Improvement of a ‘Leaky' Intestinal Barrier

2017 ◽  
Vol 35 (1-2) ◽  
pp. 21-24 ◽  
Author(s):  
Eduard F. Stange
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Barrier ◽  
Bacterial Attachment ◽  
Phase Iii ◽  
Colonic Disease ◽  
Mucus Layer ◽  
Tissue Destruction ◽  
Liquid Form ◽  
Mucus Production

In Crohn's disease, the mucus layer appears to be defective in terms of low defensin levels and lack of antibacterial activity. These deficiencies actually explain the Montreal phenotypes and the stable localization of disease in the terminal ileum with low α-defensins from Paneth cells and/or low β-defensins in colonic disease, respectively. Conversely, in ulcerative colitis (UC) the defensin production is normal or even induced, but the mucus layer is thinner and patchy, more in the liquid form and also chemically altered so that antibacterial peptides are not retained and lost into the luminal bacterial bulk. Therefore, both barrier problems allow slow bacterial attachment and invasion, ultimately triggering the massive response of adaptive immunity and tissue destruction. Therefore, leakiness should refer to the antibacterial barrier and not to the general barrier against small molecules, such as mannitol or lactulose, which are not antigenic. The most promising approach in UC seems to be the use of probiotics or the natural compound lecithin as a stabilizer of mucus structure to enhance the barrier. While a phase II study has yielded positive results, the results of the ongoing phase III study are eagerly awaited. It is quite possible that the protective effect of smoking in UC is related to mucus production in the colon also, but this is not an option. Another alternative would be to shift cell differentiation in the colon towards goblet cell; the relevant differentiation factors are known. In Crohn's disease, the direct oral application of defensins might be effective if release and binding to the mucus are achieved. In the experimental colitis model, this works quite well. In conclusion, in a situation where enthusiasm about so-called biologics is declining due to loss of response over time, searching for the primary defects in inflammatory bowel disease and treating them may well be worthwhile, although it is unlikely to provide rapid relief.

scholarly journals Erythema Nodosum and Pyoderma Gangrenosum in 50 Patients with Crohn’s Disease

2005 ◽  
Vol 19 (10) ◽  
pp. 603-606 ◽  
Author(s):  
Hugh J Freeman
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Pyoderma Gangrenosum ◽  
Complex Disease ◽  
Erythema Nodosum ◽  
Colonic Disease ◽  
Detection Rates ◽  
Dependent Effect ◽  
Age Dependent ◽  
Dermatological Disorders

Erythema nodosum and pyoderma gangrenosum may occur in Crohn's disease. In the present evaluation of consecutive patients with Crohn's disease spanning more than two decades, erythema nodosum was seen in 45 patients and pyoderma gangrenosum was seen in seven patients. Forty-one of 566 women (7.2%) and nine of 449 men (2.0%) were affected. Of these, 45 (4.4%) had erythema nodosum and seven (0.7%) had pyoderma gangrenosum, including two (0.2%) with both dermatological disorders at different times during their clinical courses. Recurrent erythema nodosum was also detected in nine patients (20%) including eight women, while recurrent pyoderma gangrenosum was seen in two patients (28.6%). There was an age-dependent effect on the appearance of erythema nodosum in women, with the highest percentages seen in those younger than 20 years of age. Detection rates for erythema nodosum in women only approached the low mens' rates in Crohn's disease at older than 40 years of age. Most patients with these dermatological disorders had colonic disease with or without ileal involvement as well as complex disease, usually with penetrating complications. The present study documents a sex-based and age-dependent effect on the clinical expression of erythema nodosum in Crohn's disease. This suggests that some components of the inflammatory process in Crohn's disease may be modulated by estrogen-mediated events, particularly in adolescents and young adults.

