scholarly journals Decreased Colonic Activin Receptor-Like Kinase 1 Disrupts Epithelial Barrier integrity and is associated with a poor clinical outcome in Crohn’s disease

2020 ◽  
Author(s):  
Takahiko Toyonaga ◽  
Benjamin P. Keith ◽  
Jasmine B. Barrow ◽  
Matthew S. Schaner ◽  
Elisabeth A. Wolber ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Functional Characterization ◽  
Epithelial Barrier ◽  
Small Rna Sequencing ◽  
Specific Marker ◽  
Activin Receptor ◽  
Barrier Integrity ◽  
Receptor Like Kinase ◽  
The Impact

AbstractObjectiveIntestinal epithelial cell (IEC) barrier dysfunction is critical to the development of Crohn’s disease (CD). However, the mechanism is understudied. We recently reported increased microRNA-31-5p (miR-31-5p) expression in colonic IECs of CD patients, but downstream targets are unknown.DesignMiR-31-5p target genes were identified by integrative analysis of RNA- and small RNA-sequencing data from colonic mucosa and confirmed by qPCR in colonic IECs. Functional characterization of Activin Receptor-Like Kinase 1 (ACVRL1 or ALK1) in IECs was performed ex vivo using 2 dimensional-cultured human primary colonic IECs. The impact of altered colonic ALK1 signaling in CD for the risk of surgery and endoscopic relapse was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator.ResultsALK1 was identified as a target of miR-31-5p in colonic IECs of CD patients and confirmed using a 3’-UTR reporter assay. Activation of ALK1 restricted the proliferation of colonic IECs in an EdU proliferation assay and down-regulated the expression of stemness-related genes. Activated ALK1 signaling directed the fate of colonic IEC differentiation toward colonocytes. Down-regulated ALK1 signaling was associated with increased stemness and decreased colonocyte-specific marker expression in colonic IECs of CD patients compared to healthy controls. Activation of ALK1 enhanced epithelial barrier integrity in a trans-epithelial electrical resistance permeability assay. Lower colonic ALK1 expression was identified as an independent risk factor for surgery and associated with a higher risk of endoscopic relapse in CD patients.ConclusionDecreased colonic ALK1 disrupted colonic IEC barrier integrity and associated with deteriorated clinical outcomes in CD patients.

scholarly journals Decreased Colonic Activin Receptor-Like Kinase 1 Disrupts Epithelial Barrier Integrity in Patients With Crohn’s Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 779-796 ◽  
Author(s):  
Takahiko Toyonaga ◽  
Erin C. Steinbach ◽  
Benjamin P. Keith ◽  
Jasmine B. Barrow ◽  
Matthew R. Schaner ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Epithelial Barrier ◽  
Activin Receptor ◽  
Barrier Integrity ◽  
Receptor Like Kinase

P149 DECREASED COLONIC ACTIVIN RECEPTOR-LIKE KINASE 1 DISRUPTS EPITHELIAL BARRIER INTEGRITY AND IS ASSOCIATED WITH A POOR CLINICAL OUTCOME IN CROHN’S DISEASE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S29-S29
Author(s):  
Takahiko Toyonaga ◽  
Benjamin Keith ◽  
Jasmine Barrow ◽  
Matthew Schaner ◽  
Elizabeth Wolber ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Rna Sequencing ◽  
Small Rna ◽  
Integrative Analysis ◽  
Epithelial Barrier ◽  
Small Rna Sequencing ◽  
Poor Clinical Outcome ◽  
Barrier Integrity ◽  
Receptor Like Kinase

