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Anti-neuronal autoantibodies can lead to subacute gastrointestinal dysmotility, presenting with various symptoms typical of intestinal pseudoobstruction, achalasia, gastroparesis, or slow intestinal transit, among others. Such autoantibodies may be produced in response to a remote tumor and accelerate the diagnosis of malignancy, but in other cases they appear without an identifiable underlying cause. One example is the type I anti-neuronal nuclear antibody (ANNA-1 otherwise known as anti-Hu), which is usually linked to small cell-lung carcinoma. Anti-Hu can directly activate enteric neurons and visceral sensory nerve fibers and has a cytotoxic effect. Various other anti-neuronal antibodies have been described, targeting different ion channels or receptors on nerve cells of the central or the enteric nervous system. Autoimmune processes targeting enteric neurons may also play a role in more common disorders such as esophageal achalasia, celiac disease, or multiple sclerosis. Furthermore, anti-enteric neuronal antibodies have been found more abundant in the common functional gastrointestinal disorder, irritable bowel syndrome (IBS), than in controls. The pathogenesis of IBS is very complex, involving the release of various mediators from immune cells in the gut wall. Products of mast cells, such as histamine and tryptase, excite visceral afferents and enteric neurons, which may contribute to symptoms like abdominal pain and disturbed motility. Elevated serine- and cysteine-protease activity in stool of IBS-D and IBS-C patients, respectively, can be a factor leading to leaky gut and visceral hypersensitivity. More knowledge on these mediators in IBS may facilitate the development of novel diagnostic methods or therapies.

International audience; Background: Colorectal cancer (CRC) is one of the leading malignancies worldwide, therefore cheap noninvasive screening methods are of great importance. Matrix-metalloproteinase-9 (MMP-9) has a role in the progression of CRC, and its level is elevated in tumour biopsies. Faecal MMP-9 levels are increased in active ulcerative colitis patients, but in CRC patients, they have never been measured. We aimed to assess the faecal MMP-9 levels in patients undergoing total colonoscopy according to endoscopic and histological diagnosis. Methods: One hundred and nine patients provided faecal samples for MMP-9 analysis. A total colonoscopy was performed; suspicious lesions were evaluated by histology. Faecal MMP-9 levels were measured by ELISA. Results: The number of patients allocated to different groups were: negative/diverticulosis: 34 (referred to as controls); hyperplastic polyps: 15; adenomas: 32 (22 at high risk); and CRC: 28. Faecal MMP-9 was significantly increased in CRC compared with all other groups (P

International audience; Background: Ulcerative colitis (UC) is characterized by frequent relapses, with the presence of colorectal inflammation and mucosal lesions. Matrix-metalloprotease 9 (MMP-9) is elevated in colonic biopsies, urine, and blood plasma of UC patients. MMP-9 has been suggested as a predictor of UC in the urine of children; however, 20% of the controls tested positive. So far, fecal MMP-9 levels have never been measured. Our aims were: 1) to compare fecal MMP-9 levels in UC patients to control subjects and a functional gastrointestinal disorder characterized by diarrhea (IBS-D); 2) to test the correlation between UC disease activity and fecal levels of MMP-9; and 3) to correlate fecal MMP-9 levels with a known fecal marker of UC activity, calprotectin. Methods: UC (n = 47), IBS-D (n = 23) patients, and control subjects (n = 24) provided fecal samples for MMP-9 analysis. In UC patients, disease severity was evaluated by the Mayo score. Fecal MMP-9 and calprotectin levels were measured by enzyme-linked immunosorbent assay and lateral flow assay, respectively. Results: MMP-9 was undetectable or

