Intestinal Mucosal Healing Research Articles

Neutrophil-derived microRNAs put the (DNA) breaks on intestinal mucosal healing.

A predominant feature of intestinal inflammation is the accumulation of neutrophils, which dictates a fine balance between epithelial repair or progression to chronic inflammation. While the processes of mucosal healing are well studied, how neutrophils advance an inflammatory insult towards epithelial neoplasia is less understood. In this issue of the JCI, Butin-Israeli et al. outline a mechanism whereby neutrophils control epithelial fitness and genomic instability via delivery of miR-23a-and miR-155-containing microparticles. Localized delivery of antisense oligonucleotides targeting miR-23a and miR-155 reversed this genomic instability and accelerated mucosal healing. This mechanism of neutrophil-derived microRNA shuttling opens up new therapeutic potential to enhance epithelial healing and limit mucosal injury.

Establishment of a system to evaluate the therapeutic effect and the dynamics of an investigational drug on ulcerative colitis using human colonic organoids.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable, recurrent course. The goal of UC therapy is to target mucosal healing because immune-suppressive therapy for UC frequently results in relapse. However, few drugs directly target mucosal healing. We, therefore, aim to evaluate the therapeutic effect of an investigational drug on intestinal epithelial cells in an in vitro UC model using human colonic organoids. Colonic organoids were isolated from human colon and cultured. A mixture of cytokines and bacterial components were used to mimic UC in humans. The effect of the investigational drug on colonic organoid was evaluated by microarray analysis and 3D immunofluorescence. The enrichment of stem cells was assessed with a colony formation assay. Inflammatory stimulation resulted in a significant induction of inflammatory-related genes in colonic organoids whereas cell differentiation was suppressed. Treatment with the investigational drug KAG-308 showed reciprocal dynamics of gene expression to inflammatory stimulation, which resulted in not only the suppression of immune response but also the promotion of cellular differentiation towards secretory lineages. Moreover, SPDEF and Reg4 were identified as novel targets for the enrichment of intestinal epithelial stem cells and mucosal healing. The establishment of in vitro UC model using human colonic organoid could reveal the effects and targets of investigational drugs in intestinal epithelial cells under inflammation conditions. Further maturation of this system might be more efficient to predict the effect on UC, as compared with the use of animal model, for the development of new drugs.

Effect of <i>Commiphora molmol</i> (Myrrh) Extract on Mice Infected by <i>Giardia lamblia</i>

Objective: To investigate the efficacy of (Commiphora molmol(Myrrh)) extract as alternative treatment in hamsters against giardiasis. This study was conducted to evaluate the effect of the new compound (Commiphora molmol(Myrrh)), as agent a natural product extracted from the roots of Zingiber officinal, on Giardia lamblia infection as anti-protozoal and to study the parasitological and Histopathological impact of this treatment on the duodenal mucosa of infected hamsters. Fifty hamsters were divided into five groups: Group (A): normal control. Group (B): Giardia lamblia infected and untreated hamsters served as control. Group (C): infected with Giardia lamblia and treated with metronidazole in dose (120 μg/kg body weight twice daily for 7 successive days). Group (D) Giardia lamblia infected and orally treated with Myrrh (500 mg/Kg for 1 week). Group (E): Giardia lamblia infected and orally treated with combination 1/3 dose of (120 μg/kg body weight) metronidazole and Myrrh (250 mg/Kg) for 1 week). After 2 weeks of the treatment, hamsters were sacrificed. The highest percentages of reduction in the number of Giardia lamblia cysts and trophozoites were in the group receiving combined metronidazole and myrrh. Histopathological examination revealed complete healing of intestinal mucosa after the combined treatment, while partial healing of the lining epithelium of the intestine was noticed after metronidazole and either myrrh plant treatment.

