The Impact of PAD4-dependent Neutrophil Extracellular Trap formation on the Early Development of Intestinal Fibrosis in Crohn’s Disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236655 | GEO | 2024/08/14
REPOSITORIES: GEO
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Project description:Background: Perianal fistulising Crohn’s disease (pfCD) is a disabling phenotype of Crohn’s disease (CD) with suboptimal outcomes. We assessed neutrophil extracellular traps (NETs) in perianal fistulas and implicated their roles in pfCD healing. Methods: Patients with complex pfCD who developed preplaced seton drainage were recruited during the verified maintenance of remission in CD. Fistula tracts were sampled during definitive surgery plus seton removal. Patient demographics, CD classification, medication strategy, and healing of pfCD were recorded. RNA sequencing was applied for transcriptomic profile analysis. NETs components, including myeloperoxidase (MPO), neutrophil elastase (NE), and citrullinated histone H3 (CitH3), were identified using immunofluorescence. Serum infliximab (IFX), anti-IFX antibodies, and tissue levels of IFX, adalimumab (ADA), MPO and CitH3 were determined using enzyme-linked immunosorbent assays. Peptidyl arginine deiminase IV (PAD4), tumour necrosis factor (TNF)-α, and NE were detected using immunohistochemistry. Gene expression levels of PAD family members were assessed with qPCR. Results: Twenty-one patients were included, 15 of whom adopted IFX as maintenance treatment. RNA-seq revealed difference in neutrophil associated pathways between unhealed and healed fistulas. NETs components (MPO/NE/CitH3) were detectable in the fistulas and were parallel with the PAD4 levels. Eleven of 21 (52%) patients experienced complete healing of the pfCD 108 weeks post-operatively. Fistula NETs were significantly increased in patients with unhealed pfCD. Increased NETs were associated with abundant TNF-α production and the absence of IFX in fistulas. Conclusions: NETs exist in pfCD fistulas, which are associated with unhealed post-operative fistulas in pfCD, suggesting their prognostic roles in pfCD.
2023-10-07 | GSE215067 | GEO
Project description:The clinical course of Crohn's disease (CD) is highly heterogeneous, confounding effective personalized therapy. There is a critical need to better understand the cellular mechanisms responsible for the variability in disease presentation and response to therapeutic modalities. We carried out whole transcriptome profiling in colon tissue from adult CD patients and controls and found that CD patients segregate into the same two molecular subtypes based on mRNA, long non-coding RNA, or microRNA profiles. MicroRNA-31 (miR-31) in colonic epithelium was identified as a primary contributor to this molecular stratification. We further performed small RNA-seq on formalin-fixed paraffin embedded colon and ileum biopsies obtained at the time of diagnosis from 130 treatment-naïve pediatric CD patients and controls. Colonic expression of miR-31 in pediatric patients was identified as predictive of either medically refractory rectal CD or fibrostenotic ileal CD. Our study reveals miRNAs as important molecular stratifiers and prognostic determinants of CD subtypes.
2018-10-01 | GSE101816 | GEO
Project description:Crohn's disease (CD) is a chronic inflammatory gut disorder. Molecular mechanisms underlying the clinical heterogeneity of CD remain poorly understood. MicroRNAs (miRNAs) are important regulators of gut physiology and several have been implicated in the pathogenesis of adult CD. However, there is a dearth of large-scale miRNA studies for pediatric CD. We hypothesized that specific miRNAs uniquely mark pediatric CD. We performed small RNA-sequencing of patient-matched non-inflamed colon and ileum biopsies from treatment-naïve pediatric patients with CD (n=169) and a control cohort (n=108). Comprehensive miRNA analysis revealed 58 miRNAs altered in pediatric CD. Notably, multinomial logistic regression analysis revealed that index levels of ileal miR-29 are strongly predictive of severe inflammation and stricturing. Transcriptomic analyses of transgenic mice overexpressing miR-29 show a significant reduction of the tight junction protein gene Pmp22 and classic Paneth cell markers. The dramatic loss of Paneth cells was confirmed by histologic assays. Moreover, we also found that pediatric CD patients with elevated miR-29 exhibit significantly lower Paneth cell counts, increased inflammation scores, and reduced levels of PMP22. These findings strongly indicate that miR-29 up-regulation is a distinguishing feature of pediatric CD, highly predictive of severe phenotypes, and associated with inflammation and Paneth cell loss.
2022-12-23 | GSE221261 | GEO
Project description:The aim of this study was to investigate differential intestinal gene expression in patients with Crohn's disease (CD) and controls. 172 biopsies from CD and control subjects were studied. Endoscopic biopsies were taken at ileocolonoscopy from five specific anatomical locations including the terminal ileum for RNA extraction.
