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Background
Inflammatory bowel disease (IBD) is commonly divided into 2 entities: Crohn’s disease (CD) and ulcerative colitis (UC). Differentiating between these entities when dealing with IBD confined to the colon is important, especially when planning surgical treatment. Due to ambiguous histological or endoscopic findings, accurate diagnosis is n...
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Context 1
... real-time polymerase chain reac- tion (qRT-PCR) was completed using the ViiA7 real-time PCR system (Applied Biosystems), according to the manufacturer's protocol, as previously described. 18 Reference gene selection NORMFINDER software was used on our screening data, together with published data on accepted reference genes (Supplemental Table 2). Based on this analysis, miR-16 was chosen as our endogenous reference gene both due to its sta- bility and expression within our samples. ...
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Objectives
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Autophagy is an intracellular catabolic process that is essential for a variety of cellular responses. Due to its role in the maintenance of biological homeostasis in conditions of stress, dysregulation or disruption of autophagy may be linked to human diseases such as inflammatory bowel disease (IBD). IBD is a complicated inflammatory colitis diso...
Citations
... There were very limited studies on miRNA profiles that help in differentiating UC from CD whenever the histopathological results failed to clarify the IBD phenotype, especially in the case of isolated colonic CD versus UC [22,23], however, none of these studies included miRNA 106a and miRNA 146b-5p in their investigated miRNA profiles. Very few studies have investigated the role of miRNA 106a and 146b-5P in the diagnosis and evaluation of IBD. ...
... Previous studies have reported that fecal miRNAs, 8,9 circulating miRNAs, [10][11][12] peripheral blood miRNAs and colonic tissue miRNAs all show diagnostic and/or monitoring value in Crohn's disease. [13][14][15][16][17] However, fecal miR-NAs may have large variation due to degradation through different duration of defecation or storage time. ...
Crohn's disease is a recurrent, progressive, immune‐mediated inflammatory disease and merely manifests non‐specific symptoms at early stage. In this study, we isolated peripheral blood mononuclear cells (PBMCs) to determine whether PBMC miRNAs are reliable biomarkers for Crohn's disease diagnosing and monitoring. 5 Crohn's disease patients and 5 healthy controls were recruited to find differentially expressed miRNAs by next generation sequencing. Candidate PBMC miRNAs were further validated by qRT‐PCR in another cohort consisting of 86 Crohn's disease patients and 39 healthy controls. We found PBMC miR‐582‐5p could diagnose Crohn's disease with the area under receiver operating characteristic curve (AUROC) of 0.701(95%CI 0.606–0.796, p < .001). While PBMC miR‐96‐5p was significantly higher in active Crohn's disease and correlated with both clinical (ρ = 0.376, p < .001) and endoscopic activity (ρ = 0.512, p = .015). Furthermore, PBMC miR‐96‐5p had a better performance in recognizing active Crohn's disease with AUROC of 0.727 (95%CI 0.609–0.844, p = .001) than C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fecal calprotectin. In conclusion, PBMC miR‐582‐5p may be further utilized as a diagnostic biomarker, while miR‐96‐5p may be a novel and valuable biomarker in monitoring disease activity.
... The study also noted these miRNA "signatures" were more homogenous in the peripheral blood samples of active disease patients as opposed to inactive remission patients. Another study determined after screening assays that miRs-598 and -642 were significantly upregulated in the UC patients' plasma in comparison to CD patients', though both were significantly elevated in UC and CD compared to healthy controls [16]. Furthermore, miRs-16, -21, and, in particular, -223 were more prominently increased in active CD sera versus that of active UC [19]. ...
Inflammatory bowel disease (IBD), classified primarily between Crohn’s disease and ulcerative colitis, is a collection of chronic gastrointestinal inflammatory conditions that cause multiple complications because of systemic alterations in the immune response. One major player is microRNA (miRNA), which is found to be associated with multiple pathways in mediating inflammation, especially those of a chronic nature in IBD, as well as irritable bowel syndrome. Although there have been studies linking miRNA alterations in IBD, even differentiating Crohn’s disease and ulcerative colitis, this review focuses mainly on how miRNAs cause and mechanistically influence the pathologic complications of IBD. In addition to its role in the well-known progression towards colorectal cancer, we also emphasize how miRNA manifests the many extraintestinal complications in IBD such as cardiovascular diseases; neuropsychiatric conditions such as depression and anxiety disorders; and others, including various musculoskeletal, dermatologic, ocular, and hepatobiliary complications. We conclude through a description of its potential use in bettering diagnostics and the future treatment of IBD and its systemic symptoms.
