P146 OXPHOS INDUCTION IN HEALING: A CRITICAL MISSING STEP IN INFLAMMATORY BOWEL DISEASE?

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S30-S31
Author(s):  
Neeraj Kapur ◽  
Emily Bradford ◽  
Justin Thomas ◽  
Courtney Perry ◽  
Terrence Barrett
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Epithelial To Mesenchymal Transition ◽  
Healing Process ◽  
Gene Signature ◽  
Enzymatic Digestion ◽  
Mucosal Healing ◽  
Mesenchymal Transition ◽  
Atp Production ◽  
Inflammatory Bowel

Abstract Background In Inflammatory Bowel Disease (IBD), mucosal healing represents a key outcome in clinical remission. Mitochondrial dysfunction is one of the major features of IBD, which is hallmarked by increased oxidative stress and impaired ATP production. However, partial wound healing continues even with repressed mitochondrial respiration in an inflammatory environment. In this study, we demonstrate that intestinal epithelial cells (IEC) responding to colitis produce a gene signature with downregulated mitochondrial expression associated with oxidative phosphorylation (OxPHOS) and upregulate epithelial-to-mesenchymal transition (EMT). These data were consistent with the notion that EMT induced in IEC is fueled by glycolysis (repressed OxPHOS). We also wish to determine if this OxPHOS repression is present in normal healing. Methods We are actively enrolling patients with Ulcerative Colitis (UC) and normal patients into a prospective study evaluating biopsy site healing. Biopsy samples from UC patients were collected in Allprotect® or PBS. Biopsy samples collected in PBS were processed for IEC isolation using enzymatic digestion followed by flow sorting of EpCAM+ cells. To investigate the healing process in colitis and normal patients, the sigmoid colon is tattooed at initial endoscopy and 10–12 biopsies are collected in Allprotect®. Patients are brought back a week later for a flexible sigmoidoscopy. The tattooed area is examined, and biopsies are obtained from the previous biopsy sites (“biopsy of the biopsy”) and collected in Allprotect®. RNA is extracted from Allprotect® preserved tissue or isolated IECs and analyzed with RT-PCR. Results Genes corresponding to subunits of NADH dehydrogenase (Ubiquinone) of complex I (ND1, ND2, ND3, ND4, ND5 and ND6) were consistently downregulated in ulcer sites of colitis patients as compared to “biopsy of the biopsy” sites near the tattoo in normal patients. As expected, samples from colitis patients exhibited significant upregulation of inflammatory markers (iNOS, NLRP3, CCL2, RANTES, TGF-b1, CCL20 and CXCL10) compared to “biopsy of the biopsy” sites in normal patients undergoing healing. Intriguingly, epithelial marker E-cadherin was noted to be decreased in samples obtained from colitis patients with concomitant increase in mesenchymal markers (Vimentin, Snail, Twist-1 and Zeb-1) compared to previously biopsied normal controls. Discussion Our data suggests that repressed OxPHOS observed in inflamed IEC from colitis patients may serves as an inducer of EMT governing delayed but partial healing in IBD. We found this to be in stark opposition to healing in normal patients, who exhibit enhanced OxPHOS associated with rapid healing. These important findings indicate OxPHOS metabolism may be an important target for therapeutic agents to improve healing in refractory colitis.

Role of Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease

2018 ◽  
Vol 13 (5) ◽  
pp. 659-668 ◽  
Author(s):  
Sara Lovisa ◽  
Giannicola Genovese ◽  
Silvio Danese
Keyword(s):  
Inflammatory Bowel Disease ◽  
Wound Healing ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Clinical Manifestations ◽  
Mesenchymal Transition ◽  
Intestinal Fibrosis ◽  
Inflammatory Bowel

Abstract Intestinal fibrosis is an inevitable complication in patients with inflammatory bowel disease [IBD], occurring in its two major clinical manifestations: ulcerative colitis and Crohn’s disease. Fibrosis represents the final outcome of the host reaction to persistent inflammation, which triggers a prolonged wound healing response resulting in the excessive deposition of extracellular matrix, eventually leading to intestinal dysfunction. The process of epithelial-to-mesenchymal transition [EMT] represents an embryonic program relaunched during wound healing, fibrosis and cancer. Here we discuss the initial observations and the most recent findings highlighting the role of EMT in IBD-associated intestinal fibrosis and fistulae formation. In addition, we briefly review knowledge on the cognate process of endothelial-to-mesenchymal transition [EndMT]. Understanding EMT functionality and the molecular mechanisms underlying the activation of this mesenchymal programme will permit designing new therapeutic strategies to halt the fibrogenic response in the intestine.