2010-07-19 | GSE20881 | GEO
Project description:We performed a comparison of transcriptome between monocyte-derived dendritic cells (moDC) cultured with neutrophil extracellular traps (NETs) from healthy donors or type 1 diabetes (T1D) patients. The source of moDCs is healthy donors and T1D patients
2020-01-07 | GSE143143 | GEO
Project description:BACKGROUND: The intestinal microbiota play a key role in the onset, progression, and recurrence of Crohn’s disease (CD). Most microbiome studies assay fecal material, which does not provide region-specific information on mucosally adherent bacteria that directly interact with host systems. Changes in luminal oxygen has been proposed as a contributor to CD dybiosis. METHODS: 16S rRNA data was generated using colonic and ileal mucosal from patients with CD and without inflammatory bowel diseases (nonIBD). We developed profiles reflecting bacterial abundance within defined aerotolerance categories. Bacterial diversity, composition, and aerotolerance profiles were compared across intestinal regions and disease phenotypes. RESULTS: Bacterial diversity decreased in CD in both ileum and colon. Aerotolerance profiles significantly differed between intestinal segments in nonIBD, though both were dominated by obligate anaerobes, as expected. In CD, high relative levels of obligate anaerobes were maintained in the colon and increased in the ileum. Relative abundance of similar and distinct taxa were altered in colon and ileum. Notably, several obligate anaerobes, such as Bacteroides fragilis, dramatically increased in CD in one or both intestinal segments, though specific increasing taxa varied across patients. Increased abundance of taxa from the Proteobacteria phylum was found only in the ileum. Bacterial diversity was significantly reduced in resected pre-operative tissues of patients that developed disease recurrence across two independent cohorts, with common lower abundance of bacteria from the Bacteroides, Streptococcus, and Blautia genera. CONCLUSIONS: Mucosally adherent bacteria in colon and ileum show distinct alterations in CD that provide additional insights not revealed in fecal material.
2020-04-15 | GSE147600 | GEO
Project description:This study aimed at genome-wide gene expression analysis of colonic biopsies from confirmed cases of intestinal tuberculosis (ITB) and Crohn's disease (CD) in comparison to controls. Further, to evaluate the role of T regulatory cells, Foxp3 mRNA expression was quantified in serum as well as colonic biopsies of patients with intestinal tuberculosis, Crohn's disease and controls. Paired samples, i.e. serum and colonic biopsies, were taken from 33 study subjects, which included patients with ITB and CD, and controls. RNA extraction was done and stringent quality checks performed. Human whole genome gene expression microarray analysis was performed on the Illumina HumanWG-6 Bead Chip with six total RNA samples of the 3 groups in duplicates. Real-time PCR for FOXP3 mRNA expression was analyzed in serum samples (4-CD, 5-ITB, 4-controls) and colonic biopsy samples (4-CD, 5-ITB, 4-controls).
2011-01-04 | E-GEOD-26305 | biostudies-arrayexpress
Project description:Objective: The clinical presentation and course of Crohn’s disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterize the cellular processes associated with disease phenotypes. Design: We examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult CD and control patients. To support the generality of our findings, we analyzed previously published expression data from a large cohort of treatment-naïve pediatric CD and control ileum. Results: We found that adult CD patients clearly segregated into two classes based on colon tissue gene expression—one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Further, gene expression from the ilea of the treatment-naïve pediatric CD patient cohort could be similarly subdivided into colon- and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behavior, including rectal and perianal disease and need for colectomy. Conclusion: Our results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.
2016-12-11 | GSE85499 | GEO
Project description:Short title: Innate Gene/miRNA MDP-response in CD RNA-seq and small RNA-seq were used to identify the expression of gene and microRNA (miRNA) in monocytes from healthy controls and patients with Crohn's Disease (CD), with and without NOD2 (nucleotide-binding oligomerization domain-containing protein 2) single nucleotide polymorphisms (SNPs) after stimulation with muramyl dipeptide (MDP).
2017-02-15 | GSE69446 | GEO
Project description:The aim of this study was to investigate differential intestinal gene expression in patients with Crohn's disease (CD) and controls. 172 biopsies from CD and control subjects were studied. Endoscopic biopsies were taken at ileocolonoscopy from five specific anatomical locations including the terminal ileum for RNA extraction. Biopsies from one of four anatomic locations, from healthy controls and treated (with non-biologic standard of care) or untreated CD patients.
2010-07-19 | E-GEOD-20881 | biostudies-arrayexpress