... Researchers are now focusing more and more on serum microRNAs, which are found to be indicative of both distinguishing between CD and UC and could shed some insight into disease severity [112][113][114]. Due to GWAS studies over 240 IBD related genetic loci [6] regarding CD or UC diagnosis, susceptibility, prognosis and therapy response have been identified, including but not limited to programmed death-ligand 1 (PD-L1) [115], mannose-binding lectin (MBL2) [116], autophagy related 16 like 1 (ATG16L1) [117], CD74 [118], nucleotide-binding oligomerization domaincontaining protein 2 NOD2/CARD15 [119], IGRM [120], IL23R [121]. ...
Crohn’s disease and ulcerative colitis, the two most common inflammatory bowel diseases (IBD), arecharacterized by chronic relapsing inflammation. Although recent progress regarding the therapeutic approachto these diseases has been made in the development of biologic therapies, not every patient responds well,resulting in a high percentage of ineffectiveness. Even though the immunological cascades range between thecurrent pharmacological agents for IBD treatment and the constant research for more possible pharmacologicaltargets, a lot of progress still needs to be made regarding the correct therapeutical choice for each individualpatient. Therefore, it is still important to find proper, inexpensive, and measurable biomarkers, in order to beable to assess the efficacy of these therapies, to make personalized choices, as well as to avoid potential adversedrug reactions and side effects. The biomarkers that are available in the present vary; metabolic, microbial,cytokine-related, genetic, disease-specific and drug-specific. This review presents the existing biological agentsfor IBD and focuses both on the cascades affected by each biologic agent and on the different markers thathave been found to be indicative of their effectiveness.
... Blood miRNAs have been established to distinguish two common inflammatory bowel diseases CD and UC e.g. miR-19a, miR-21, miR-31, miR-101, miR-146a, miR-375 19 and miR-598, miR-642 20 23 . Our small RNA profiling with ileocaecal/ileal tissue of ITB and CD patients followed by validation with qRT-PCR revealed that only two microRNAs (miR-215-5p, and miR-31-5p) were significantly downregulated in the ileocaecal/ileal tissue of ITB patients compared to CD. ...
Differentiation of Crohn’s disease (CD) from intestinal tuberculosis (ITB) is a big challenge to gastroenterologists because of their indistinguishable features and insensitive diagnostic tools. A non-invasive biomarker is urgently required to distinguish ITB/CD patients particularly in India, a TB endemic region, where CD frequency is increasing rapidly due to urbanization. Among the three differentially expressed miRNAs obtained from small RNA transcriptomic profiling of ileocaecal/terminal ileal tissue of ITB/CD patients (n = 3), only two down-regulated miRNAs, miR-31-5p, and miR-215-5p showed comparable data in qRT-PCR. Out of which, only miR-215-5p was detectable in the patient’s plasma, but there was no significant difference in expression between ITB/CD. On the other hand, miR-375-3p, the pulmonary TB specific marker was found in higher amount in the plasma of ITB patients than CD while reverse expression was observed in the ileocaecal/terminal ileal tissues of the same patients. Next, using Bioplex pro-human cytokine 48-plex screening panel, only three chemokines, Eotaxin-1/CCL11, SDF-1α/CXCL12, and G-CSF have noted significantly different levels in the serum of ITB/CD patients. ROC analysis has revealed that compared to a single molecule, a combination of miR-375-3p + Eotaxin-1/CCL11 + SDF-1α /CXCL12 + G-CSF showed a better AUC of 0.83, 95% CI (0.69–0.96) with 100% specificity and positive predictive value while sensitivity, negative predictive value, and accuracy were 56%, 69%, and 78% respectively in distinguishing ITB from CD. This study suggests that a combination of plasma markers shows better potential in differentiating ITB from CD than a single marker and this panel of markers may be used for clinical management of ITB/CD patients.
... Since then, there have been several reports stating correlation of ncRNA expression between colonic tissue and peripheral blood or feces [67,68] and ncRNA expression is continuously investigated in feces or peripheral blood and its components. Several studies have reported distinct ncRNA expression in feces of inflammatory bowel disease patients and healthy controls [69][70][71][72] and many studies have reported altered ncRNA expression in the peripheral blood of inflammatory bowel disease patients [67,68,71,[73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92], although there are differences in the amount of deregulated ncRNAs and their diagnostic accuracy being reported. While some studies show unremarkable accuracy of ncRNAs in distinguishing between patients and healthy controls with receiver operating characteristics analysis showing area under the curve (AUC) of 0,65 -0,79 [80,84,86] others report really promising results with AUC of 0,97 -0,99 for miRNA pairs of miR-215/miR-30e-3p, miR-215/miR-145 and miR-203/miR-145 [81], 0,94 for serum miR-372 [67], 0,88 for fecal miR-223 [71], and 0,91 for miR-874-3p in distinguishing between colonic Crohn's disease and ulcerative colitis. ...
