Pathogenesis of Crohn's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Boyapati R
PROVIDER: S-EPMC4447044 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Pathogenesis of Crohn's disease.
Boyapati Ray R Satsangi Jack J Ho Gwo-Tzer GT
F1000prime reports 20150402
Significant progress in our understanding of Crohn's disease (CD), an archetypal common, complex disease, has now been achieved. Our ability to interrogate the deep complexities of the biological processes involved in maintaining gut mucosal homeostasis is a major over-riding factor underpinning this rapid progress. Key studies now offer many novel and expansive insights into the interacting roles of genetic susceptibility, immune function, and the gut microbiota in CD. Here, we provide overview ...[more]
Similar Datasets
Project description:Sustained, transmural inflammation of the bowel wall may result in the development of a fistula in Crohn's disease (CD). Fistula formation is a recognized complication and cause of morbidity, occurring in 40% of patients with CD. Despite advanced treatment, one-third of patients experience recurrent fistulae. Development of targeting treatment for fistulae will be dependent on a more in depth understanding of its pathogenesis. Presently, pathogenesis of CD-associated fistulae remains poorly defined, in part due to the lack of accepted in vitro tissue models recapitulating the pathogenic cellular lesions linked to fistulae and limited in vivo models. This review provides a synthesis of the existing knowledge of the histopathological, immune, cellular, genetic, and microbial contributions to the pathogenesis of CD-associated fistulae including the widely accredited contribution of epithelial-to-mesenchymal transition, upregulation of matrix metalloproteinases, and overexpression of invasive molecules, resulting in tissue remodeling and subsequent fistula formation. We conclude by exploring how we might utilize advancing technologies to verify and broaden our current understanding while exploring novel causal pathways to provide further inroads to future therapeutic targets.
| S-EPMC9667304 | biostudies-literature
Project description:Crohn's disease (CD) is the main type of chronic inflammatory bowel disease of unknown etiology. Evidence from family and twin studies suggests that genetics plays a significant role in predisposing an individual to develop Crohn's disease. A susceptibility locus for Crohn's disease has been mapped 3 to chromosome 16: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators which is expressed in hematopoietic compartment cells and intestinal epithelial cells as well as in paneth cells, where NOD2 may play an important role in the pathogenesis of Crohn disease in the gastrointestinal system. This leads to alteration the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has two functions, first an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. Thus, NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in intestinal epithelial cells as well as in paneth cells. Further confirmation of a genetic predisposition comes from studies of the association between the human leukocyte antigen (HLA) system and CD. The immunogenetic predisposition may be considered an important requirement for the development of CD, as several alleles of human major histocompatibility complex had an association with CD. Although it is difficult to estimate the importance of this region in determining overall genetic susceptibility in a population, studies of HLA allele sharing within families suggest that this region contributes between 10% and 33% of the total genetic risk of Crohn's disease.
| S-EPMC4537883 | biostudies-literature
Project description:Crohn's disease (CD) is a chronic inflammatory bowel disease. Research has identified genetic predisposition and environmental factors as key elements in the development of the disease. However, the precise mechanism that initiates immune activation remains undefined. One pathway for luminal antigenic molecules to enter the sterile lamina propria and activate an immune response is via transcytosis. Transcytosis, although tightly regulated by the cell, has the potential for transepithelial transport of bacteria and highly antigenic luminal molecules whose uncontrolled translocation into the lamina propria can be the source of immune activation. Viewed as a whole, the evidence suggests that unregulated intestinal epithelial transcytosis is involved in the inappropriate presentation of immunogenic luminal macromolecules to the intestinal lamina propria. Thus fulfilling the role of an early pre-morbid mechanism that can result in antigenic overload of the lamina propria and initiate an immune response culminating in chronic inflammation characteristic of this disease. It is the aim of this paper to present evidence implicating enterocyte transcytosis in the early etio-pathogenesis of CD.
| S-EPMC3070014 | biostudies-other
Project description:Inflammatory bowel disease is a group of diseases that includes Crohn's disease (CD) and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mouth to the anus. Although there are gross pathological and histological similarities between CD and Johne's disease of cattle, the cause of CD remains controversial. It is vital to understand fully the cause of this disease because it affects approximately 500,000 people in North America and Europe. It ranges from 27 to 48 cases per 100,000 people. There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the patients. Regardless of the environmental trigger, there is strong evidence that a genetic disposition is a major key in acquiring CD. Many studies have proven the link between mutations in the ATG16L, NOD2/CARD15, IBD5, CTLA4, TNFSF15 and IL23R genes, and CD. The purpose of this review is to examine all genetic aspects and theories of CD, including up to date multiple population studies performed worldwide.