scholarly journals Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

2020 ◽  
Author(s):  
Elke M. Muntjewerff ◽  
Kechun Tang ◽  
Lisanne Lutter ◽  
Gustaf Christoffersson ◽  
Mara J.T. Nicolasen ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Chromogranin A ◽  
Intestinal Barrier ◽  
Enteroendocrine Cells ◽  
Leaky Gut ◽  
Gut Permeability ◽  
Gut Barrier ◽  
Ultrastructural Studies ◽  
New Findings

AbstractBackground and AimsA ‘leaky’ gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we asked how Chromogranin A (CgA), a major hormone produced by the enteroendocrine cells, and Catestatin (CST), the most abundant CgA-derived proteolytic peptide, affect the gut barrier.Methods and ResultsUltrastructural studies on the colons from Catestatin (CST: hCgA352-372) knockout (CST-KO) mice revealed (i) altered morphology of tight (TJ) and adherens (AJ) junctions and desmosomes, indicative of junctional stress and (ii) an increased infiltration of immune cells compared to controls. Flow cytometry studies confirmed these cells to be macrophages and CD4+ T cells. Gene expression studies confirmed that multiple TJ-markers were reduced, with concomitant compensatory elevation of AJ and desmosome markers. Consistently, the levels of plasma FITC-dextran were elevated in the CST-KO mice, confirming leakiness’ of the gut. Leaky gut in CST-KO mice correlated with inflammation and a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in a multitude of diseases. Supplementation of CST-KO mice with recombinant CST reversed this leakiness and key phenotypes. Supplementation of CgA-KO mice with either CST alone, or with the pro-inflammatory proteolytic CgA fragment pancreastatin (PST: CgA250-301) showed that gut permeability is regulated by the antagonistic roles of these two peptide hormones: CST reduces and PST increases leakiness.ConclusionWe conclude that the enteroendocrine cell-derived hormone, CgA regulates gut permeability. CST is both necessary and sufficient to reduce the leakiness. CST acts primarily via antagonizing the effects of PST.What you need to knowBackground and ContextThe intestinal barrier is disrupted in many intestinal diseases such as Crohn’s disease. Chromogranin A (CgA) is produced by enteroendocrine cells in the gut. CgA is proteolytically cleaved into bioactive peptides including catestatin (CST) and pancreastatin (PST). The role of CgA in the gut is unknown.New findingsCgA is efficiently processed to CST in the gut and this processing might be decreased during active Crohn’s disease. CST promotes epithelial barrier function and reduces inflammation by counteracting PST.LimitationsThe complete mechanism of intestinal barrier regulation by CST likely involves a complex interplay between the enteroendocrine system, metabolism, the epithelium, the immune system and the gut microbiota.ImpactOur findings indicate that CST is a key modulator of the intestinal barrier and immune functions that correlates with disease severity of Crohn’s disease. CST could be a target for therapeutic interventions in Crohn’s disease.

Colonoscopy in Childhood

PEDIATRICS ◽  
1984 ◽  
Vol 73 (5) ◽  
pp. 594-599
Author(s):  
Eric Hassall ◽  
Glen N. Barclay ◽  
Marvin E. Ament
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Abdominal Pain ◽  
Crohn's Disease ◽  
Barium Enema ◽  
Colonic Disease ◽  
Radiographic Diagnosis ◽  
Inflammatory Bowel ◽  
Fiberoptic Colonoscopy