Background:
Various non-invasive biomarkers have been used in the diagnosis, prognosis and treatment of different gastrointestinal (GI) diseases for years. Novel technological developments and profound perception of molecular processes related to GI diseases over the last decade has allowed researchers to evaluate genetic, epigenetic and many other potential molecular biomarkers in different diseases and clinical settings. Here we present a review of recent most relevant papers in order to summarize major findings on novel biomarkers in the diagnosis of benign and malignant GI diseases.
Summary:
Genetic variations, non-coding RNAs (ncRNAs), cell-free DNA (cfDNA), and microbiome-based biomarkers have been extensively analyzed as potential biomarkers in benign and malignant GI diseases. Multiple single nucleotide polymorphisms (SNPs) have been linked with a number of GI diseases and these observations are further being used to build-up disease specific genetic risk scores. MicroRNA and long non-coding RNAs have a large potential as non-invasive biomarkers in the management of inflammatory bowel diseases and GI tumors. Altered microbiome profiles were observed in multiple GI diseases but most of the findings still lack translational clinical application. As of today, cfDNA appears to be the most potent biomarker for early detection and screening of gastrointestinal cancers. Key messages. Novel non-invasive molecular biomarkers show huge potential as useful tools in the diagnostics and management of different GI diseases. However, the use of these biomarkers in real-life clinical practice still remains limited and further large studies are needed to elucidate the ultimate role of these potential non-invasive clinical tools.
... exosome, which is thereby transported out of the cell into the blood. Exosomes that enter the blood can enter the receptor cell again through endocytosis (Netz et al., 2017). Its coating can be removed in the receptor cell to release miRNA, thus exerting its biological function. ...
Ulcerative colitis (UC) is a chronic and non-specific inflammatory bowel disease (IBD). Its pathogenesis remains unclear, but its morbidity shows an increasing trend year by year. The pathogenesis of UC may be related to the genetic susceptibility, immune factor and intestinal microflora. In the last few years, an increasing number of studies have examined the relationship between the expression levels of peripheral CircRNA and UC. We aimed to evaluate the efficacy of CircRNA MFHAS1 in colitis and its possible mechanism. The expression of CircRNA MFHAS1 was reduced in colitis, and miR-486-5p expression was also increased in citrobacter rodentium-induced murine colitis. In vitro model, over-expression of CircRNA MFHAS1 reduced inflammatory responses, induced SIRT1 protein expression, and suppressed NF-κB protein expression. However, miR-486-5p CircRNA MFHAS1 suppressed SIRT1 protein expression, and induced NF-κB protein expression in vitro model. The inactivation of SIRT1 reduced the anti-inflammation effects of CircRNA MFHAS1 on inflammatory responses in vitro model. Over-expression of miR-486-5p also reduced the anti-inflammation effects of CircRNA MFHAS1 in vitro model. Our results demonstrated that CircRNA MFHAS1 reduces inflammatory responses in Colitis via SIRT1/NF-κB by miR-486-5p.
... 23 Netz et al. have identified 2 plasma miRNAs (miR-598, miR-642) that differentiated Crohn's colitis from UC, that were consistently different between their patients' groups. 24 As regards miR-16, Paraskevi et al. identified that 6 miRs (miR-16, miR-21, miR-28-5p, miR-151-5p, miR-155 and miR-199a-5p) were elevated in UC blood samples compared to healthy controls. Of the miRs tested, miR-16 and miR-199a-5p were elevated in both UC and CD as compared to healthy controls. ...