Correlation of Intestinal Mucosal Healing and Tight Junction Protein Expression in Ulcerative Colitis Patients

BackgroundThe aim of this study was to investigate the relationship between intestinal mucosal healing and tight junction (TJ) protein expression in patients with ulcerative colitis (UC). Materials and MethodsA total of 40 patients with UC were included as an experimental group and UC disease activity was evaluated using the Mayo clinic score (MCS) and 8 patients with normal distal colon served as the control group. The expression of TJ proteins including occludin, ZO-1 and claudin-2 were determined by immunohistochemistry and their correlation with clinical characteristics were also analyzed. ResultsStatistically significant differences regarding the MCS and Mayo endoscopic subscore (MES) were observed in both groups (P < 0.01). The Geboes index was significantly increased in patients with active UC compared to patients with quiescent UC and normal controls (P < 0.01). Patients with active and quiescent UC had upregulated expression of claudin-2 and reduced expression of occludin and ZO-1 compared to those of normal controls. The expression of ZO-1 was significantly higher in patients with quiescent UC with mucosa healing (P < 0.05) compared with those without mucosal healing. The expression of ZO-1 and occludin was negatively correlated with MCS, MES, Geboes, C-reaction protein and erythrocyte sedimentation rate. The expression of claudin-2 was positively correlated with MCS, MES, Geboes, C-reaction protein and erythrocyte sedimentation rate. ConclusionsThese findings suggest that TJ proteins play a crucial role in mucosal healing, and may be a potential marker of response when evaluating therapeutic interventions.

Ginsenoside Rb1 promotes intestinal epithelial wound healing through extracellular signal-regulated kinase and Rho signaling.

Daikenchuto, a traditional Japanese herbal medicine, has been reported to exhibit anti-inflammatory effects against intestinal inflammation. However, whether daikenchuto has a therapeutic effect against intestinal mucosal injuries remains unclear. Thus, the aim of this study was to determine the effect of daikenchuto on intestinal mucosal healing. Colitis was induced in male Wistar rats by using trinitrobenzenesulfonic acid. Daikenchuto (900mg/kg/day) was administered for 7days after the induction of colitis. Thereafter, intestinal mucosal injuries were evaluated by determining the colonic epithelial regeneration ratio ([area of epithelial regeneration/area of ulcer]×100). Restoration of rat intestinal epithelial cells treated with daikenchuto and its constituent herbs (Zanthoxylum fruit, processed ginger, and ginseng) and ginsenoside Rb1, which is a ginseng ingredient, was evaluated using a wound-healing assay. The colon epithelial regeneration ratio in the daikenchuto-treated rats was significantly higher than that in the control rats. Daikenchuto, ginseng, and ginsenoside Rb1 enhanced wound healing, and the ginsenoside Rb1-induced enhancement was inhibited by extracellular signal-regulated kinase and Rho inhibitors. Daikenchuto and its constituent, ginsenoside Rb1, promoted wound healing. Because mucosal healing is one of the most important therapeutic targets in patients with inflammatory bowel disease, ginsenoside Rb1 may be a novel therapeutic agent against intestinal mucosal damage such as that occurring in intestinal bowel disease.

Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice

Current treatments for inflammatory bowel disease (IBD) target the overactive immune response of the intestinal mucosa. However, epidermal growth factor (EGF), an activating ligand of the EGF receptor (EGFR), has been shown to induce disease remission through direct targeting of intestinal mucosal healing. Despite promising preclinical and clinical results, this EGFR-activating therapy has not progressed, in part due to the potential for carcinogenesis associated with long-term use and the increased risk of colitis-associated cancer (CAC) in IBD. Here we tested whether pharmacological modulation of EGFR altered outcomes of CAC in the murine azoxymethane/dextran sulfate sodium model. We found that administering EGF during the period of maximum colitis severity (“early”), coincident with the initiation and early promotion of tumors, improved outcomes of colitis and reduced tumor size. In contrast, daily EGF administration beginning ~2 months after tumor initiation (“late”) increased tumor size. Administration of the EGFR kinase inhibitor gefitinib increased the tumor size when the drug was given early and decreased the tumor size when the drug was administered late. EGF administration not only reduced colonic cytokine and chemokine expression during injury, but also baseline chemokine expression in homeostasis. These results suggest that EGFR activation during acute bouts of colitis may reduce the long-term burden of CAC.