scholarly journals The Role of MicroRNAs upon Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1461 ◽  
Author(s):  
Éva Boros ◽  
István Nagy
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Acute Inflammation ◽  
Epithelial To Mesenchymal Transition ◽  
Systemic Complications ◽  
Altered Expression ◽  
Mesenchymal Transition ◽  
Multistage Carcinogenesis ◽  
Inflammatory Bowel

Increasing evidence suggest the significance of inflammation in the progression of cancer, for example the development of colorectal cancer in Inflammatory Bowel Disease (IBD) patients. Long-lasting inflammation in the gastrointestinal tract causes serious systemic complications and breaks the homeostasis of the intestine, where the altered expression of regulatory genes and miRNAs trigger malignant transformations. Several steps lead from acute inflammation to malignancies: epithelial-to-mesenchymal transition (EMT) and inhibitory microRNAs (miRNAs) are known factors during multistage carcinogenesis and IBD pathogenesis. In this review, we outline the interactions between EMT components and miRNAs that may affect cancer development during IBD.

scholarly journals Elevated Expression of AXL May Contribute to the Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Éva Boros ◽  
Zoltán Kellermayer ◽  
Péter Balogh ◽  
Gerda Strifler ◽  
Andrea Vörös ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Mesenchymal Transition ◽  
Inflammatory Bowel ◽  
Chronic Intestinal Inflammation

Understanding the molecular mechanisms inducing and regulating epithelial-to-mesenchymal transition (EMT) upon chronic intestinal inflammation is critical for understanding the exact pathomechanism of inflammatory bowel disease (IBD). The aim of this study was to determine the expression profile of TAM family receptors in an inflamed colon. For this, we used a rat model of experimental colitis and also collected samples from colons of IBD patients. Samples were taken from both inflamed and uninflamed regions of the same colon; the total RNA was isolated, and the mRNA and microRNA expressions were monitored. We have determined that AXL is highly induced in active-inflamed colon, which is accompanied with reduced expression of AXL-regulating microRNAs. In addition, the expression of genes responsible for inducing or maintaining mesenchymal phenotype, such as SNAI1, ZEB2, VIM, MMP9, and HIF1α, were all significantly induced in the active-inflamed colon of IBD patients while the epithelial marker E-cadherin (CDH1) was downregulated. We also show that, in vitro, monocytic and colonic epithelial cells increase the expression of AXL in response to LPS or TNFα stimuli, respectively. In summary, we identified several interacting genes and microRNAs with mutually exclusive expression pattern in active-inflamed colon of IBD patients. Our results shed light onto a possible AXL- and microRNA-mediated regulation influencing epithelial-to-mesenchymal transition in IBD.

scholarly journals Optimal Range of Fecal Calprotectin for Predicting Mucosal Healing in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

2021 ◽  
pp. 1-11
Author(s):  
Bing-Jie Xiang ◽  
Min Jiang ◽  
Ming-Jun Sun ◽  
Cong Dai
Keyword(s):  
Inflammatory Bowel Disease ◽  
Diagnostic Accuracy ◽  
Likelihood Ratio ◽  
Sensitivity And Specificity ◽  
Bowel Disease ◽  
Meta Analysis ◽  
Positive Likelihood Ratio ◽  
Fecal Calprotectin ◽  
Mucosal Healing ◽  
Inflammatory Bowel

<b><i>Objective:</i></b> Fecal calprotectin (FC) is a promising marker for assessment of inflammatory bowel disease (IBD) activity. However, the utility of FC for predicting mucosal healing (MH) of IBD patients has yet to be clearly demonstrated. The objective of our study was to perform a meta-analysis evaluating the diagnostic accuracy of FC in predicting MH of IBD patients. <b><i>Methods:</i></b> We systematically searched the databases for studies from inception to April 2020 that evaluated MH in IBD. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. The extracted data were pooled using a summary receiver operating characteristic curve model. Random-effects model was used to summarize the diagnostic odds ratio, sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio. <b><i>Results:</i></b> Sixteen studies comprising 1,682 ulcerative colitis (UC) patients and 4 studies comprising 221 Crohn’s disease (CD) patients were included. The best performance of FC for predicting MH in UC was at cut-off range of 60–75 μg/g with area under the curve (AUC) of 0.88 and pooled sensitivity and specificity of 0.87 and 0.79, respectively. The pooled sensitivity and specificity values of cutoff range 180–250 μg/g for predicting MH in CD were 0.67 and 0.76, respectively. The AUC of 0.79 also revealed improved discrimination for identifying MH in CD with FC concentration. <b><i>Conclusion:</i></b> Our meta-analysis has found that FC is a simple, reliable noninvasive marker for predicting MH in IBD patients. FC cutoff range 60–75 μg/g appears to have the best overall accuracy in UC patients.