A review was made of 139 fiberoptic colonoscopies performed between 1975 and 1982 on 113 patients aged 1 month to 20 years. General anesthesia was used in four procedures. All others were done under sedation with meperidine (mean dose 2.9 mg/kg) and diazepam (mean dose 0.5 mg/kg). Indications were rectal bleeding in 52 patients; assessment and surveillance of known inflammatory bowel disease in 33 patients; and diagnostic evaluation of abdominal pain, diarrhea, and/or fever in 28 patients. The cecum was reached in 84% of diagnostic examinations. Comparison of findings on colonoscopy with barium enema in 75 patients showed agreement in 46, colonoscopic superiority in 25, and barium enema superiority in four. Bleeding sufficient to cause anemia was seen in 10/26 patients with polyps. Five minor complications and no major complications occurred. Flexible fiberoptic colonoscopy and polypectomy may be done usefully in childhood by physicians well versed and experienced with these procedures. Colonoscopy and biopsy changed the radiographic diagnosis from ulcerative colitis to Crohn's disease in several cases and indicated greater extent of colonic disease in several cases of ulcerative colitis and Crohn's disease. Colonoscopy is usually the most sensitive and accurate diagnostic tool for the evaluation of colonic disease, but barium enema and colonoscopy are complementary tests and barium enema should usually precede colonoscopy, with certain exceptions.

Tu1862 BI 695501 DEMONSTRATES SIMILAR EFFICACY AND COMPARABLE SAFETY TO ADALIMUMAB REFERENCE PRODUCT IN PATIENTS WITH ACTIVE CROHN'S DISEASE: FINAL ANALYSIS OF THE PHASE III VOLTAIRE-CD STUDY

2020 ◽  
Vol 158 (6) ◽  
pp. S-1192-S-1193
Author(s):  
Stephen B. Hanauer ◽  
Stefan Schreiber ◽  
Sigrid E. Balser ◽  
Ekkehard Brockstedt ◽  
Viktoria Moschetti ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Reference Product ◽  
Final Analysis ◽  
Similar Efficacy ◽  
Phase Iii

scholarly journals Microbial Signature in Adipose Tissue of Crohn’s Disease Patients

2020 ◽  
Vol 9 (8) ◽  
pp. 2448
Author(s):  
Carolina Serena ◽  
Maribel Queipo-Ortuño ◽  
Monica Millan ◽  
Lidia Sanchez-Alcoholado ◽  
Aleidis Caro ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Pathogenic Bacteria ◽  
Sulfur Metabolism ◽  
Clinical Status ◽  
Subcutaneous Fat ◽  
Intestinal Barrier ◽  
Fecal Calprotectin ◽  
Inactive Disease

Crohn’s disease (CD) is characterized by compromised immune tolerance to the intestinal commensal microbiota, intestinal barrier inflammation, and hyperplasia of creeping fat (CF) and mesenteric adipose tissue (AT), which seems to be directly related to disease activity. Gut microbiota dysbiosis might be a determining factor in CD etiology, manifesting as a low microbial diversity and a high abundance of potentially pathogenic bacteria. We tested the hypothesis that CF is a reservoir of bacteria through 16S-rRNA sequencing of several AT depots of patients with active and inactive disease and controls. We found a microbiome signature within CF and mesenteric AT from patients, but not in subcutaneous fat. We failed to detect bacterial DNA in any fat depot of controls. Proteobacteria was the most abundant phylum in both CF and mesenteric AT, and positively correlated with fecal calprotectin/C-reactive protein. Notably, the clinical status of patients seemed to be related to the microbiome signature, as those with the inactive disease showed a reduction in the abundance of pathogenic bacteria. Predictive functional profiling revealed many metabolic pathways including lipopolysaccharide biosynthesis and sulfur metabolism overrepresented in active CD relative to that in inactive CD. Our findings demonstrate that microbiota dysbiosis associated with CD pathophysiology is reflected in AT and might contribute to disease severity.

scholarly journals P160 A novel PillCam Crohn’s capsule score (Eliakim score) for quantification of mucosal inflammation in Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S218-S219
Author(s):  
R Eliakim ◽  
D Yablecovitch ◽  
A Lahat ◽  
B Ungar ◽  
E Shachar ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Small Bowel ◽  
Crohn's Disease ◽  
Clinical Remission ◽  
Colonic Disease ◽  
Study Cohort ◽  
The Novel ◽  
Colonic Preparation ◽  
Pearson's R ◽  
Pearson’S R