In Inflamed Intestinal Tissues and Epithelial Cells, Interleukin 22 Signaling Increases Expression of H19 Long Noncoding RNA, Which Promotes Mucosal Regeneration

Inflammation affects regeneration of the intestinal epithelia; long noncoding RNAs (lncRNAs) regulate cell functions, such as proliferation, differentiation, and migration. We investigated the mechanisms by which the lncRNA H19, imprinted maternally expressed transcript (H19) regulates regeneration of intestinal epithelium using cell cultures and mouse models of inflammation. We performed RNA-sequencing transcriptome analyses of intestinal tissues from mice with lipopolysaccharide (LPS)-induced sepsis to identify lncRNAs associated with inflammation; findings were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization analyses of intestinal tissues from mice with sepsis or dextran sulfate sodium (DSS)-induced mucosal wound healing and patients with ulcerative colitis compared to healthy individuals (controls). We screened cytokines for their ability to induce expression of H19 in HT-29 cells and intestinal epithelial cells (IECs), and confirmed findings in crypt epithelial organoids derived from mouse small intestine. IECs were incubated with different signal transduction inhibitors and effects on H19 lncRNA levels were measured. We assessed intestinal epithelial proliferation or regeneration in H19ΔEx1/+ mice given LPS or DSS vs wild-type littermates (control mice). H19 was overexpressed in IECs using lentiviral vectors and cell proliferation was measured. We performed RNA antisense purification, RNA immunoprecipitation, and luciferase reporter assays to study functions of H19 in IECs. In RNA-sequencing transcriptome analysis of lncRNA expression in intestinal tissues from mice, we found that levels of H19 lncRNA changed significantly with LPS exposure. Levels of H19 lncRNA increased in intestinal tissues of patients with ulcerative colitis, mice with LPS-induced and polymicrobial sepsis, or mice with DSS-induced colitis, compared with controls. Increased H19 lncRNA localized to epithelial cells in the intestine, regardless of Lgr5 messenger RNA expression. Exposure of IECs to interleukin 22 (IL22) increased levels of H19 lncRNA with time and dose, which required STAT3 and protein kinase A activity. IL22 induced expression of H19 in mouse intestinal epithelial organoids within 6 hours. Exposure to IL22 increased growth of intestinal epithelial organoids derived from control mice, but not H19ΔEx1/+ mice. Overexpression of H19 in HT-29 cells increased their proliferation. Intestinal mucosa healed more slowly after withdrawal of DSS from H19ΔEx1/+ mice vs control mice. Crypt epithelial cells from H19ΔEx1/+ mice proliferated more slowly than those from control mice after exposure to LPS. H19 lncRNA bound to p53 and microRNAs that inhibit cell proliferation, including microRNA 34a and let-7; H19 lncRNA binding blocked their function, leading to increased expression of genes that promote regeneration of the epithelium. The level of lncRNA H19 is increased in inflamed intestinal tissues from mice and patients. The inflammatory cytokine IL22 induces expression of H19 in IECs, which is required for intestinal epithelial proliferation and mucosal healing. H19 lncRNA appears to inhibit p53 protein and microRNA 34a and let-7 to promote proliferation of IECs and epithelial regeneration.

Regulation of Intestinal Mucosal Wound Healing by Serotonin

Regulation of Intestinal Mucosal Wound Healing by Serotonin

MicroRNA-7-5p regulates the proliferation and migration of intestinal epithelial cells by targeting trefoil factor 3 via inhibiting the phosphoinositide 3-kinase/Akt signalling pathway.

Trefoil factor 3 (TFF3) reconstructs the epithelial barrier by stimulating epithelial cell migration and proliferation, and significantly contributes to intestinal mucosal damage and healing. In a previous study, TFF3 was identified as a novel target of microRNA-7-5p (miR-7-5p). The aim of the present study was to investigate the roles and mechanisms of miR-7-5p in the proliferation and migration of intestinal epithelial cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression level of miR-7-5p in the experimental groups. In addition, western blot analysis was performed to examine the expression levels of TFF3, phosphoinositide 3-kinase (PI3K), Akt and phosphorylated (p)-AKT when miR-7-5p or TFF3 was overexpressed, and the effects of miR-7-5p and TFF3 on LS174T cell proliferation and migration were simultaneously investigated. miR-7-5p was demonstrated to decrease the expression level of TFF3, and inhibit LS174T cell proliferation and migration, which was accompanied by decreased expression levels of PI3K and p-Akt. miR-7-5p was decreased following combined treatment with the TFF3 plasmid and miR-7-5p mimics, compared with treatment with miR-7-5p mimics alone, which was accompanied by increased expression levels of TFF3, PI3K and p-Akt, and enhanced LS174T cell proliferation and migration effects. The expression levels of miR-7-5p in the miRNA negative control (NC) + LY294002 group, the miR-7-5p mimic + LY294002 group, and the miR-7-5p mimic + TFF3 plasmid + LY294002 group were higher than those in the NC group, the miR-7-5p mimic group and the miR-7-5p mimic + TFF3 plasmid group, respectively. Accordingly, the expression level of TFF3 was downregulated and the proliferation and migration ability of the cells was downregulated. The present study demonstrates that overexpressed miR-7-5p may inhibit the proliferation and migration of LS174T cells by targeting the expression of TFF3 via inhibiting the PI3K/Akt signalling pathway. The PI3K/Akt signalling pathway may exert a feedback regulation effect on miR-7-5p, inhibiting the activity of this signalling pathway, which increases the miR-7-5p expression levels and further enhances the effects of miR-7-5p on cell proliferation and migration.

Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice With Colitis and Is Increased in Mucosa of Patients With Inflammatory Bowel Disease

We investigated the roles of interleukin 28A (also called IL28A or interferon λ2) in intestinal epithelial cell (IEC) activation, studying its effects in mouse models of inflammatory bowel diseases (IBD) and intestinal mucosal healing. Colitis was induced in C57BL/6JCrl mice (controls), mice with IEC-specific disruption of Stat1 (Stat1IEC-KO), mice with disruption of the interferon λ receptor 1 gene (Il28ra-/-), and mice with disruption of the interferon regulatory factor 3 gene (Irf3-/-), with or without disruption of Irf7 (Irf7-/-). We used high-resolution mini-endoscopy and invivo imaging methods to assess colitis progression. We used 3-dimensional small intestine and colon organoids, along with RNA-Seq and gene ontology methods, to characterize the effects of IL28 on primary IECs. We studied the effects of IL28 on the human intestinal cancer cell line Caco-2 in a wound-healing assay, and in mice colon wounds. Colonic biopsies and resected tissue from patients with IBD (n= 62) and patients without colon inflammation (controls, n= 23) were analyzed by quantitative polymerase chain rection to measure expression of IL28A, IL28RA, and other related cytokines; biopsy samples were also analyzed by immunofluorescence to identify sources of IL28 production. IECs were isolated from patient tissues and incubated with IL28; signal transducer and activator of transcription 1 (STAT1) phosphorylation was measured by immunoblots and confocal imaging. Lamina propria cells in colon tissues of patients with IBD, and mice with colitis, had increased expression of IL28 compared with controls; levels of IL28R were increased in the colonic epithelium of patients with IBD and mice with colitis. Administration of IL28 induced phosphorylation of STAT1 inprimary human and mouse IECs, increasing with dose. Il28ra-/-, Irf3-/-, Irf3-/-Irf7-/-, as well as Stat1IEC-KO mice, developed more severe colitis after administration of dextran sulfate sodium than control mice, with reduced epithelial restitution. Il28ra-/- and Stat1IEC-KO mice also developed more severe colitis in response to oxazolone than control mice. We found IL28 to induce phosphorylation (activation) of STAT1 in epithelial cells, leading to their proliferation in organoid culture. Administration of IL28 to mice with induced colonic wounds promoted mucosal healing. IL28 controls proliferation of IECs in mice with colitis and accelerates mucosal healing by activating STAT1. IL28 might be developed as a therapeutic agent for patients with IBD.

Efficacy of adalimumab for Crohn's disease in real clinical practice

To evaluate the efficacy and safety of adalimumab (ADA) in patients with Crohn's disease (CD) treated at the Department of Inflammatory Bowel Diseases, Moscow Clinical Research and Practical Center, and to determine the predictors of a therapy response. All the patients with CD treated with ADA were followed up for at least 6 months or until the drug was discontinued. Therapeutic effectiveness was evaluated at 4 weeks and 6 months after the initiation of treatment and at the end of a follow-up. Complete intestinal mucosal healing was assessed at 3 and 12 months following treatment initiation. Univariate and multivariate analyses were used to determine the predictors of treatment response. A clinical analysis covered 70 patients (57.1% male); the follow-up period averaged 112 weeks. Perianal fistulas were at baseline established in 22 (31.4%) patients with CD. 12 (17.4%) patients had been previously treated with infliximab (INF), 7 of them discontinued the drug for secondary loss of response and 5 for adverse reactions. 68 (97.1%) patients responded to an induction course of ADA. At 4 weeks, 6 months, and at the end of the follow-up, clinical remission occurred in 66.7, 80.4 and 67.4 % of patients with luminal CD and in 45.4, 36.5, and 36.4% of those with perianal CD, respectively. At 3 and 12 months and at the end of the follow-up, there was complete healing of the intestinal mucosa in 23.5, and 41.2 and 29.5% of cases, respectively. Six (8.8%) patients responding to the induction course needed to be optimized with ADA to 40 mg weekly. The time interval between treatment initiation and dose optimization averaged 30 weeks (range 12-120 months). There were 15 (21,4%) adverse events that were responsible for ADA discontinuation in 3 (4,2%) patients. The findings demonstrate the efficacy and safety of ADA used in clinical practice.