Abstract Background and Aims Intestinal epithelial cell (IEC) barrier dysfunction is critical to the development of Crohn’s disease (CD). Mechanisms controlling colonocyte differentiation and barrier defects are understudied in CD. We recently reported increased expression of microRNA-31-5p (miR-31-5p) in colonic IECs of CD patients compared to non-IBD (NIBD) controls. In this study we identify and characterize the miR-31-5p target gene Activin Receptor-Like Kinase 1 (ALK1) as a key regulator of colonocyte maturation and IEC barrier integrity, specifically the functional impact of aberrant ALK1 signaling on colonocyte differentiation, barrier integrity, and clinical disease outcomes in CD. Methods MiR-31-5p target genes were identified in CD patients by integrative analysis of RNA- and small RNA-sequencing data from colonic mucosa and confirmed by quantitative RT-PCR (qPCR) in isolated colonic IECs. Functional characterization of ALK1 in colonic IECs was performed ex vivo using 2- or 3-dimensional cultured human primary colonic IECs. The impact of altered colonic ALK1 signaling for the risk of surgery and endoscopic relapse was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator among CD patients. Results Integrative analysis of RNA- and small RNA-sequencing and follow-up qPCR identified ALK1 as a candidate target of miR-31-5p in the colonic IECs of CD patients. A 3’-UTR reporter assay with site-directed mutagenesis confirmed the direct regulation of ALK1 expression by miR-31-5p in HEK293T cells. Increased activation of ALK1 restricted the proliferation of primary colonic IECs in an EdU proliferation assay and down-regulated the expression of stemness-related genes, such as LGR5 and ASCL2. Activated ALK1 signaling directed the fate of human colonic IEC differentiation toward colonocytes. Down-regulated ALK1 signaling was associated with increased stemness-related gene expression and decreased colonocyte-specific gene expression in the isolated colonic IECs of CD patients compared to non-IBD controls. Activation of ALK1 did not affect colonic IEC migration in a wound healing assay, but enhanced epithelial barrier integrity in a trans-epithelial electrical resistance (TEER)-based permeability assay. Lower colonic ALK1 expression was associated with higher risks of surgery and endoscopic relapse in CD patients. Conclusion Decreased colonic ALK1 signaling disrupts colonic IEC barrier integrity and is associated with a poor clinical outcome in CD patients.

scholarly journals P681 Higher in vitro mucin degradation, but no increased paracellular permeability by faecal water from Crohn’s disease patients

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S601-S601
Author(s):  
H Becker ◽  
N Kameli ◽  
A Rustichelli ◽  
H Britt ◽  
F Stassen ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Barrier Function ◽  
Disease Onset ◽  
Paracellular Permeability ◽  
Epithelial Barrier ◽  
Rrna Gene ◽  
Relative Abundances ◽  
The Impact

Abstract Background Crohn’s disease (CD) is a chronic inflammatory gastro-intestinal condition with a variable disease course. Impaired intestinal integrity and microbial dysbiosis are associated with disease onset and exacerbations. We hypothesized that a perturbed microbial activity in CD patients may contribute to the impaired barrier function. Therefore, this study aimed to examine the impact of faecal bacterial products of active CD patients, CD patients in remission, and healthy controls (HC) on mucin degradation and intestinal epithelial barrier function in vitro. Methods Six HC and twelve CD patients were included. Faecal samples were obtained within one week prior to endoscopy processed within 6 hours after collection. Disease activity was determined by the short endoscopic score for CD (SES-CD). Faecal water (FW) and bacterial membrane vesicles (MVs) were applied on mucin agar to determine mucin degradation. Further, differentiated Caco-2 cell monolayers were exposed to FW and MVs to assess transepithelial electrical resistance (TEER) and paracellular junction stability using permeation of fluorescein isothiocyanate-labelled dextran of 4 kDa. Relative abundances of faecal bacterial genera were evaluated by 16S rRNA gene amplicon sequencing. Results FW-induced mucin degradation was higher in CD samples as compared to HC (p<0.01), but was not linked to specific bacterial relative abundances. FW resulted in 78–87% decrease of TEER in three of the remissive (p<0.001) but not the active CD or HC samples. The decrease of TEER was not linked to increased paracellular permeability. MVs did not induce mucin degradation or epithelial barrier disruption. Conclusion The higher mucin degradation capacity of CD patient-derived FW might indicate contributions of microbial products to CD pathophysiology and warrants further investigation. Moreover, the altered epithelial resistance in some individuals is not due to paracellular alterations.

scholarly journals Olaparib: A Clinically Applied PARP Inhibitor Protects from Experimental Crohn’s Disease and Maintains Barrier Integrity by Improving Bioenergetics through Rescuing Glycolysis in Colonic Epithelial Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Dominika Kovács ◽  
Viola Bagóné Vántus ◽  
Eszter Vámos ◽  
Nikoletta Kálmán ◽  
Rudolf Schicho ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Epithelial Cells ◽  
Intestinal Permeability ◽  
Parp Inhibitor ◽  
Epithelial Barrier ◽  
Extracellular Acidification ◽  
Barrier Integrity ◽  
Lymphocyte Ratio ◽  
Extracellular Acidification Rate