37 Monitoring the evolution of inflammatory bowel disease (IBD) in pediatric and adult cohorts of patients to identify biomarkers to predict cancer risk

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A38-A38
Author(s):  
Shilpa Ravindran ◽  
Heba Sidahmed ◽  
Harshitha Manjunath ◽  
Rebecca Mathew ◽  
Tanwir Habib ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Hamad Medical Corporation ◽  
Inflammatory Bowel ◽  
Left And Right

BackgroundPatients with inflammatory bowel disease (IBD) have increased risk of developing colorectal cancer (CRC), depending on the duration and severity of the disease. The evolutionary process in IBD is driven by chronic inflammation leading to epithelial-to-mesenchymal transition (EMT) events in colonic fibrotic areas. EMT plays a determinant role in tumor formation and progression, through the acquisition of ‘stemness’ properties and the generation of neoplastic cells. The aim of this study is to monitor EMT/cancer initiating tracts in IBD in association with the deep characterization of inflammation in order to assess the mechanisms of IBD severity and progression towards malignancy.Methods10 pediatric and 20 adult IBD patients, admitted at Sidra Medicine (SM) and Hamad Medical Corporation (HMC) respectively, have been enrolled in this study, from whom gut tissue biopsies (from both left and right side) were collected. Retrospectively collected tissues (N=10) from patients with malignancy and history of IBD were included in the study. DNA and RNA were extracted from fresh small size (2–4 mm in diameter) gut tissues using the BioMasher II (Kimble) and All Prep DNA/RNA kits (Qiagen). MicroRNA (miRNA; N=700) and gene expression (N=800) profiling have been performed (cCounter platform; Nanostring) as well as the methylation profiling microarray (Infinium Methylation Epic Bead Chip kit, Illumina) to interrogate up to 850,000 methylation sites across the genome.ResultsDifferential miRNA profile (N=27 miRNA; p<0.05) was found by the comparison of tissues from pediatric and adult patients. These miRNAs regulate: i. oxidative stress damage (e.g., miR 99b), ii. hypoxia induced autophagy; iii. genes associated with the susceptibility to IBD (ATG16L1, NOD2, IRGM), iv. immune responses, such as TH17 T cell subset (miR 29). N=6 miRNAs (miR135b, 10a196b, 125b, let7c, 375) linked with the regulation of Wnt/b-catenin, EM-transaction, autophagy, oxidative stress and play role also in cell proliferation and mobilization and colorectal cancer development were differentially expressed (p<0.05) in tissues from left and right sides of gut. Gene expression signature, including genes associated with inflammation, stemness and fibrosis, has also been performed for the IBD tissues mentioned above. Methylation sites at single nucleotide resolution have been analyzed.ConclusionsAlthough the results warrant further investigation, differential genomic profiling suggestive of altered pathways involved in oxidative stress, EMT, and of the possible stemness signature was found. The integration of data from multiple platforms will provide insights of the overall molecular determinants in IBD patients along with the evolution of the disease.Ethics ApprovalThis study was approved by Sidra Medicine and Hamad Medical Corporation Ethics Boards; approval number 180402817 and MRC-02-18-096, respectively.

scholarly journals Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products

2020 ◽  
Vol 9 (5) ◽  
pp. 1273 ◽  
Author(s):  
Karma Yeshi ◽  
Roland Ruscher ◽  
Luke Hunter ◽  
Norelle L. Daly ◽  
Alex Loukas ◽  
...  
Keyword(s):  
Health Care ◽  
Inflammatory Bowel Disease ◽  
Natural Products ◽  
Bowel Disease ◽  
Inflammatory Diseases ◽  
Treatment Options ◽  
Mucosal Healing ◽  
Main Challenge ◽  
Long Term Treatment ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is a chronic and life-long disease characterized by gastrointestinal tract inflammation. It is caused by the interplay of the host’s genetic predisposition and immune responses, and various environmental factors. Despite many treatment options, there is no cure for IBD. The increasing incidence and prevalence of IBD and lack of effective long-term treatment options have resulted in a substantial economic burden to the healthcare system worldwide. Biologics targeting inflammatory cytokines initiated a shift from symptomatic control towards objective treatment goals such as mucosal healing. There are seven monoclonal antibody therapies excluding their biosimilars approved by the US Food and Drug Administration for induction and maintenance of clinical remission in IBD. Adverse side effects associated with almost all currently available drugs, especially biologics, is the main challenge in IBD management. Natural products have significant potential as therapeutic agents with an increasing role in health care. Given that natural products display great structural diversity and are relatively easy to modify chemically, they represent ideal scaffolds upon which to generate novel therapeutics. This review focuses on the pathology, currently available treatment options for IBD and associated challenges, and the roles played by natural products in health care. It discusses these natural products within the current biodiscovery research agenda, including the applications of drug discovery techniques and the search for next-generation drugs to treat a plethora of inflammatory diseases, with a major focus on IBD.