MicroRNA‑7‑5p regulates the expression of TFF3 in inflammatory bowel disease.

Trefoil factor 3 (TFF3) serves an important role in intestinal mucosal damage and healing, and contributes to the pathogenesis and treatment of inflammatory bowel disease (IBD). The aim of the present study was to determine the association between TFF3 and microRNA-7-5p (miR-7-5p) in IBD. Tissue immunohistochemistry was applied to evaluate the relative expression of TFF3, and reverse transcription-quantitative polymerase chain reaction was performed to determine the expression of miR-7-5p in lesional tissue obtained from patients with IBD and healthy control tissues. A dual-luciferase reporter assay was used to investigate whether TFF3 was a target of miR-7-5p, and western blotting was performed to determine the expression of TFF3 when miR-7-5p was overexpressed or suppressed. The protein expression levels of TFF3 were decreased and miR-7-5p was overexpressed in the lesional tissue of patients with IBD compared with in healthy control tissues. TFF3 was identified as a target of miR-7-5p, and TFF3 protein expression was negatively regulated by miR-7-5p in human colonic epithelial LS174T cells. The present study demonstrated a negative association between the expression of miR-7-5p and TFF3 in IBD lesional tissues and normal tissues. In conclusion, TFF3 was identified as a novel target of miR-7-5p and miR-7-5p may serve as a promising therapeutic target for IBD.

Risk factors analysis of initial surgery and postoperative complications of Crohn′s disease

