Rudolf Mennigen

Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis

Changes in epithelial tight junction protein expression and apoptosis increase epithelial permeability in inflammatory bowel diseases. The effect of the probiotic mixture VSL#3 on the epithelial barrier was studied in dextran sodium sulfate (DSS)-induced colitis in mice. Acute colitis was induced in BALB/c mice (3.5% DSS for 7 days). Mice were treated with either 15 mg VSL#3 or placebo via gastric tube once daily during induction of colitis. Inflammation was assessed by clinical and histological scores. Colonic permeability to Evans blue was measured in vivo. Tight junction protein expression and epithelial apoptotic ratio were studied by immunofluorescence and Western blot. VSL#3 treatment reduced inflammation (histological colitis scores: healthy control 0.94 +/- 0.28, DSS + placebo 14.64 +/- 2.55, DSS + VSL#3 8.43 +/- 1.82; P = 0.011). A pronounced increase in epithelial permeability in acute colitis was completely prevented by VSL#3 therapy [healthy control 0.4 +/- 0.07 (extinction/g), DSS + placebo 5.75 +/- 1.67, DSS + VSL#3 0.26 +/- 0.08; P = 0.003]. In acute colitis, decreased expression and redistribution of the tight junction proteins occludin, zonula occludens-1, and claudin-1, -3, -4, and -5 were observed, whereas VSL#3 therapy prevented these changes. VSL#3 completely prevented the increase of epithelial apoptotic ratio in acute colitis [healthy control 1.58 +/- 0.01 (apoptotic cells/1,000 epithelial cells), DSS + placebo 13.33 +/- 1.29, DSS + VSL#3 1.72 +/- 0.1; P = 0.012]. Probiotic therapy protects the epithelial barrier in acute colitis by preventing 1) decreased tight junction protein expression and 2) increased apoptotic ratio.

Effect of Probiotics on Intestinal Barrier Function

Impairment of the intestinal barrier is a key event in various gastrointestinal diseases, including inflammatory bowel diseases, celiac disease, gastrointestinal infections, diarrhea, and critical illness. Recent studies demonstrated that probiotic bacteria have beneficial effects in these diseases by effectively improving intestinal barrier function. This article reviews available data on the effect of probiotics on intestinal barrier function in vitro, in animal models, and in clinical studies.

Novel treatment options for perforations of the upper gastrointestinal tract: Endoscopic vacuum therapy and over-the-scope clips

Endoscopic management of leakages and perforations of the upper gastrointestinal tract has gained great importance as it avoids the morbidity and mortality of surgical intervention. In the past years, covered self-expanding metal stents were the mainstay of endoscopic therapy. However, two new techniques are now available that enlarge the possibilities of defect closure: endoscopic vacuum therapy (EVT), and over-the-scope clip (OTSC). EVT is performed by mounting a polyurethane sponge on a gastric tube and placing it into the leakage. Continuous suction is applied via the tube resulting in effective drainage of the cavity and the induction of wound healing, comparable to the application of vacuum therapy in cutaneous wounds. The system is changed every 3-5 d. The overall success rate of EVT in the literature ranges from 84% to 100%, with a mean of 90%; only few complications have been reported. OTSCs are loaded on a transparent cap which is mounted on the tip of a standard endoscope. By bringing the edges of the perforation into the cap, by suction or by dedicated devices, such as anchor or twin grasper, the OTSC can be placed to close the perforation. For acute endoscopy associated perforations, the mean success rate is 90% (range: 70%-100%). For other types of perforations (postoperative, other chronic leaks and fistulas) success rates are somewhat lower (68%, and 59%, respectively). Only few complications have been reported. Although first reports are promising, further studies are needed to define the exact role of EVT and OTSC in treatment algorithms of upper gastrointestinal perforations.

Endocytosis and Recycling of Tight Junction Proteins in Inflammation

A critical function of the epithelial lining is to form a barrier that separates luminal contents from the underlying interstitium. This barrier function is primarily regulated by the apical junctional complex (AJC) consisting of tight junctions (TJs) and adherens junctions (AJs) and is compromised under inflammatory conditions. In intestinal epithelial cells, proinflammatory cytokines, for example, interferon-gamma (IFN-γ), induce internalization of TJ proteins by endocytosis. Endocytosed TJ proteins are passed into early and recycling endosomes, suggesting the involvement of recycling of internalized TJ proteins. This review summarizes mechanisms by which TJ proteins under inflammatory conditions are internalized in intestinal epithelial cells and point out comparable mechanism in nonintestinal epithelial cells.