Ulcerative colitis is one of the IBDs. Its etiology and pathogenesis remain undefined with an interaction between environmental, genetic and immunological factors is the most accepted explanation. Several recent studies have examined microRNA expression in the peripheral blood and tissues from IBD patients. The study aims at assessing the expression of serum miR-16 in ulcerative colitis patients and its correlation with disease extent, activity and severity. It included 30 treatment naïve ulcerative colitis patients of different presentations. Serum miR-16 expression was assessed using reverse transcriptase quantitative real time PCR (RT-qPCR), and then correlated with that of a group of 20 healthy subjects to assess its role in diagnosis of ulcerative colitis. Also, it was correlated with disease extent (proctitis, left sided colitis, extensive colitis) and disease activity and severity indices (Truelove and Witts criteria, fecal calprotectin and UCEIS). Thirty ulcerative colitis patients were enrolled, 53% had mild, 37% had moderate, while 10% had severe disease. Concerning endoscopic extent, 8 had proctitis, 14 had left sided colitis and 8 had extensive colitis. Serum expression of miR-16 in the 30 patients were compared to that of the healthy control subjects. The patients’ group showed median serum miR-16 expression of 1.91, 1.13 for the control group with a significant difference between both groups. Correlation between serum miR-16 expression with disease extent, activity and severity showed no significant relation. From the current study we can conclude that increased serum expression of miR-16 is associated with ulcerative colitis despite no significant relation to disease activity extent or severity.
... 16 Previous studies have identified distinct tissue and plasma miRNA expression patterns in patients with Crohn's disease. [17][18][19] The TGF-β1 signaling pathway has numerous miRNA regulators, including a miR-199a-binding site in the 3'-UTR of Smad1 and Smad4 mRNA. 20,21 Hybridization analysis also reveals that the ER stress chaperone GRP78 and sensors ATF-6α and XBP1 are potential targets for regulation by miR-199a. ...
Background
Endoplasmic reticulum (ER) stress is an essential response of epithelial and immune cells to inflammation in Crohn’s disease. The presence and mechanisms that might regulate the ER stress response in subepithelial myofibroblasts (SEMFs) and its role in the development of fibrosis in patients with Crohn’s disease have not been examined.
Methods
Subepithelial myofibroblasts were isolated from the affected ileum and normal ileum of patients with each Montreal phenotype of Crohn’s disease and from normal ileum in non-Crohn’s subjects. Binding of GRP78 to latent TGF-β1 and its subcellular trafficking was examined using proximity ligation-hybridization assay (PLA). The effects of XBP1 and ATF6 on TGF-β1 expression were measured using DNA-ChIP and luciferase reporter assay. Endoplasmic reticulum stress components, TGF-β1, and collagen levels were analyzed in SEMF transfected with siRNA-mediated knockdown of DNMT1 and GRP78 or with DNMT1 inhibitor 5-Azacytidine or with overexpression of miR-199a-5p.
Results
In SEMF of strictured ileum from patients with B2 Crohn’s disease, expression of ER stress sensors increased significantly. Tunicamycin elicited time-dependent increase in GRP78 protein levels, direct interaction with latent TGF-β1, and activated TGF-β1 signaling. The TGFB1 DNA-binding activity of ATF-6α and XBP1 were significantly increased and elicited increased TGFB1 transcription in SEMF-isolated from affected ileum. The levels of ER stress components, TGF-β1, and collagen expression in SEMF were significantly decreased following knockdown of DNMT1 or GRP78 by 5-Azacytidine treatment or overexpression of miR-199a-5p.
Conclusions
Endoplasmic reticulum stress is present in SEMF of patients susceptible to fibrostenotic Crohn’s disease and can contribute to development of fibrosis. Targeting ER stress may represent a novel therapeutic target to prevent fibrosis in patients with fibrostenotic Crohn’s disease.
... In Table 1, we present some of the most prominently identified and studied miRNAs, and their respective dysregulation depending on the type of disease. Table 1 is not an exhaustive review of the existing literature, as there are several specialized review papers on identifying possible miRNA mediators for various GI tract diseases [58,59,[73][74][75][76]. Our analysis demonstrates how miRNA dysregulations are prominent in GI tract diseases. ...
Nucleic acid-based therapeutics are evaluated for their potential of treating a plethora of diseases, including cancer and inflammation. Short nucleic acids, such as miRNAs, have emerged as versatile regulators for gene expression and are studied for therapeutic purposes. However, their inherent instability in vivo following enteral and parenteral administration has prompted the development of novel methodologies for their delivery. Although research on the oral delivery of siRNAs is progressing, with the development and utilization of promising carrier-based methodologies for the treatment of a plethora of gastrointestinal diseases, research on miRNA-based oral therapeutics is lagging behind. In this review, we present the potential role of miRNAs in diseases of the gastrointestinal tract, and analyze current research and the cardinal features of the novel carrier systems used for nucleic acid oral delivery that can be expanded for oral miRNA administration.