Objective To explore the risk factors of initial surgery and postoperative complications of Crohn′s disease (CD). Methods The retrospective case-control study was conducted. The clinical data of 227 patients with CD who were admitted to the Cangzhou Central Hospital from April 2011 to July 2015 were collected. Treatment principles included reducing the clinical symptoms, promoting healing of intestinal mucosa under endoscopy, delaying CD progression and preventing intestinal exhaustion and related complications. The medication was performed in the early period. The resection of partial intestines was applied to patients if there was poor effect of medication or combined with intestinal obstruction, intestinal fistula, digestive tract perforation, abdominal abscess and complex anal fistula. Observation indicators: (1) treatment situation, (2) follow-up situation, (3) related factors analysis affecting initial surgery of patients with CD, (4) related factors analysis affecting postoperative complications of patients after initial surgery for CD. Follow-up using regular telephone interview and outpatient examination was performed up to May 2016. Follow-up included the wound infection, abdominal abscess, intestinal obstruction, anastomotic fistula and pulmonary infection. Measurement data with normal distribution were represented as ±s and comparison between groups was analyzed using the t test. Count data were represented as the proportion and analyzed by the chi-square test. The univariate analysis was done using the chi-square test and Kruskal-Wallis test, and multivariate analysis was done using the Logistic regression model. Results (1) Treatment situation: of 227 patients, 68 underwent initial surgery and 159 didn′t undergo surgery. The duration from diagnosis to initial surgery in 68 patients was (4.7±2.5) months. Of 68 patients with surgery, 28 received the emergency surgery and 40 received the selective surgery. Operation time and volume of intraoperative blood loss were (175±44)minutes and (285±110)mL, respectively. The side-to-side anastomosis was conducted in 47 patients and non-side-to-side anastomosis in 21 patients. Other 159 patients without surgery received the medication of mesalazine, hydrocortisone, methotrexate and infliximab. (2) Follow-up situation: 68 patients with initial surgery were followed up for 5-61 months, and 22 had postoperative complications. Of 9 patients with anastomotic fistula, 6 had enterocutaneous fistula (5 patients with enterocutaneous fistula were improved by selective surgery, and the other patient was progress to acute diffuse peritonitis and then was improved by peritoneal lavage, adequate drainage and nutritional support therapy after emergency surgery). Three patients with anastomotic abscess were improved by adequate drainage. Six patients with secondary intestinal obstruction were improved by conservative treatment. Three patients with abdominal abscess were improved after anti-inflammatory treatment and adequate drainage. Two patients with wound infection were improved by regular dressing change. Two patients with pulmonary infection were improved by anti-inflammatory and phlegm conservative treatment. (3) The related factors analysis affecting initial surgery of patients with CD. The results of univariate analysis showed that age of diagnosis, smoking history and behavior of disease were the related factors affecting initial surgery of patients with CD (Z=-2.120, χ2=5.082, 50.512, P<0.05). The results of multivariate analysis showed that A3 of age of diagnosis, B2 and B3 of pattern of disease were the independent risk factors affecting initial surgery of patients with CD [OR=15.624, 10.535, 28.509, 95% confidence interval (CI): 4.856-29.375, 3.609-17.637, 8.526-79.228, P<0.05]. (4) The related factors analysis affecting postoperative complications of patients after initial surgery for CD. The results of univariate analysis showed that preoperative levels of albumin (Alb) and hemoglobin (Hb), emergency surgery, operation time and anastomotic method were the related factors affecting postoperative complications of patients after initial surgery for CD (χ2=10.757, 7.639, 6.773, 4.309, 16.346, P<0.05). The results of multivariate analysis showed that preoperative Alb≤28 g/L, Hb≤100 g/L, emergency surgery and non-side-to-side anastomosis were the independent risk factors affecting postoperative complications of patients after initial surgery for CD (OR=9.592, 8.849, 6.538, 12.645, 95%CI: 2.209-25.235, 2.034-24.773, 1.846-15.893, 3.935-38.873, P<0.05). Conclusions The age of diagnosis>40 years, B2 and B3 of CD are high risk group of initial surgery. The poor preoperative nutritional status, emergency surgery and non-side-to-side anastomosis are independent risk factors affecting postoperative complications of patients after initial surgery for CD. Key words: Crohn′s disease; Surgical procedures, operative; Complications; Risk factors

Therapeutic drug monitoring in inflammatory bowel disease.

There are an expanding number of therapies available to treat pediatric inflammatory bowel disease (IBD). As pediatric gastroenterologists attempt to achieve complete intestinal mucosal healing for their patients, it has become more important to gain an understanding of how to maximize the efficacy of our medications while minimizing their toxicities. We aim to provide an overview of therapeutic drug monitoring in IBD with an emphasis on the biologic therapies (antitumor necrosis factor and anti-integrin monoclonal antibodies). Recent findings do support optimized drug dosing for infliximab based on early trough levels, but question the utility of checking these values in patients doing well in maintenance therapy. Patients with severe colonic inflammation may be at increased risk for needing optimization with dose escalation because of medication loss in the stool. Dose escalation can recapture response in some patients with a secondary loss of response, including those with low level antibody formation. The monitoring of nontrough drug levels to allow timelier dose adjustment as well as the role of drug monitoring with anti-integrin therapy are areas of active research. Therapeutic drug monitoring is an effective strategy in the management of pediatric IBD that can help patients achieve mucosal healing and aid the clinical decision-making of the pediatric gastroenterologist.

Tu1979 Capsule Endoscopy Reveals Small Intestinal Mucosal Crohn's Disease Healing After Treatment With Adalimumab: Preliminary Results of the SIMCHA Study

Tu1979 Capsule Endoscopy Reveals Small Intestinal Mucosal Crohn's Disease Healing After Treatment With Adalimumab: Preliminary Results of the SIMCHA Study

Neutrophil interactions with epithelial-expressed ICAM-1 enhances intestinal mucosal wound healing.