| S-EPMC3270503 | biostudies-literature
Project description:Background and aimExpression profiling of genes specific to pediatric Crohn's Disease (CD) patients was performed to elucidate the molecular mechanisms underlying disease cause and pathogenesis at disease onset.MethodsWe used suppressive subtractive hybridization (SSH) and differential screening analysis to profile the mRNA expression patterns of children with CD and age- and sex-matched controls without inflammatory bowel disease (IBD).ResultsSequence analysis of 1000 clones enriched by SSH identified 75 functionally annotated human genes, represented by 430 clones. The 75 genes have potential involvement in gene networks, such as antigen presentation, inflammation, infection mechanism, connective tissue development, cell cycle and cancer. Twenty-eight genes were previously described in association with CD, while 47 were new genes not previously reported in the context of IBD. Additionally, 29 of the 75 genes have been previously implicated in bacterial and viral infections. Quantitative real-time reverse transcription polymerase chain reaction performed on ileal-derived RNA from 13 CD and nine non-IBD patients confirmed the upregulation of extracellular matrix gene MMP2 (P = 0.001), and cell proliferation gene REG1A (P = 0.063) in our pediatric CD cohort.ConclusionThe retrieval of 28 genes previously reported in association with adult CD emphasizes the importance of these genes in the pediatric setting. The observed upregulation of REG1A and MMP2, and their known impact on cell proliferation and extracellular matrix remodeling, agrees with the clinical behavior of the disease. Moreover, the expressions of bacterial- and virus-related genes in our CD-patient tissues support the concept that microbial agents are important in the etiopathogenesis of CD.
| S-EPMC7167032 | biostudies-literature
Project description:Background: Despite significant progress in the research of fibrosis in various organs, fibrosis remains a poorly understood complication of Crohn's disease (CD). We analyzed pathologic features of fibrosis and inflammation in CD and compared them with the normal bowel, aiming to clarify whether fibrosis in CD pathogenetically resembles fibrosis in other organs. Methods: Resection specimens from 30 patients with CD were included. Normal bowel from resection specimens of colorectal carcinoma was used for comparison. Trichrome Masson staining, immunohistochemistry for α-smooth muscle actin, fibroblast activation protein, CD34 and erg, in situ hybridization for TGF-β1 and analysis of selected fibrosis-related microRNAs were performed. Results: In normal bowel, CD34-positive fibroblasts/pericytes were detected in the submucosa and subserosa, particularly around blood vessels. In CD, fibrosis prevailed in the submucosa and subserosa, together with proliferation of myofibroblasts and disappearance of CD34-positive fibroblasts/pericytes. TGF-β1 was present in the lamina propria in normal bowel and CD, and in deeper parts of the bowel wall in CD. MicroRNAs miR-29c, miR-155 miR-150, and miR-155, which have been demonstrated to contribute to fibrosis in various organs, showed significant deregulation in CD. Conclusions: Distribution of fibroblasts/pericytes in the submucosa and subserosa of normal bowel, their disappearance in fibrosis in CD, together with the appearance of myofibroblasts, suggest that fibroblasts/pericytes are the most likely source of myofibroblasts in CD. Furthemore, fibrosis-related microRNAs showed deregulation in fibrotic areas. Pathogenesis of fibrosis in CD is thus comparable to fibrosis in other organs, in which myofibroblasts are the key effector cells, and pericytes have emerged as the main origin of myofibroblasts. Fibrosis in CD should be regarded as a result of (over)response of the bowel wall to the presence of inflammation in deep structures of the bowel wall, presenting another example of a common pathogenetic pathway of fibrosis development.