Impairment of the colonic epithelial barrier and neutrophil infiltration are common features of inflammatory bowel disease. Luminal proteases affect colonic permeability through protease-activated receptors (PARs). We evaluated: (i) whether fecal supernatants from patients with ulcerative colitis (UC) trigger alterations of colonic paracellular permeability and inflammation, and (ii) the roles of cathepsin G (Cat-G), a neutrophil serine protease, and its selective receptor, PAR4, in these processes. Expression levels of both PAR4 and Cat-G were determined in colonic biopsies from UC and healthy subjects. The effects of UC fecal supernatants on colonic paracellular permeability were measured in murine colonic strips. Involvement of Cat-G and PAR4 was evaluated using pepducin P4pal-10 and specific Cat-G inhibitor (SCGI), respectively. In addition, the effect of PAR4-activating peptide was assessed. UC fecal supernatants, either untreated or pretreated with SCGI, were infused into mice, and myeloperoxidase activity was determined. PAR4 was found to be overexpressed in UC colonic biopsies. Increased colonic paracellular permeability that was triggered by UC fecal supernatants was blocked by both SCGI (77%) and P4pal-10 (85%). Intracolonic infusion of UC fecal supernatants into mice increased myeloperoxidase activity. This effect was abolished by SCGI. These observations support that both Cat-G and PAR4 play key roles in generating and/or amplifying relapses in UC and provide a rationale for the development of new therapeutic agents in the treatment of this disease.

Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory disorders, which require long term treatment to achieve remission and to prevent relapses and cancer. While current therapies are effective in most cases, they can have rare but serious side effects and are often associated with high costs. On the other hand, early discontinuation of an effective treatment may lead to a quick relapse and to complications at the restart of therapy. Therefore it is essential to determine the optimal duration of maintenance therapy, but clear guidelines are missing. The most important questions when deciding whether to continue or withdraw therapy in quiescent UC and CD patients are the efficacy of the continuous treatment to maintain remission in the long term, the frequency and severity of side effects, and the chance of relapse after discontinuation of therapy. This review summarizes the current knowledge on these topics with respect to 5-aminosalicylates, thiopurines, methotrexate, and biological therapies and collects information regarding when and in which specific patient groups, in the absence of risk factors, can withdrawal of therapy be considered without a high risk of relapse. Additionally, the particular aspect of colorectal cancer prevention by current therapies will also be discussed.

A 19-year-old man with a 1-year history of ulcerative colitis presented with fever, bloody diarrhea and severe dehidration. He was on po.48 mg methylprednisolon and 3 g mesalazine daily, and has recently finished taking chlarythromycin for Campylobacter jejuni infection. On physical examination, no abdominal tenderness was found, but surprisingly, extensive bilateral subcutaneous emphysema was detected in the supraclavicular regions. Laboratory tests proved anaemia, elevated white blood cell count, thrombocyte count and CRP levels. Stool culture was negative. Chest X-ray and CT scan revealed pneumomediastinum and subcutaneous air on the neck spreading to the scapular regions. Besides blood transfusion, iv. cyclosporin therapy was initiated (200 mg/day) along with iv. methylprednisolon (1mg/kg/day) and iv. ceftriaxon (2 g/day). Stool frequency and bloody stools decreased remarkably within one week, and subcutaneous emphysema has resolved. Colonoscopy one week later revealed deep, extensive ulcerations in the transverse and descending colon without any sign of previous perforation. Cyclosporin and methylprednisolon was continued orally. Pneumomediastinum and subcutaneous emphysema in ulcerative colitis are unusual complications, typically linked to retroperitoneal colonic perforation or toxic megacolon, and are extremely rare without preceding endoscopic procedures. Except from two cases in the literature, conservative treatment with iv. antibiotics and steroids failed to save from urgent surgical procedure, resulting in a partial or total colectomy. In our case we were able to avoid urgent surgery by the immediate use of iv. cyclosporin in combination with iv. steroids and antibiotics, while the outcome of the bowel remains questionable in the next few months.

Background: Only limited data are available regarding the diagnostic accuracy of fecal matrix metalloprotease-9 [MMP-9] for inflammatory bowel disease [IBD]. The aims of our study were to assess the diagnostic accuracy of fecal MMP-9 in patients with active Crohn’s disease [CD], ulcerative colitis [UC], and pouchitis, and to compare the diagnostic accuracy of fecal MMP-9 and fecal calprotectin [CP] in IBD. Methods Stool and blood samples were collected in 50 CD, 54 UC, and 34 ileal pouch-anal anastomosis patients before control endoscopies were performed. Biopsies were taken for histologic purposes. The activities of CD, UC, and pouchitis were defined with the use of clinical, endoscopic, and histologic activity scores. Fecal CP and MMP-9 levels were quantified by enzyme-linked immunosorbent assay. Results Active CD, UC, and pouchitis were detected in 38%, 54%, and 29% of the patients, respectively. A significant correlation was revealed between fecal CP and the clinical activities of CD and UC, and between fecal CP and the endoscopic activity of UC and pouchitis. Fecal MMP-9 did not correlate with any of the activity indices of CD; however, strong associations were shown between fecal MMP-9 and clinical, endoscopic, and histologic activities of both UC and pouchitis. Conclusions This is the first study assessing the diagnostic accuracy of MMP-9 in different types of IBD. Our results showed that fecal MMP-9 has high sensitivity in the detection of endoscopically active UC and pouchitis. These non-invasive methods help assess intestinal inflammation.