A characteristic feature of gastrointestinal tract inflammatory disorders, such as inflammatory bowel disease, is polymorphonuclear neutrophil (PMN) transepithelial migration (TEM) and accumulation in the gut lumen. PMN accumulation within the intestinal mucosa contributes to tissue injury. While epithelial infiltration by large numbers of PMNs results in mucosal injury, we found that PMN interactions with luminal epithelial membrane receptors may also play a role in wound healing. Intercellular adhesion molecule-1 (ICAM-1) is a PMN ligand that is upregulated on apical surfaces of intestinal epithelial cells under inflammatory conditions. In our study, increased expression of ICAM-1 resulted in enhanced PMN binding to the apical epithelium, which was associated with reduced PMN apoptosis. Following TEM, PMN adhesion to ICAM-1 resulted in activation of Akt and β-catenin signaling, increased epithelial-cell proliferation, and wound healing. Such responses were ICAM-1 dependent as engagement of epithelial ICAM-1 by antibody-mediated cross-linking yielded similar results. Furthermore, using an in-vivo biopsy-based, colonic-mucosal-injury model, we demonstrated epithelial ICAM-1 plays an important role in activation of epithelial Akt and β-catenin signaling and wound healing. These findings suggest that post-migrated PMNs within the intestinal lumen can regulate epithelial homeostasis, thereby identifying ICAM-1 as a potential therapeutic target for promoting mucosal wound healing.

Intestinal healing after anti-TNF induction therapy predicts long-term response to one-year treatment in patients with ileocolonic Crohn's disease naive to anti-TNF agents.

IntroductionObjective assessment of Crohn’s disease (CD) activity in patients treated with anti-tumour necrosis factor (anti-TNF) antibodies is crucial for the prediction of its long-term results. Mucosal healing estimated endoscopically has a strong predictive value; however, only combined assessment together with transmural healing in magnetic resonance enterography (MRE) gives full information about the whole spectrum of inflammatory lesions in CD.AimTo assess the usefulness of intestinal healing phenomenon in CD, defined as improvement both in endoscopy and MRE, after anti-TNF induction therapy, in predicting long-term results of 1-year treatment.Material and methodsTwenty-six patients with ileocolonic CD were enrolled into the study. In this group a parallel assessment of disease activity was estimated before and after induction doses of anti-TNF antibodies with ileocolonoscopy and MRE by using appropriate scores. Subsequently the patients were treated until 12 months and then followed-up. The associations between intestinal healing (assessed in MRE and endoscopy), and mucosal and transmural healing with long-term results of 1-year anti-TNF therapy were analysed statistically.ResultsThe median time of follow-up was 29 months (interquartile range – IQR: 14–46). Intestinal healing was significantly associated with favourable therapeutic outcomes (p = 0.02) and had 75% (IQR: 35–97%) sensitivity and 72% (IQR: 46–90%) specificity in predicting long-term remission. Other parameters were not useful (transmural healing) or their usefulness was of borderline significance (mucosal healing).ConclusionsDynamic assessment of intestinal healing is an accurate method in predicting long-term outcomes in CD patients responding to 1-year anti-TNF therapy.

Vedolizumab Therapy in Crohnʼs Disease and Ulcerative Colitis: A Retrospective Review of Post-procedural Complications

Introduction: Vedolizumab (VDZ) was approved for the treatment of moderate to severe ulcerative colitis (UC) and Crohn's disease (CD) in May 2014. This case series reviews the occurrence of any post-procedure complications after initiation of VDZ therapy in 73 patients seen at a large tertiary referral center. Methods: Retrospective chart review of patients on VDZ therapy from June 2014 to May 2015. Data collected included age, sex, smoking status, disease phenotype, disease distribution, and all endoscopic and surgical procedures after initiation of VDZ. Body mass index (BMI), serum albumin, duration of VDZ therapy and pre-procedure timing of VDZ dosing was recorded for patients who had a procedure. Post-procedural complications were scored using the Accordion Classification scale, a validated tool to grade the severity of post-operative complications. Results: 73 patients were identified: 35 male/38 female, 45 CD/28 UC, 55/73 had never smoked, 4/73 were current smokers, and 14/73 were former smokers. 32/45 Crohn's patients had both large and small bowel disease. 21/45 Crohn's patients had perirectal involvement. Mean duration of VDZ therapy in the study period was 5.5 (SD ± 2.27) months in CD and 6.5 (SD ± 2.28) months in UC. 46 procedures occurred in 36 patients after initiation of VDZ therapy (Table 1). 5 procedures had associated complications, including spontaneous mucosal tearing, anastomotic leak with intra-abdominal abscess, and wound dehiscence. In these patients, the mean duration of VDZ therapy prior to procedure was 5 (SD ± 1.59) months, mean number of days between VDZ infusion and procedure was 29 (SD ± 19.59) days, mean BMI was 24 (SD ± 6.61) kg/m2 and mean albumin was 3.4 (SD ± 0.38) g/dL (Table 2).Table 1: Demographics of all VDZ therapy patientsTable 2: Characteristics of Patients with ComplicationsConclusion: VDZ affects leukocyte trafficking to the intestines and therefore has a theoretically increased risk of impaired intestinal mucosal and serosal wound healing due to a reduction in the inflammatory response needed to initiate the healing of these injuries. While initial phase III trials in UC and CD did not show a significantly increased risk of bowel perforation, an open-label trial is ongoing to better characterize the long-term safety of VDZ. This is the first case series review of non-study patients on VDZ therapy to evaluate the occurrence of these potential complications. Further studies are needed to better characterize if VDZ therapy has any impact on the occurrence and severity of post-procedural complications.