Single-Incision Laparoscopic Surgery for Ileocolic Resection in Crohnʼs Disease

BACKGROUND: Single-incision laparoscopic surgery is a development in the field of minimally invasive surgery that is being increasingly used for colorectal procedures. OBJECTIVE: We report on the short-term results of single-port laparoscopic ileocolic resection in patients with ileocecal Crohns disease. DESIGN: This investigation is a retrospective matched-pair control study. Data were obtained from a prospectively maintained single-institution inflammatory bowel disease database. SETTINGS: This study was conducted at a tertiary care university hospital. PATIENTS: Twenty consecutive patients receiving elective single-port ileocolic resection between April 2010 and May 2011 were included (6 male, 14 female; age, 31.6 ± 10.8 years; BMI, 21.5 ± 2.6 kg/m2). Their data were compared with the data of 20 individually matched patients who had undergone standard 3-trocar laparoscopic-assisted ileocolic resection between 2007 and 2010 (6 male, 14 female; age, 31.7 ± 10.7 years; BMI, 21.2 ± 2.5 kg/m2). All patients had medically refractory stenosis of the terminal ileum in histologically confirmed Crohns disease. INTERVENTIONS: Single-port laparoscopic-assisted or standard laparoscopic-assisted ileocolic resection was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were the surgical details and early outcome. RESULTS: The mean length of the paraumbilical single-port incision was 3.8 cm (range, 2.5–5.0 cm). Conversion rates were similar in both groups (1/20 vs 2/20, p = 0.55). Additional strictureplasties or short-segment small-bowel resections were performed in both groups. The overall complication rate was 20% (4/20) in both groups. There were no observed differences in postoperative pain scores and hospital stay duration. LIMITATIONS: The limitations of this study were as follows: this study was a comparison of 2 different time points with possible selection bias, there was no prestudy power calculation, and the study might be underpowered. CONCLUSIONS: Single-port ileocolic resection is a safe procedure for the surgical treatment of stenotizing Crohns disease of the terminal ileum. Avoidance of additional trocars was the only identified benefit.

Expression of tight and adherens junction proteins in ulcerative colitis associated colorectal carcinoma: upregulation of claudin-1, claudin-3, claudin-4, and β-catenin

BackgroundTight junction (TJ) proteins play a critical role in cellular adhesion, glandular differentiation, and cellular proliferation. The function of these proteins is compromised in a number of intestinal diseases, including ulcerative colitis that has an increased incidence for colorectal carcinoma (CAC). The aim of this study was to determine the expression of TJ proteins, claudin-1–4, occludin, ZO-1, and the adherens junction (AJ) protein β-catenin in CAC.MethodsSixteen colectomy specimens with CAC, adjoining intraepithelial neoplasia, and normal mucosa were studied by immunofluorescence. A semiquantitative evaluation of all investigated proteins was performed by scoring the staining intensity, and the TJ and AJ protein expression in neoplastic cells was compared to normal and intraepithelial neoplastic colonic mucosa.ResultsUsing an intensity scoring system, mucosa of crypts and surfaces of CAC exhibited significantly elevated expression levels of claudin-1, claudin-3, claudin-4, and β-catenin compared to intraepithelial neoplasia and normal mucosa (p < 0.05). These data were confirmed by a comparative score. The expression of claudin-2, occludin, and ZO-1 showed no differences between the groups.ConclusionTJ proteins claudin-1, claudin-3, claudin-4, and the AJ protein β-catenin are overexpressed in CAC. This suggests that these proteins may become potential markers and targets in CAC.

Pouch function and quality of life after successful management of pouch-related septic complications in patients with ulcerative colitis

PurposeRestorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis is associated with pouch-related septic complications (PRSC) in 10% of patients. This study questioned if PRSC have a negative impact on pouch function and quality of life.Patients and methodsOne hundred thirty consecutive patients undergoing IPAA for ulcerative colitis between 1997 and 2009 were reviewed. At 1-year follow-up, patients were asked to complete questionnaires including a pouch function score (Oresland score, 0–16 points, 0 optimum) and two quality of life scores [Short Inflammatory Bowel Disease Questionnaire (SIBDQ), 1–7 points, 7 optimum; Gastrointestinal Quality of Life Index (GIQLI), 0–144 points, 144 optimum].ResultsTwelve out of 130 patients (9.2%) undergoing IPAA developed PRSC. These included anastomotic dehiscence (five), pouch leakage (three, one patient had a combined leak), peripouchal abscess (three), pouch-anal fistula (one), and pouch-vaginal fistula (one). Omission of diverting ileostomy was a risk factor for PRSC (OR 4.62, CI 1.17–18.4). PRSC led to four pouch failures (33%), whereas no failure occurred in the control group (p < 0.001). Median 3 (range, 1–10) further operations were necessary until the pouch was salvaged or definitively lost. If the pouch was salvaged, functional Oresland score (8.2 ± 1.3 vs. 6.6 ± 0.5; p = 0.127), SIBDQ (5.0 ± 0.5 vs. 5.5 ± 0.1; p = 0.203), and GIQLI (95.8 ± 8.4 vs. 107.3 ± 2.6; p = 0.119) were not significantly inferior to uncomplicated controls.ConclusionsIn case of PRSC, even multiple surgical approaches are worthwhile as the outcome of salvaged pouches in terms of function and quality of life is not substantially inferior to patients without septic complications.

