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Integration of genome-wide DNA methylome and transcriptome of human intestinal fibroblasts reveals novel candidate gene signatures in Crohn’s disease-associated fibrosis

ABSTRACT: Tissue fibrosis is a serious complication of Crohn’s disease (CD) as well as of a variety of other complex, chronic pathologies. Understanding the underlying pathophysiology of tissue fibrosis is crucial for the development of tissue-specific prevention and interventional treatment strategies. To identify molecular states specific to fibrotic disease, we employed deep sequencing to define the genome-wide DNA methylome and the whole transcriptome of purified human intestinal fibrotic fibroblasts (HIFs) isolated from the colon of patients with fibrotic CD. Integration of this information, via computational tools, identified candidate molecular interactions that could lead to fibrosis pathology. Our definition of a genome-wide fibrosis-specific DNA methylome provides a new paradigm for understanding mechanisms of pathological gene expression that lead to intestinal fibrosis and may have relevance to fibrogenesis in other organs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67250 | GEO | 2016/03/22

SECONDARY ACCESSION(S): PRJNA279340

REPOSITORIES: GEO

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Integration of genome-wide DNA methylome and transcriptome of human intestinal fibroblasts reveals novel candidate gene signatures in Crohnâs disease-associated fibrosis

Project description:Tissue fibrosis is a serious complication of Crohnâs disease (CD) as well as of a variety of other complex, chronic pathologies. Understanding the underlying pathophysiology of tissue fibrosis is crucial for the development of tissue-specific prevention and interventional treatment strategies. To identify molecular states specific to fibrotic disease, we employed deep sequencing to define the genome-wide DNA methylome and the whole transcriptome of purified human intestinal fibrotic fibroblasts (HIFs) isolated from the colon of patients with fibrotic CD. Integration of this information, via computational tools, identified candidate molecular interactions that could lead to fibrosis pathology. Our definition of a genome-wide fibrosis-specific DNA methylome provides a new paradigm for understanding mechanisms of pathological gene expression that lead to intestinal fibrosis and may have relevance to fibrogenesis in other organs. Human intestinal fibroblasts (HIFs) were extracted and cultured from colon specimens of two groups: Crohnâs disease with associated fibrosis (n=3) and normal fibroblasts from patients with Diverticulitis (n=3). Both RNA-seq and MBD-isolated genome sequencing (MiGS) were performed on every sample.

2016-03-22 | E-GEOD-67250 | biostudies-arrayexpress

Fibrosis associated changes detected in the proteome of surface epithelium overlying Crohn’s Disease Strictures

Project description:Background and aims: Intestinal fibrosis is a common complication of Crohn’s disease (CD). It is characterised by an excessive accumulation of fibroblasts differentiating into activated myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. Methods: A total of 113 CD and control subjects were studied. We performed a pilot proteomic study comparing the proteome of surface epithelium isolated by laser capture microdissection in normal and fibrotic zones of resected ileal CD strictures (n=5). Selected proteins were validated by immunohistochemistry (IHC) in colonic and ileal samples of stricturing CD patients (n=44), pure inflammatory CD (n=29) and control subjects (n=40). Functional assays with cell lines cultures and a fibroblast to myofibroblast differentiation model were used to assess the role of the highlighted epithelial proteins in CD fibrosis. Results: Proteomic study revealed an endoplasmic reticulum (ER) stress and unfolded protein response (UPR) markers increase in the epithelium overlying ileal fibrotic strictures, involving Anterior gradient protein 2 homolog (AGR2) and Binding immunoglobulin protein (BiP). This was confirmed by IHC. The ER stress induction in intestinal epithelial cells increased AGR2 as well as BiP expression and led to an extracellular secreted AGR2. A fibroblast to myofibroblast differentiation was obtained with the supernatant of intestinal epithelial cells pre-conditioned by ER stress and with recombinant AGR2. Conclusions: AGR2 and other ER stress markers are increased within the intestinal epithelium overlying fibrotic strictures and might contribute to profibrotic signals involved in CD fibrosis.

2022-04-04 | PXD022214 | Pride

Agilent Microarray of formalin-fixed, paraffin-embedded mesenteric adipose tissue associated with different amount of fibrosis from ileocolonic resection specimens of Crohn’s disease patients

Project description:In Crohn’s disease (CD) pathology, we observed that: 1) a continuous process of fibrosis includes all the layers of the intestine as well as the surrounding mesenteric adipose tissue (MAT); 2) the amount of fibrosis in the MAT varies between samples even within a single case. To further investigate the molecular features of this fibrosis pattern, we did a paired study using formalin-fixed, paraffin-embedded blocks from ileocolonic resection specimens of seven CD patients. Specifically, one block contained ≥10% fibrosis amount while the other block contained <10% fibrosis amount within the MAT from the same case. MAT was selectively collected from serial histologic sections and total RNA was extracted for the Agilent Microarray analysis.

2021-07-16 | E-MTAB-8570 | biostudies-arrayexpress

RNA-seq of nonstenotic and stenotic areas of patients with Crohn’s disease

Project description:Fibrostenotic disease is a common complication in Crohn’s disease (CD). We performed bulk RNA sequencing (n=16) of paired intestinal biopsies taken from nonstenotic and stenotic areas of patients with CD (n=8).