Abstract Background Capsule endoscopy (CE) is an important modality for monitoring of Crohn’s disease (CD). We recently established that small bowel (SB) inflammation on CE quantified by a Lewis score >350 accurately predicts risk of relapse within 2 years in CD patients in clinical remission. Recently, a novel pan-enteric capsule (PillCam Crohn’s (PCCE), Medtronic, USA) was approved for use. However, no quantitative index for pan-enteric PCCE is currently available. The current study was undertaken as a sub-study of a prospective randomised controlled CURE-CD trial aiming to optimise treatment of CD patients in remission using a PCCE- based treat-to-target approach; the aim of this ancillary study was to compare the correlation and reliability of the novel PCCE inflamatory score (Eliakim score) with the Lewis score as performed by 2 independent experienced CE readers. Methods The study cohort includes CD patients in clinical remission (CDAI<150). The patients were prospectively enrolled and underwent patency capsule evaluation; if excreted within 30 h, PCCE was performed following bowel preparation. PCCE was repeated every 6 months; if no colonic disease was detected on first PCCE, subsequent examinations were performed without colonic preparation. Each PCCE was independently reviewed by 2 experienced readers (RE (reader 1);UK (reader 2)). All studies were scored using the Lewis score and Eliakim score (comprised of a sum of scores for most common and most severe lesions multiplied by percentage of involvement per bowel segment (3 for small bowel and 2 for colon) with an additional stricture score). Pearson’s and Spearman’ correlation, Cohen’s kappa and inter-rater reliability coefficient (IRC) between the scores and the readers were calculated as appropriate. Results Forty PCCE exams were included. The median LS was 225 for both readers (interquartile range (IQR)—157–815 for reader 1, 33- 1125 for reader 2). Both readers identified significant SB inflammation (LS>350) in 17/40 (42.5%) of the patients with strong agreement between the readers (Spearman’s r = 0.87, p < 0.0001). The median PCCE score was 6 (4–14.75) and 4 (2–14.75) for reader 1 and 2, respectively. There was a high IRC between the two readers for LS (0.88, p < 0.0001 for absolute agreement) and PCCE score (0.91, p < 0.0001). For the small bowel, the correlation between LS and PCCE was moderate for reader 1 (Pearson’s r = 0.72, p < 0.0001 and strong for reader 2 Pearson’s r = 0.84, p < 0.0001). Conclusion There is a need for a quantitative pan-enteric score for the novel Pillcam Crohns capsule. The presently proposed score, while mandating further clinical validation, has strong inter-reader reliability and moderate-to-strong correlation with the validated small bowel capsule score (LS)

P058 ISOLATED TERMINAL ILEITIS AT COLONOSCOPY – WHAT FACTORS PREDICT A NEW DIAGNOSIS OF CROHN’S DISEASE?

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S14-S14
Author(s):  
Rajan Patel ◽  
Kar Mun Ang ◽  
Saadiq Moledina ◽  
Saif Musa ◽  
Akeel Alisa ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Terminal Ileum ◽  
Binary Logistic Regression ◽  
Poor Correlation ◽  
Colonic Disease ◽  
Chi Square ◽  
Terminal Ileitis ◽  
Faecal Calprotectin ◽  
New Diagnosis