The Tripeptide KdPT Protects from Intestinal Inflammation and Maintains Intestinal Barrier Function

Treatment options for inflammatory bowel disease (IBD) are incompletely helpful, and surgery is often needed. One promising class of future therapeutic agents for IBD is melanocortin-related peptides, which exhibit potent immunomodulatory effects. We investigated KdPT, a tripeptide derivative of the C-terminus of α-melanocyte-stimulating hormone, as an anti-inflammatory small molecule in vivo and in vitro. Intestinal inflammation was studied after oral administration of dextran sodium sulfate and in IL-10 gene-deficient mice. The effects of KdPT on key colonic epithelial cell functions were studied in vitro and in vivo by evaluating proliferation, wound healing, transepithelial resistance, and expression of tight junction proteins. Melanin assays were performed to determine the melanotropic effects of KdPT. KdPT-treated animals showed markedly reduced severity of inflammation in both colitis models. In colonic epithelial cells, KdPT increased proliferation, accelerated closure of wounds, and improved transepithelial electrical resistance after stimulation with interferon-γ/tumor necrosis factor-α. Moreover, treatment with KdPT also prevented the loss of tight junction protein expression and improved barrier function in vivo. KdPT acted independently of IL-1 receptor type I in vivo and did not affect melanogenesis in vitro. KdPT is capable of attenuating the course of experimental colitis in different models and maintains epithelial cell function. Furthermore, KdPT does not induce pigmentation, emphasizing the potential of this small molecule for the future treatment of IBD.

Temporary Fecal Diversion in the Management of Colorectal and Perianal Crohn’s Disease

Aim. To evaluate the results of temporary fecal diversion in colorectal and perianal Crohns disease. Method. We retrospectively identified 29 consecutive patients (14 females, 15 males; median age: 30.0 years, range: 18–76) undergoing temporary fecal diversion for colorectal (n = 14), ileal (n = 4), and/or perianal Crohns disease (n = 22). Follow-up was in median 33.0 (3–103) months. Response to fecal diversion, rate of stoma reversal, and relapse rate after stoma reversal were recorded. Results. The response to temporary fecal diversion was complete remission in 4/29 (13.8%), partial remission in 12/29 (41.4%), no change in 7/29 (24.1%), and progress in 6/29 (20.7%). Stoma reversal was performed in 19 out of 25 patients (76%) available for follow-up. Of these, the majority (15/19, 78.9%) needed further surgical therapies for a relapse of the same pathology previously leading to temporary fecal diversion, including colorectal resections (10/19, 52.6%) and creation of a definitive stoma (7/19, 36.8%). At the end of follow-up, only 4/25 patients (16%) had a stable course without the need for further definitive surgery. Conclusion. Temporary fecal diversion can induce remission in otherwise refractory colorectal or perianal Crohns disease, but the chance of enduring remission after stoma reversal is low.

Single-Port Laparoscopic Surgery for Inflammatory Bowel Disease

Background. Single Port Laparoscopic Surgery (SPLS) is being increasingly employed in colorectal surgery for benign and malignant diseases. The particular role for SPLS in inflammatory bowel disease (IBD) has not been determined yet. In this review article we summarize technical aspects and short term results of SPLS resections in patients with Crohns disease or ulcerative colitis. Methods. A systematic review of the literature until January 2012 was performed. Publications were assessed for operative techniques, equipment, surgical results, hospital stay, and readmissions. Results. 34 articles, published between 2010 and 2012, were identified reporting on 301 patients with IBD that underwent surgical treatment in SPLS technique. Surgical procedures included ileocolic resections, sigmoid resections, colectomies with end ileostomy or ileorectal anastomosis, and restorative proctocolectomies with ileum-pouch reconstruction. There was a wide variety in the surgical technique and the employed equipment. The overall complication profile was similar to reports on standard laparoscopic surgery in IBD. Conclusions. In experienced hands, single port laparoscopic surgery appears to be feasible and safe for the surgical treatment of selected patients with IBD. However, evidence from prospective randomized trials is required in order to clarify whether there is a further benefit apart from the avoidance of additional trocar incisions.