Crohn’s disease (CD) is an inflammatory disorder of the intestines characterized by epithelial barrier dysfunction and mucosal damage. The activity of poly(ADP-ribose) polymerase-1 (PARP-1) is deeply involved in the pathomechanism of inflammation since it leads to energy depletion and mitochondrial failure in cells. Focusing on the epithelial barrier integrity and bioenergetics of epithelial cells, we investigated whether the clinically applied PARP inhibitor olaparib might improve experimental CD. We used the oral PARP inhibitor olaparib in the 2,4,6-trinitrobenzene sulfonic acid- (TNBS-) induced mouse colitis model. Inflammatory scoring, cytokine levels, colon histology, hematological analysis, and intestinal permeability were studied. Caco-2 monolayer culture was utilized as an epithelial barrier model, on which we used qPCR and light microscopy imaging, and measured impedance-based barrier integrity, FITC-dextran permeability, apoptosis, mitochondrial oxygen consumption rate, and extracellular acidification rate. Olaparib reduced the inflammation score, the concentration of IL-1β and IL-6, enhanced the level of IL-10, and decreased the intestinal permeability in TNBS-colitis. Blood cell ratios, such as lymphocyte to monocyte ratio, platelet to lymphocyte ratio, and neutrophil to lymphocyte ratio were improved. In H2O2-treated Caco-2 monolayer, olaparib decreased morphological changes, barrier permeability, and preserved barrier integrity. In oxidative stress, olaparib enhanced glycolysis (extracellular acidification rate), and it improved mitochondrial function (mitochondrial coupling efficiency, maximal respiration, and spare respiratory capacity) in epithelial cells. Olaparib, a PARP inhibitor used in human cancer therapy, improved experimental CD and protected intestinal barrier integrity by preventing its energetic collapse; therefore, it could be repurposed for the therapy of Crohn’s disease.

Outcomes of Passable and Non-passable Strictures in Clinical Trials of Crohn’s Disease: A Post-hoc Analysis

2021 ◽  
Author(s):  
Neeraj Narula ◽  
Emily C L Wong ◽  
Parambir S Dulai ◽  
John K Marshall ◽  
Jean-Frederic Colombel ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Activity Index ◽  
Disease Activity Index ◽  
Symptom Improvement ◽  
Logistic Regression Models ◽  
Post Hoc Analysis ◽  
Endoscopic Remission ◽  
Post Hoc ◽  
The Impact

Abstract Background and Aims There is paucity of evidence on the reversibility of Crohn’s disease [CD]-related strictures treated with therapies. We aimed to describe the clinical and endoscopic outcomes of CD patients with non-passable strictures. Methods This was a post-hoc analysis of three large CD clinical trial programmes examining outcomes with infliximab, ustekinumab, and azathioprine, which included data on 576 patients including 105 with non-passable strictures and 45 with passable strictures, as measured using the Simple Endoscopic Score for Crohn’s Disease [SES-CD]. The impact of non-passable strictures on achieving clinical remission [CR] and endoscopic remission [ER] was assessed using multivariate logistic regression models. CR was defined as a Crohn’s Disease Activity Index [CDAI] <150, clinical response as a CDAI reduction of ≥100 points, and ER as SES-CD score <3. Results After 1 year of treatment, patients with non-passable strictures demonstrated the ability to achieve passable or no strictures in 62.5% of cases, with 52.4% and 37.5% attaining CR and ER, respectively. However, patients with non-passable strictures at baseline were less likely to demonstrate symptom improvement compared with those with passable or no strictures, with reduced odds of 1-year CR (adjusted odds ratio [aOR] 0.17, 95% CI 0.03–0.99, p = 0.048). No significant differences were observed between patients with non-passable strictures at baseline and those with passable or no strictures in rates of ER [aOR 0.82, 95% CI 0.23–2.85, p = 0.751] at 1 year. Conclusions Patients with non-passable strictures can achieve symptomatic and endoscopic remission when receiving therapies used to treat CD, although they are less likely to obtain CR compared with patients without non-passable strictures. These findings support the importance of balancing the presence of non-passable strictures in trial arms.