Abstract Background Faecal calprotectin (FC) is a biomarker elevated in active inflammatory bowel disease (IBD). FC is more sensitive in colonic than small bowel IBD. Ileo-colonoscopy is usually performed to confirm a diagnosis of IBD. Isolated non-specific terminal ileitis is often inconclusive despite biopsy. We aimed to assess the factors that predict terminal ileal Crohn’s disease after ileitis is seen at colonoscopy. Methods A single centre retrospective study of all endoscopic cases of isolated terminal ileitis diagnosed at colonoscopy over a 4 year period (January 2015 – December 2018) was performed. Data was obtained from the Unisoft Endoscopy reporting software. Statistical analyses included chi-square, student t-test and binary logistic regression. Faecal calprotectin, CRP and histology were noted. >150μg/mg was used as a cut off for elevated FC. Results 139 cases were identified and exclusion criteria were applied (known Crohn’s disease, colonic disease). 74 cases were included for analysis. The mean age was 43.9. 44 (59.5%) of the cases were women. 38 (51.4%) had FC performed of which 27 (71.1%) had a FC >150μg/mg. 60 (81.1%) cases had macroscopic terminal ileum ulcers, 9 (15%) of these had histological evidence of ulceration. Subsequent diagnoses of Crohn’s disease were made in 15 (20.3%) patients. Odds ratio of 1.28 (p = 0.016, Cl 0.45-0.047) in the TI ulcers + FC >150μg/mg vs. no TI ulcers + FC <150μg/mg. Conclusion 1 in 5 patients with isolated terminal ileitis were subsequently diagnosed with Crohn’s disease. Almost 90% of these new cases had a faecal calprotectin >150μg/mg. There is poor correlation between endoscopic and histological terminal ileum ulceration. We conclude that terminal ileal ulceration in combination with faecal calprotectin >150μg/mg increases the likelihood of a new diagnosis of Crohn’s disease.

scholarly journals Outcomes of Bowel Resection in Patients with Crohn's Disease

2015 ◽  
Vol 81 (10) ◽  
pp. 1021-1027 ◽  
Author(s):  
Zhobin Moghadamyeghaneh ◽  
Joseph C. Carmichael ◽  
Steven D. Mills ◽  
Alessio Pigazzi ◽  
Michael J. Stamos
Keyword(s):  
Crohn’S Disease ◽  
Small Bowel ◽  
Crohn's Disease ◽  
Mortality Risk ◽  
Bowel Disease ◽  
Large Bowel ◽  
Bowel Resection ◽  
Multivariate Regression Analysis ◽  
Colonic Disease ◽  
Small Bowel Disease

There is limited data regarding outcomes of bowel resection in patients with Crohn's disease. We sought to investigate complications of such patients after bowel resection. The Nationwide Inpatient Sample databases were used to examine the clinical data of Crohn's patients who underwent bowel resection during 2002 to 2012. Multivariate regression analysis was performed to investigate outcomes of such patients. We sampled a total of 443,950 patients admitted with the diagnosis of Crohn's disease. Of these, 20.5 per cent had bowel resection. Among patients who had bowel resection, 51 per cent had small bowel Crohn's disease, 19.4 per cent had large bowel Crohn's disease, and 29.6 per cent had both large and small bowel Crohn's disease. Patients with large bowel disease had higher mortality risk compared with small bowel disease [1.8% vs 1%, adjusted odds ratio (AOR): 2.42, P < 0.01]. Risks of postoperative renal failure (AOR: 1.56, P < 0.01) and respiratory failure (AOR: 1.77, P < 0.01) were higher in colonic disease compared with small bowel disease but postoperative enteric fistula was significantly higher in patients with small bowel Crohn's disease (AOR: 1.90, P < 0.01). Of the patients admitted with the diagnosis of Crohn's disease, 20.5 per cent underwent bowel resection during 2002 to 2012. Although colonic disease has a higher mortality risk, small bowel disease has a higher risk of postoperative fistula.

scholarly journals Efficacy of JAK inhibitors in Crohn’s Disease

2019 ◽  
Vol 14 (Supplement_2) ◽  
pp. S746-S754 ◽  
Author(s):  
Gerhard Rogler
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Clinical Development ◽  
Phase Iii ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Janus Kinases ◽  
Double Blinded

Abstract Inhibition of Janus kinases [JAKs] in Crohn’s disease [CD] patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor, showed efficacy in ulcerative colitis [UC] and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in CD patients were disappointing and the primary end point of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently, phase III programmes in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are being tested in clinical programmes. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity [Tyk2 inhibitors]. In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.

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