scholarly journals P378 Mucosal healing is achieved in most of the inflammatory bowel disease patients in clinical remission with vedolizumab: a real-life single-centre experience

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S355-S355
Author(s):  
M I Calvo Moya ◽  
I Omella Usieto ◽  
M I Vera Mendoza ◽  
V Matallana Royo ◽  
I Gonzalez Partida ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Clinical Practice ◽  
Bowel Disease ◽  
Clinical Remission ◽  
Real Life ◽  
Mucosal Healing ◽  
Surveillance Colonoscopy ◽  
Previously Treated ◽  
Inflammatory Bowel

Abstract Background Current therapeutic goals in inflammatory bowel disease (IBD) include not only the mere absence of symptoms but also the resolution of endoscopic lesions, so-called mucosal healing (MH), which has been related to better outcomes. Data regarding the achievement of MH with vedolizumab (VDZ) in real-life clinical practice is still scarce. Methods Retrospective cohort study was carried out in a tertiary hospital between January 2015 and April 2019 including patients with a basal colonoscopy showing activity and who achieved clinical remission under treatment with VDZ, defined by partial Mayo score &lt;2 for ulcerative colitis (UC) and Harvey–Bradshaw Index score (HBI) &lt;4 for Crohn’s disease (CD). Surveillance colonoscopy was performed along with the follow-up according to clinical practice. In UC patients, MH was defined as Mayo Endoscopic Subscore (MES) = 0; the endoscopic response was defined by a decrease in MES ≥1 point. In CD, MH was defined by achievement SES-CD = 0–3 or Rutgeerts index i0; the endoscopic response was defined by a decrease of SES-CD of 50% or Rutgeerts index &lt;i2 with at least 1 point of decease compared with baseline. Results In total, 118 patients treated with VDZ were analysed, but only 45 met inclusion criteria with a median follow-up of 21 (IQR: 14–19) months. Surveillance colonoscopy was performed after a median time of 12 months (IQR:9–17) of treatment. MH achieved in 33/45 patients (73%): 17/23 CD patients (74%) and 16/22 UC patients (73%). The endoscopic response was achieved in 9 of the remaining 12 patients: 3/6 CD patients and 6/6 UC patients. Only 3 (7%) of patients included showed no endoscopic benefit at the time of surveillance endoscopy. In multivariate analysis, probability of not achieving MH was 75% in patients previously treated with immunosuppressants (ISS) (HR 0.25, 0.11–0.55 IC95; p = 0.001) and 60% in patients previously treated with anti-TNFα (HR 0.40, 0.18–0.90 95% CI; p = 0.026). Type of IBD, concomitant ISS, corticosteroid use at induction, baseline endoscopy score or duration of disease before VDZ treatment were not associated with the achievement of MH. Conclusion In our experience, most of the patients who achieve clinical remission with VDZ also achieve MH. Refractory patients were less likely to achieve MH despite having achieved clinical remission.

scholarly journals The Role of Long-Chain Fatty Acids in Inflammatory Bowel Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Chunxiang Ma ◽  
Reshma Vasu ◽  
Hu Zhang
Keyword(s):  
Inflammatory Bowel Disease ◽  
Fatty Acids ◽  
Bowel Disease ◽  
Mucosal Healing ◽  
Long Chain Fatty Acids ◽  
Inflammatory Bowel ◽  
Underlying Mechanisms ◽  
Long Chain ◽  
Chain Fatty Acids

Inflammatory bowel disease (IBD) is a complicated disease involving multiple pathogenic factors. The complex relationships between long-chain fatty acids (LCFAs) and the morbidity of IBD drive numerous studies to unravel the underlying mechanisms. A better understanding of the role of LCFAs in IBD will substitute or boost the current IBD therapies, thereby obtaining mucosal healing. In this review, we focused on the roles of LCFAs on the important links of inflammatory regulation in IBD, including in the pathogen recognition phase and in the inflammatory resolving phase, and the effects of LCFAs on immune cells in IBD.

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