scholarly journals Anastomotic Ulcers After Ileocolic Resection for Crohn’s Disease Are Common and Predict Recurrence

2019 ◽  
Vol 26 (7) ◽  
pp. 1050-1058 ◽  
Author(s):  
Robert P Hirten ◽  
Ryan C Ungaro ◽  
Daniel Castaneda ◽  
Sarah Lopatin ◽  
Bruce E Sands ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Multivariable Analysis ◽  
Disease Recurrence ◽  
Ileocolic Resection ◽  
Anastomotic Ulcer ◽  
Endoscopic Recurrence ◽  
Academic Center ◽  
Endoscopic Remission ◽  
The Impact

Abstract Background Crohn’s disease recurrence after ileocolic resection is common and graded with the Rutgeerts score. There is controversy whether anastomotic ulcers represent disease recurrence and should be included in the grading system. The aim of this study was to determine the impact of anastomotic ulcers on Crohn’s disease recurrence in patients with prior ileocolic resections. Secondary aims included defining the prevalence of anastomotic ulcers, risk factors for development, and their natural history. Methods We conducted a retrospective cohort study of patients undergoing an ileocolic resection between 2008 and 2017 at a large academic center, with a postoperative colonoscopy assessing the neoterminal ileum and ileocolic anastomosis. The primary outcome was disease recurrence defined as endoscopic recurrence (>5 ulcers in the neoterminal ileum) or need for another ileocolic resection among patients with or without an anastomotic ulcer in endoscopic remission. Results One hundred eighty-two subjects with Crohn’s disease and an ileocolic resection were included. Anastomotic ulcers were present in 95 (52.2%) subjects. No factors were associated with anastomotic ulcer development. One hundred eleven patients were in endoscopic remission on the first postoperative colonoscopy. On multivariable analysis, anastomotic ulcers were associated with disease recurrence (adjusted hazard ratio [aHR] 3.64; 95% CI, 1.21–10.95; P = 0.02). Sixty-six subjects with anastomotic ulcers underwent a second colonoscopy, with 31 patients (79.5%) having persistent ulcers independent of medication escalation. Conclusion Anastomotic ulcers occur in over half of Crohn’s disease patients after ileocolic resection. No factors are associated with their development. They are associated with Crohn’s disease recurrence and are persistent.

scholarly journals P237 Annual incidence and prevalence of ulcerative colitis and Crohn’s disease from 2010 to 2017 in four Nordic countries: Results from the TRINordic study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S261-S262
Author(s):  
M Lördal ◽  
J Burisch ◽  
E Langholz ◽  
T Knudsen ◽  
M Voutilainen ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Observational Study ◽  
Nordic Countries ◽  
Annual Incidence ◽  
University Hospital ◽  
Retrospective Observational Study ◽  
Western World ◽  
The Impact

Abstract Background Incidence and prevalence of inflammatory bowel diseases (IBD) have been increasing for the past decades in the western world, however with an emerging trend of incidence stabilisation in recent years. There is an indication of higher IBD incidence and prevalence in northern Europe, especially in the Nordic region, compared with southern Europe. Methods This retrospective observational study collected data from the National Patient Registries and National Prescription Registries (Sweden [SWE], Norway [NOR], Denmark [DEN]) and one university hospital database (Turku, Finland [FIN]) during 2010–2017 to investigate the annual incidence and prevalence of ulcerative colitis (UC) and Crohn’s disease (CD). Patients with ≥2 ICD-10 diagnosis codes for UC (K51) or CD (K50) from 2010 or later and no K51 or K50 codes prior to 2010 were included; patients were classified according to their last code. The look-back period for SWE was until 2000, for NOR until 2008, for DEN until 1995, and for FIN until 2004. Incidence proportions highlight results through 2016, as 2017 patients had less than 1-year follow-up. Results In total, 69,876 patients were included (SWE n = 27,902, NOR n = 20,761, FIN n = 2,118, DEN n = 19,095), of which 44 367 patients were diagnosed with UC and 25,509 with CD. In 2016, the annual incidence of UC was 28 patients per 100,000 persons in NOR, 32 patients per 100,000 persons in DEN, 25 patients per 100,000 persons in SWE, and 44 patients per 100,000 in FIN. The corresponding results for the annual incidence of CD per 100,000 persons were 22 in NOR, 16 in DEN, 16 in SWE, and 21 in FIN. The prevalence per 100,000 persons of both UC and CD was the highest in DEN, followed by SWE and NOR, and lowest in FIN. Prevalence estimates increased in all four Nordic countries during 2010–2017: for UC, from 409 to 488 patients in SWE, from 256 to 428 in NOR, from 129 to 375 in FIN, and from 577 to 798 in DEN. For CD, it increased from 261 to 313 patients in SWE, from 164 to 258 in NOR, from 54 to 164 in FIN, and from 280 to 400 in DEN. Conclusion This retrospective observational study showed that during 2016, the annual incidence of UC ranged from 25–44 patients per 100,000 persons across the evaluated Nordic countries, whereas the annual incidence of CD was 16–22 patients per 100,000 persons. Prevalence of both UC and CD increased during 2010–2017 in all four countries. Estimates of UC and CD incidence and prevalence in this analysis are greater than reported in the published literature. Additional analyses are underway to further explore the impact of methodological decisions on the estimates of UC and CD annual incidence and prevalence.