Irritable bowel syndrome (IBS) is a long-lasting, relapsing disorder characterized by abdominal pain/discomfort and altered bowel habits. Intestinal motility impairment and visceral hypersensitivity are the key factors among its multifactorial pathogenesis, both of which require effective treatment. Voltage-gated calcium channels mediate smooth muscle contraction and endocrine secretion and play important roles in neuronal transmission. Antispasmodics are a group of drugs that have been used in the treatment of IBS for decades. Alverine citrate, a spasmolytic, decreases the sensitivity of smooth muscle contractile proteins to calcium, and it is a selective 5-HT1A receptor antagonist. Alverine, in combination with simethicone, has been demonstrated to effectively reduce abdominal pain and discomfort in a large placebo-controlled trial. Mebeverine is a musculotropic agent that potently blocks intestinal peristalsis. Non-placebo-controlled trials have shown positive effects of mebeverine in IBS regarding symptom control; nevertheless, in recent placebo-controlled studies, mebeverine did not exhibit superiority over placebo. Otilonium bromide is poorly absorbed from the GI tract, where it acts locally as an L-type calcium channel blocker, an antimuscarinic and a tachykinin NK2 receptor antagonist. Otilonium has effectively reduced pain and improved defecation alterations in placebo-controlled trials in IBS patients. Pinaverium bromide is also an L-type calcium channel blocker that acts locally in the GI tract. Pinaverium improves motility disorders and consequently reduces stool problems in IBS patients. Phloroglucinol and trimethylphloroglucinol are non-specific antispasmodics that reduced pain in IBS patients in a placebo-controlled trial. Antispasmodics have excellent safety profiles. T-type calcium channel blockers can abolish visceral hypersensitivity in animal models, which makes them potential candidates for the development of novel therapeutic agents in the treatment of IBS.

The pathogenesis of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD) is complex, and our knowledge on the topic is constantly growing. The two disorders are distinct, yet overlap in their clinical manifestations and underlying causes. This review aims to provide a broad overview of the numerous pathogenetic factors that can lead to the development of IBD, focusing on novel findings and on the differences between UC and CD. Recent advances in genetics have identified new components in the pathogenesis, as an example, the importance of Th17 lymphocytes and the IL-17/IL-23 pathway have been highlighted in both diseases, apart from the previously known Th1-Th2 driven processes. Genetic background of increased permeability has been explored in UC, and the role of defective autophagy was recently described in CD. Genetic alterations can lead to an exaggerated immune response to the resident microbial flora. This microflora is altered in IBD patients, probably due to their reduced ability to stabilize its bacterial components and due to different environmental factors. An exhaustive exploration of environmental factors is particularly important, as they can be influential in many cases. The impact of smoking is the most established environmental factor, having deleterious effects in CD and protective in UC. Recent opinions on other factors, such as early appendectomy, diet, reduced vitamin D levels, the use of specific medications, breastfeeding, personal hygiene and psychological factors are also discussed. Epigenetics, a new field of research, links environmental factors to genetics. Understanding these factors is of great significance as changing lifestyles and improving life circumstances have started to increase the prevalence of IBD also in developing countries.