| S-EPMC7215240 | biostudies-literature
Project description:BackgroundIn this review, we were interested to identify the wide universe of enzymes associated with epigenetic modifications, whose gene expression is regulated by miRNAs with a high relative abundance in Crohn's disease (CD) affected tissues, with the aim to determine their impact in the pathogenesis and evolution of the disease.MethodsWe used HMDD and Bibliometrix R-package in order to identify the miRNAs overexpressed in CD. The identified enzymes associated with epigenetic mechanisms and post-translational modifications, regulated by miRNAs upregulated in CD, were analyzed using String v11 database.ResultsWe found 190 miRNAs with great abundance in patients with CD, of which 26 miRNAs regulate the gene expression of enzymes known to catalyze epigenetic modifications involved in essentials pathophysiological processes, such as chromatin architecture reorganization, immune response regulation including CD4+ T cells polarization, integrity of gut mucosa, gut microbiota composition and tumorigenesis.ConclusionThe integrated analysis of miRNAs with a high relative abundance in patients with CD showed a combined and superimposed gene expression regulation of enzymes associated with relevant epigenetic mechanisms and that could explain, in part, the pathogenesis of CD.
| S-EPMC7890887 | biostudies-literature
Project description:The Relationship between Fecal Bile Acids and Microbiome Community Structure in Pediatric Crohn’s Disease
| PRJEB35587 | ENA
Project description:Crohn's disease (CD) is a type of inflammatory bowel disease that cannot be fully cured by medication or surgery. In the present study, the aim was to understand the underlying mechanisms of CD. Two CD microarray datasets were downloaded from The Gene Expression Omnibus database: GSE36807 (13 CD and 7 normal samples) and GSE59071 (8 CD and 11 normal samples). A series of bioinformatics analyses were conducted, including weighted gene co?expression network analysis to identify stable modules, and analysis of differentially expressed genes (DEGs) between CD and normal samples. The common DEGs in the GSE36807 and GSE59071 datasets were screened. Subsequently, overlapping genes in the stable modules and the DEGs were selected to construct a protein?protein interaction (PPI) network using Cytoscape software. Enrichment analysis of genes in the network was performed to explore their biological functions. A total of 10 stable modules and 927 DEGs were identified, of which 234 genes were shared in the stable modules and the DEGs. After removal of 32 uncharacterized genes, 202 genes were selected to build the PPI network. Low density lipoprotein receptor (LDLR), toll?like receptor 2 (TLR2), lipoprotein lipase (LPL), forkhead box protein M1 (FOXM1) and neuropeptide Y (NPY) were revealed as key nodes with high degree. Pathway enrichment analysis demonstrated that LPL was enriched in the peroxisome proliferator?activated receptor (PPAR) signaling pathway. In conclusion, LDLR, TLR2, FOXM1 and NPY, as well as LPL in the PPAR signaling pathway may serve critical roles in the pathogenesis of CD.
| S-EPMC6102736 | biostudies-literature
Project description:A common genotypic basis for ulcerative colitis (UC) and Crohn's disease (CD) is implied by overlapping clinical characteristics, epidemiological studies, and association of genes with both UC and CD. We evaluated the overlap between CD and UC genetic loci stratified by pathogenetic pathways and by disease location.The allele frequencies of six UC-associated and 34 CD-associated single nucleotide polymorphisms (SNPs) were determined in a Canadian IBD cohort (n = 2374). Differences between CD, UC, colon-only CD, ileal CD, and controls were analyzed controlling for ethnicity, age of diagnosis, and gender.In all, 21 of 34 CD-associated SNPs had similar allele frequencies in UC (n = 1230) and CD (n = 1144). Three of six UC-associated SNPs had significantly different frequencies in CD (n = 1144). Most of the divergence in allele frequency among CD and UC was noted in NOD2/autophagy pathway SNPs, while most SNPs with similar frequencies were in IL-22/23 Th17, adaptive immunity, and barrier pathways. Colon-only CD (n = 228) was compared with healthy controls: three of six UC SNPs (in MST1, HLA-DRA, and IL-23R) and 11 of 34 CD SNPs: in IRGM, NOD2 (rs2066845), CCNY, MST1, IL23R, PTPN22, C11orf30, ZNF365, PTPN2, PSMG1, and rs1456893 were significantly associated. In all, 29 of 34 CD SNPs had similar allele frequencies in colonic CD compared with ileal CD (n = 366). All UC SNPs had similar frequencies in UC and colonic CD.Our results suggest that CD and UC share common genetic associations related to impaired adaptive immunity and diverge in pathways of foreign antigen processing. Colon-only CD overlaps extensively with UC and considerably with ileal CD.
| S-EPMC3164287 | biostudies-literature