P007 CROHN’S DISEASE: PREDICTORS OF HOSPITAL DISPOSITION AND COSTS USING DEMOGRAPHIC, CLINICAL, AND TREATMENT DATA

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S48-S48
Author(s):  
Hartman Brunt ◽  
Mason Adams ◽  
Michael Barker ◽  
Diana Hamer ◽  
J C Chapman
Keyword(s):  
Logistic Regression ◽  
Crohn’S Disease ◽  
Abdominal Pain ◽  
Crohn's Disease ◽  
Hospital Admission ◽  
Categorical Variables ◽  
History Of ◽  
The Difference ◽  
The Impact ◽  
Total Charges

Abstract Purpose Crohn’s disease (CD) is an inflammatory bowel disease (IBD) caused by an abnormal immune response to intestinal microbes in a genetically susceptible host. The objective of this cohort analysis is to compare demographic characteristics, cost difference, and treatment modalities between patients who were discharged from the Emergency Department (ED) and those who were admitted to the hospital. Methods This study is a retrospective chart review of adult patients diagnosed with CD who were discharged from the ED and those who were admitted to the hospital between January 1, 2014 and January 1, 2017. We compared demographic and clinical characteristics as well as total charges incurred by these patients. A chi square test of independence and a Mann Whitney U-Test were used to compare categorical variables. Linear and logistic regression analyses were utilized to identify predictors of hospitalization and total charges. Results Of a total 195 patients, 97 were discharged from the ED and 98 were admitted to the hospital (Table 1). Patients who presented with fever, nausea/vomiting, or abdominal pain or who had a history of a fistula or stenosis were more likely to be hospitalized, as were patients who presented on steroids, 5-ASA compounds, or narcotics (Table 2). A logistic regression adjusted for these factors showed patients presenting with abdominal pain (OR=0.239, 95% CI 0.07 – 0.77) are less likely, while patients presenting with fever (OR=7.0, 95% CI 1.9 – 24.5) and history of stenosis (OR=17.8, 95% CI 5.7 – 55.9) are more likely to have a hospital admission. An increase in age and white blood cell count was associated with an increase in likelihood of admission (OR=1.04, 95% CI 1.01 – 1.07 and OR=1.2, 95% CI 1.1 – 1.4), while an increase in HGB was associated with a decrease in likelihood of admission (OR=0.682, 95% CI 0.55 – 0.83). Patients on 5-ASA compounds had the strongest association with hospital admission (OR=4.5, 95% CI 1.03 – 20.4). A linear regression analysis predicting total charges of hospitalization identified an increase of $37,500 (95% CI 6,600 – 68,489) for obese patients and of $29,000 (95% CI 20 – 57,000) for patients on narcotics prior to hospitalization. Notably, blacks were on average 6 years younger than whites (μ=36.2, st.d.=13.2 v μ=42.7, st.d.=18.2, p=0.031, respectively). No other differences in presentation or outcomes of CD were identified between these races. Conclusion This study describes the difference between CD patients who were admitted to the hospital compared to those who were discharged from the ED. The impact that 5-ASA compound, steroid, and narcotic use prior to presentation has on hospital admission and charges highlights the need for consistent outpatient care to manage the symptoms and disease progression in patients with CD in Baton Rouge. The difference in age at presentation between blacks and whites should also be considered in future research.

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