Potential utility of a new ulcerative colitis segmental endoscopic index combining disease severity and the extent of inflammation.

To investigate the potential utility of a new scoring system, the Ulcerative Colitis Segmental Endoscopic Index (UCSEI), which combines measures of disease severity and extent of inflammation. Intestinal mucosal healing (MH) is a new therapeutic goal for ulcerative colitis (UC). Discontinuous lesions are common in UC and endoscopic observation of the entire colon is important. Patients with active mild-to-moderate UC received daily treatment with oral mesalazine (4 g/d) and mesalazine enemas (1 g/d) for 8 weeks. Endoscopic evaluations, using the UCSEI and Mayo Endoscopic Score (MES), were performed in 5 colonic segments at baseline and week 8. The UCSEI criteria included erythema, vascular pattern, friability, and erosion/ulcer. The sum of 5 subscores, determined for each segment, was calculated as the UCSEI. Disease activity was also assessed using the UC Disease Activity Index (UCDAI). MH was defined as MES=0 to 1. Of 58 patients, 51 completed the scheduled endoscopic evaluations. At week 8, the UCDAI score had significantly decreased from 6.63 (baseline) to 2.73 (P<0.001). The remission and MH rates were 35.3% and 55.3%, respectively. Segmental endoscopic evaluation, using UCSEI, showed that baseline inflammation tended to be more severe in the distal colon. The baseline UCSEI increased with the extent of disease, which was not seen in MES. Improvements in UCSEI were observed, even in the patients without decreases in the MES. UCSEI, reflecting disease severity and extent of inflammation, provides useful information for UC management that is not available with MES.

Mucosal healing in inflammatory bowel diseases: is there a place for nutritional supplementation?

Advanced mucosal healing (MH) after intestinal mucosal inflammation coincides with sustained clinical remission and reduced rates of hospitalization and surgical resection, explaining why MH is increasingly considered as a full therapeutic goal and as an endpoint for clinical trials. Intestinal MH is a complex phenomenon viewed as a succession of steps necessary to restore tissue structure and function. These steps include epithelial cell migration and proliferation, cell differentiation, restoration of epithelial barrier functions, and modulation of cell apoptosis. Few clinical studies have evaluated the needs for specific macronutrients and micronutrients and their effects on intestinal MH, most data having been obtained from animal and cell studies. These data suggest that supplementation with specific amino acids including arginine, glutamine, glutamate, threonine, methionine, serine, proline, and the amino acid-derived compounds, polyamines can favorably influence MH. Short-chain fatty acids, which are produced by the microbiota from undigested polysaccharides and protein-derived amino acids, also exert beneficial effects on the process of intestinal MH in experimental models. Regarding supplementation with lipids, although the effects of ω-3 and ω-6 fatty acids remain controversial, endogenous prostaglandin synthesis seems to be necessary for MH. Finally, among micronutrients, several vitamin and mineral deficiencies with different frequencies have been observed in patients with inflammatory bowel diseases and supplementation with some of them (vitamin A, vitamin D3, vitamin C, and zinc) are presumed to favor MH. Future work, including clinical studies, should evaluate the efficiency of supplementation with combination of dietary compounds as adjuvant nutritional intervention for MH of the inflamed intestinal mucosa.