Background/Aims: Defective epithelial barrier has been implicated in the pathogenesis of irritable bowel syndrome (IBS) and inflammatory bowel diseases. The aim of this study was to investigate gut permeability in patients with inactive ulcerative colitis (UC) and in patients with IBS. Methods: IBS patients of the diarrhea-predominant (IBS-D) and of the constipation-predominant subgroup (IBS-C), patients with inactive UC and healthy subjects were enrolled. Gut permeability was evaluated by measuring 24-hour urine excretion of orally administered 51Cr-EDTA. Clinical symptoms were evaluated in IBS-D patients and correlated to colonic permeability. Results: There was a significant decrease in the proximal small intestinal permeability in IBS-C patients compared to controls (0.26 ± 0.05 vs. 0.63 ± 0.1%; p < 0.05). Distal small intestinal permeability showed no significant difference in the studied group of patients compared to controls. Colonic permeability of IBS-D and inactive UC patients was significantly increased compared to controls (2.68 ± 0.35 and 3.74 ± 0.49 vs. 1.04 ± 0.18%; p < 0.05, p < 0.001). Colonic permeability of IBS-D patients correlated with stool frequency. Conclusions: Elevated gut permeability is localized to the colon both in IBS-D and in inactive UC patients.

Background: Cathepsin G (Cat-G) is a neutrophil serine-protease found in the colonic lumen of ulcerative colitis (UC) patients. Cat-G is able to activate protease-activated receptor-4 (PAR4) located at the apical side of enterocytes, leading to epithelial barrier disruption. However, the mechanisms through which Cat-G triggers inflammation are not fully elucidated. The aims of our study were to evaluate in vivo the effects of UC fecal supernatants and Cat-G on epithelial barrier function and inflammation, and the connection between these two parameters. Methods: Male balb/c mice were used in this study. We evaluated the effect of a 2-hour intracolonic infusion of 1) fecal supernatants from UC patients pretreated or not with specific Cat-G inhibitor (SCGI); 2) PAR4-activating peptide (PAR4-AP); and 3) Cat-G on colonic myeloperoxidase (MPO) activity and paracellular permeability (CPP). The involvement of PAR4 was assessed by pretreating animals with pepducin P4pal-10, which blocks PAR4 signaling. We investigated the role of myosin light chain (MLC) kinase by using its inhibitor, ML-7, and we determined phosphorylated MLC (pMLC) levels in mice colonic mucosa. Results: UC fecal supernatants, Cat-G, and PAR4 agonist increased both CPP and MPO activity in comparison with healthy subjects fecal supernatants. ML-7 inhibited the CPP increase triggered by Cat-G by 92.3%, and the enhanced MPO activity by 43.8%. Intracolonic infusion of UC fecal supernatant determined an increased phosphorylation level of MLC. Conclusions: These observations support that luminal factors such as Cat-G play an important proinflammatory role in the pathogenesis of colitis, mainly depending on CPP increase by MLC phosphorylation. (Inflamm Bowel Dis 2011)

A szisztémás amyloidosis gyakran érinti a gastrointestinalis rendszert fekély vagy polypoid elváltozás formájában, a vastagbelet körkörösen szűkítő folyamat azonban különösen ritka. Amyloidosis előfordulása a λ-könnyűláncot termelő myeloma multiplexes betegek kb. 10%-ában várható, szövettanilag AL típusú. A hematológiai betegség diagnózisa azonban szinte minden esetben megelőzi a gastrointestinalis tünetek jelentkezését. Esetismertetés: Egy 73 éves nőbeteget anémia, hasi fájdalom, haematochesia miatt vizsgáltunk. A kolonoszkópia során körkörös sigmabélstenosis igazolódott, mely neoplasia gyanúját vetette fel. A szűkület megoldására sigmaresectio történt rectosigmoidealis anastomosissal. A resecatum szövettani vizsgálata AA-amyloidosist állapított meg. A kivizsgálás során a subcutan zsírszöveti biopszia szisztémás amyloidosis lehetőségét vetette fel. Az immunelektroforézis emelkedett gamma-globulin-frakciót, ezen belül IgG-λ-monoclonalis komponenst és egy másik λ-típusú könnyűlánckomponenst állapított meg. Ezért Jamshidi-biopszia történt, mely myeloma multiplexet igazolt. Következtetések: Betegünknél a ritka, vastagbelet obstruáló, tumort utánzó bélfali amyloidosis vezetett el a myeloma multiplex diagnózisához. A hematológiai kórkép célzott kezelése mellett ilyen esetben szükséges lehet a körülírt szűkület endoszkópos stentelése vagy a sebészi terápia.

