineries are upregulated already during active inflammation, but are not effective until proinflammatory drivers have been silenced.
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Project description:Studying genes involved in the regulation of inflammation may help to clarify the pathogenesis of IBD. In search of the genes which products are known to be involved in NO signalling and altered in patients with IBD, our present aim was to determine the expression of such genes in CD and UC, respectively. To this end, microarray expression of genes known to be controlled by or which products are involved in NO signalling was studied in biopsies of colonic mucosa from patients and healthy controls. A cohort of inflamed colonic mucosa samples from 20 CD patients and 20 UC patients, as well as 6 control colonic mucosa samples, was used to acquire expression profiles. All of the inflamed samples were analysed individually, while the control samples were pooled and analysed in 4 replicates.
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Project description:We report profiling of H3Kme3 histone modifications in intestinal epithelial cells from ileal endoscopic biopsies obtained from healthy controls and newly-diagnosed Crohn's disease (CD). We identified 1066 shared sites, corresponding to 1038 genes with increased H3K4me3 in CD, and 539 sites corresponding to 548 genes with reduced H3K4me3 in CD.
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Project description:Different genes, especially cytokines, have been deregulated in the inflammatory environment of intestinal mucosa in ulcerative colitis patients. The effects of differential gene expression such as immunological factors have been described before, however, there is no evidence of alarmins deregulated by microRNAs impacting on the pathophysiology of UC. Our goal is to study deregulated genes in inflamed mucosa for microRNA pairing in a Chilean cohort of patients. We used microarrays to compare inflamed and non inflamed mucosa from chilean ulcerative colitis patients
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Project description:Biopsy samples (n=362) were collected from terminal ileum at baseline, 8 weeks after induction (Ustekinumab or placebo), and 44 weeks after maintenance (Ustekinumab 90 mg SC q12w, Ustekinumab 90 mg SC q8w, or placebo) therapies during endoscopy for RNA extraction and microarray analysis from patients with moderate-to-severe CD who participated in stelara CD phase 3 studies (UNITI-2 and IM-UNITI). These patients failed conventional therapies previously and largely naive to anti-TNF therpy. Ileum biopsies (n=26) collected from non-IBD subjects were also analyzed to serve as control. Enrichment of a core microvilli gene set was found to be reduced in UNITI-2 CD samples relative to controls, correlated with microvilli length and endoscopy score, and associated with response to treatment.
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