2023-04-26 | E-MTAB-12788 | biostudies-arrayexpress

Altered Intestinal Microbiota-Host Mitochondria Crosstalk in New Onset Crohn’s Disease

Project description:Intestinal microbial dysbiosis is associated with Crohn’s disease (CD). However, the mechanisms leading to the chronic mucosal inflammation that characterizes this disease remain unclear. To evaluate causality and mechanisms of disease, we conducted a systems level study of the interactions between the gut microbiota and host in new-onset pediatric patients. We report an altered host proteome in CD patients indicative of impaired mitochondrial functions. A downregulation of mitochondrial proteins implicated in H2S detoxification was observed, while the relative abundance of H2S microbial producers was increased. Network correlation analysis identified Atopobium parvulum as the central hub of H2S producers. Gnotobiotic and conventionalized colitis-susceptible interleukin-10-deficient (Il10-/-) mice demonstrated that A. parvulum induced colitis, a phenotype requiring the presence of the intestinal microbiota. Administration of bismuth, a H2S scavenger, prevented A. parvulum-induced colitis in Il10-/- mice. This study identified host-microbiota interactions that are disturbed in CD patients providing mechanistic insights on CD pathogenesis.

2016-09-29 | PXD002882 | Pride

Gut multi-omics profiling in Crohn’s disease: A preliminary study

Project description:Background: Inflammatory bowel diseases are classic polygenic disorders, with genetic loads that reflect immunopathological processes in response to intestinal microbiota. To assess gut bacterial community, microRNA (miRNA), and short chain fatty acid (SCFA) signatures associated with the activity of Crohn’s disease (CD). Methods: DNA, miRNA, and metabolites were extracted from stool samples of 15 CD patients, eight with active disease and seven in remission, and nine healthy individuals. Microbial, miRNA and SCFA profiles were assessed using datasets from 16s rRNA sequencing, Nanostring miRNA and GC-MS targeted analysis, respectively. Results: Pairwise comparisons showed that 11 and 27 taxa differed between controls and CD patients with active and inactive disease, respectively. Seven taxa were common to both comparisons, whereas eight taxa differed in CD patients. α-Diversity was lower in both CD groups than in controls. The levels of 13 miRNAs differed (p-value <0.05; FC >1.5) in CD patients and controls. Comparisons of controls with CD patients having active and inactive disease identified 12 and seven significantly different miRNAs, respectively. Of six SCFAs, the levels of two differed significantly (p-value <0.05, FC >1.5) in CD patients and controls, and the levels of four differed in patients with active and inactive CD. PLS-DA revealed models with high discriminatory powers (AUC >0.9) for bacteria and miRNA. The levels of 14 miRNAs and 39 bacterial taxa correlated with the level of SCFAs. Conclusion: CD-related gut dysbiosis correlates significantly with miRNA and SCFA profiling, indicating complex relationships among all these factors in response to intestinal inflammation.

2020-08-10 | GSE144535 | GEO

Isobaric labeling-based quantitative proteomics of cells purified from the intestine of Crohn’s disease patients reveals immune cell-epithelial cell crosstalk of potential importance in disease pathogenesis

Project description:Crohn's disease (CD) is a chronic condition characterized by recurrent flares of inflammation of the gastrointestinal tract. Despite decades of research, the etiology of CD is poorly understood and is characterized by dysregulated immune activation that progressively destroys the gastrointestinal tissue. At the center of the pathology is the intestinal mucosa, where the epithelium and the lamina propria are main cellular compartments. While the epithelium contains predominantly epithelial cells, the lamina propria is enriched in immune cells and contains supporting stroma. Thus, the cells constituting these compartments can be classified as epithelial cells, immune cells and stromal cells. Gaining insight into how these cell types interact with each other is important to further our understanding of CD pathogenesis. Here, using isobaric labeling-based quantitative proteomics, we perform an exploratory study to analyze in-depth proteome changes in epithelial cells, immune cells and stromal cells purified by cell sorting from the intestinal mucosa of CD patients and controls. Our workflow preserving the link between the different cell types in individuals opens the possibility to explore cellular crosstalk and to further refine data on cell-cell interactions in the development of CD.

2023-01-02 | PXD036591 | Pride

Crohn’s Disease Differentially Affects Region Specific Composition and Aerotolerance Profiles of Mucosally-Adherent Bacteria

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

Single-cell RNAseq of mesenteric adipose tissue from Crohn's disease patients and healthy controls

Project description:As a hallmark of Crohn's disease (CD)，creeping fat (CF) is intimately related to intestinal fibrosis and postoperative recurrence. It is defined as expansion of mesenteric adipose tissue envelops the diseased intestinal segment. Compared with the healthy controls, CF has enriched functions related to adipogenesis and immune response.

2023-07-30 | GSE215001 | GEO

Genome-wide gene expression analysis for target genes to differentiate patients with intestinal tuberculosis and Crohn’s disease

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

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