Background Probiotics are live microorganisms that promote gut health and regulate intestinal homeostasis. How probiotics work is incompletely understood, but may involve induction of cell survival pathways (Akt) and stress/MAP kinase-dependent induction of heat shock proteins. The possibility that probiotics might induce autophagy, however, has not been previously explored. Autophagy is believed to have an important role in promoting cell survival under conditions of stress and in clearance of potentially disease-causing intracellular microorganisms. Polymorphisms in autophagy genes have recently been linked to increased risk of human IBD. Methods Intestinal epithelial cells (human colonic Caco2BBE or rat jejunal IEC18) were treated with conditioned media from Bifidobacterium breve (BB-CM) or other intestinal bacteria (Lactobacillus plantarum, Lactobacillus rhamnosus GG). Initially time dependence was determined using 1% CM and subsequently concentration dependence was determined at 30 or 120 min and 24 hours for rapid transduction events (MAP kinase, LC3 conjugation, or Akt activation) versus long lived cellular survival proteins (heat shock protein induction), all assessed by Western blot analysis. Results BB-CM induced autophagy in a timeand concentration-dependent manner. Western blot analysis demonstrated LC3II activation by conjugation to phosphatidylethanolamine by 120 min after BB-CM. BB-CM also activated p38 MAP kinase and ERK1/2, but within 30 min of addition. Both Lactobacillus plantarum and LGG-CM also stimulated LC3, thereby demonstrating stimulation of autophagy. For BB-CM, inhibition of either p38 MAP kinase with SB203580 ort ERK1/2 activation with PD98059 blocked LC3 activation. A wider panel of gram positive and gram negative bacteria were tested only on LC3 activation and while most gram positive bacteria stimulated LC3 activation, most gram negative did not. Conclusions These studies provide evidence that bioactive agents secreted by probiotic and commensal bacteria can induce autophagy in gut epithelial cells. The induction of autophagy may underlie some of the beneficial clinical effects attributed to a healthy enteric microbiota and probiotic agents.

10+3 sec vs 250+20 sec; P 0.05). Microdialysis of the glutamate NMDA receptor antagonist AP5 (100 μM) into the ACC before but not after conditioning (CPD), blocked the acquisition of CPA learning (-2+0.5 sec vs 200+5 sec sham control; P

Introduction: Patients with IBD show higher thresholds to slow ramp distension of the rectum, as opposed to patients with a diarrhea-predominant IBS (IBS-D). Recently we have found elevated serine protease (SerP) activities in both IBS-D and ulcerative colitis (UC) fecal materials. In mice, intracolonic (IC) infusion of fecal IBS-D supernatants evokes a proteinase-activated receptor (PAR)-2 mediated colonic hypersensitivity to distension. Objectives: Our aims were to evaluate the influence of fecal supernatant from UC patients on visceral sensitivity in mice and to test the involvement of PAR-4, and its activator cathepsin G (cat-G) as possible mediators in this nociceptive response. Methods: Fecal samples from UC patients and healthy subjects were dissolved in saline, centrifuged and filtered. Under anaesthesia electrodes were inserted in the abdominal muscle to record abdominal cramps in C57/BL6 male mice. Four days after surgery mice were IC infused with 0.3 mL fecal supernatant from UC patients or controls, and colorectal distensions (CRD) were performed using a balloon inflated from 0 to 0.12 mL each steps lasting 10 sec with 5 min intervals. To evaluate the role of PAR-4, micewere treatedwith a PAR-4 antagonist (P4pal-10, pepducin, 3x0.25 mg/kg) IP before and during UC supernatant infusion. The participation of cat-G was assessed by incubating the UC supernatant with a mixture of antiproteases (aprotinin and SBTI, 0.22 and 1.70 mg/mL respectively) or with a cat-G inhibitor (0.057 mg/mL). The effect of PAR-4 activation or cat-G was tested by IC infusion of 100 ug PAR-4 agonist (PAR4AP, 0.667mg/mL) or 0.025 UN cat-G (0.167UN/mL). Results: IC infusion of UC supernatants decreased the intensity of abdominal EMG response by 71%, 49% and 35% for 0.04, 0.06 and 0.08 mL of CRD (p