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While irritable bowel syndrome (IBS) is still considered a ‘disorder of gut function’ and is diagnosed on the basis of symptoms, evidence is growing to indicate the existence of biochemical, molecular, immune, and microbiological abnormalities in large subsets of patients. According to the current view, luminal factors (e.g. derived from food, microbiota, and bile acids) permeate into the mucosa through a leaky epithelial barrier. These substances elicit abnormal responses, partly related to the activation of the immune system, which evoke altered neuro-muscular responses and stimulation of pain pathways. This research is providing a new way of thinking about the pathophysiology of IBS and will potentially lead to the development of novel treatments for these common disorders.

Alcohol is considered the most important risk factor for the development of chronic pancreatitis. The possibility of evaluating CFTR mutations and the discovery of other gene mutations has led to a better evaluation of the familiar/hereditary forms of chronic pancreatitis and the identification of autoimmune pancreatitis has further improved our knowledge of the disease. However, recent studies on chronic pancreatitis on a worldwide level reveal an increase in the idiopathic forms of the disease. Clinicians must pay greater attention to identifying the factors associated with chronic pancreatitis.

Summary: Irritable bowel syndrome (IBS), a common functional gastrointestinal disorder, is classified according to bowel habits as IBS with constipation (IBS‐C), with diarrhea (IBS‐D), with alternating constipation and diarrhea (IBS‐M), and unsubtyped (IBS‐U). The mechanisms leading to the different IBS forms are mostly unknown. This study aims to evaluate whether specific fecal bacterial taxa and/or short‐chain fatty acids (SCFAs) can be used to distinguish IBS subtypes and are relevant for explaining the clinical differences between IBS subcategories. We characterized five fecal samples collected at 4‐weeks intervals from 40 IBS patients by 16S rRNA gene profiling and SCFA quantification. Finally, we investigated the potential correlations in IBS subtypes between the fecal microbial signatures and host physiological and clinical parameters. We found significant differences in the distribution of Clostridiales OTUs among IBS subtypes and reduced levels of SCFAs in IBS‐C compared to IBS‐U and IBS‐D patients. Correlation analyses showed that the diverse representation of Clostridiales OTUs between IBS subtypes was associated with altered levels of SCFAs; furthermore, the same OTUs and SCFAs were associated with the fecal cytokine levels and stool consistency. Our results suggest that intestinal Clostridiales and SCFAs might serve as potential mechanistic biomarkers of IBS subtypes and represent therapeutic targets. [ABSTRACT FROM AUTHOR]

Background Intestinal immune activation is involved in irritable bowel syndrome ( IBS) pathophysiology. While most dietary approaches in IBS involve food avoidance, there are fewer indications on food supplementation. Palmithoylethanolamide, structurally related to the endocannabinoid anandamide, and polydatin are dietary compounds which act synergistically to reduce mast cell activation. Aim To assess the effect on mast cell count and the efficacy of palmithoylethanolamide/polydatin in patients with IBS. Methods We conducted a pilot, 12-week, randomised, double-blind, placebo-controlled, multicentre study assessing the effect of palmithoylethanolamide/polydatin 200 mg/20 mg or placebo b.d. on low-grade immune activation, endocannabinoid system and symptoms in IBS patients. Biopsy samples, obtained at screening visit and at the end of the study, were analysed by immunohistochemistry, enzyme-linked immunoassay, liquid chromatography and Western blot. Results A total of 54 patients with IBS and 12 healthy controls were enrolled from five European centres. Compared with controls, IBS patients showed higher mucosal mast cell counts (3.2 ± 1.3 vs. 5.3 ± 2.7%, P = 0.013), reduced fatty acid amide oleoylethanolamide (12.7 ± 9.8 vs. 45.8 ± 55.6 pmol/mg, P = 0.002) and increased expression of cannabinoid receptor 2 (0.7 ± 0.1 vs. 1.0 ± 0.8, P = 0.012). The treatment did not significantly modify IBS biological profile, including mast cell count. Compared with placebo, palmithoylethanolamide/polydatin markedly improved abdominal pain severity ( P < 0.05). Conclusions The marked effect of the dietary supplement palmithoylethanolamide/polydatin on abdominal pain in patients with IBS suggests that this is a promising natural approach for pain management in this condition. Further studies are now required to elucidate the mechanism of action of palmithoylethanolamide/polydatin in IBS. ClinicalTrials.gov number, NCT01370720. [ABSTRACT FROM AUTHOR]

Mucosal immune activation and altered serotonin metabolism participate in the pathophysiology of irritable bowel syndrome (IBS). However, the reciprocal interplay between these two systems remains unknown. We evaluated the expression and release of interferon (IFN)-γ from the colonic mucosa of patients with IBS and its impact on serotonin reuptake transporter (SERT) gene expression in Caco-2 cells. qPCR was used to evaluate IFN-γ gene expression in colonic mucosal biopsies, whereas IFN-γ protein amount was assessed by ELISA. Colonic T box expressed in T cells (T-bet) and phosphorylated signal transducer and activator of transcription 4 protein amount were evaluated by Western blot. The impact of colonic mucosal mediators on SERT gene expression was evaluated in Caco-2 cells using qPCR. IFN-γ receptor was silenced in Caco-2 cells to determine the effect of IFN-γ released by mucosal biopsies. Compared with asymptomatic controls (ACs), the expression of IFN-γ gene and its transcription factor T-bet were markedly increased in the colonic mucosa of patients with IBS. Compared with ACs, IFN-γ protein tissue levels and its release by mucosal biopsies were significantly increased in IBS. The exposure of Caco-2 cells to IBS supernatants induced a significant decrease in SERT gene expression, independently of IBS subtypes, compared with AC mucosal supernatants. In Caco-2 cells, IFN-γ receptor silencing reversed the reduction of SERT expression evoked by IBS supernatants vs. nonsilenced cell lines. IFN-γ gene, its transcription factor T-bet, IFN-γ protein expression, and its release are increased in the colonic mucosa of patients with IBS and downregulate SERT gene expression in vitro. These results suggest that IFN-γ downregulates SERT expression, hence likely playing a role in altered serotonin metabolism of patients with IBS. [ABSTRACT FROM AUTHOR]

Objective: Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. Design: We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/ discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. Results: A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. Conclusions: Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. [ABSTRACT FROM AUTHOR]

Objective: We wished to observe the prevalence of tinnitus in subjects on therapy with proton pump inhibitors (PPI). A possible favourable effect of the commercially available proton pump inhibitors (PPI) on inner ear disorders was recently outlined. In order to investigate this possibility the prevalence of tinnitus (an indicator of labyrinthine sufferance in general terms) among PPI users and non-users was analysed. Study design: An observational study on the prevalence of tinnitus among PPI users and non-users was carried out. Between June 2012 and March 2013 a cohort of consecutive patients who were referred to S. Orsola-Malpighi University Hospital of Bologna for various non-audiological disorders was included in the study. Each patient was instructed to complete an anonymous validated questionnaire on hearing problems. The Ethics Committee of S. Orsola Malpighi Hospital had been informed about collection of the data. Results: In the age class 60-69 years there was a statistically significant lower prevalence of non-specified tinnitus in PPI users, compared to non-users. Conclusion: Even if a favourable effect on this symptom derived from the treatment of gastroesophageal reflux cannot be excluded, a direct regulatory effect on inner ear homeostasis, through the action of PPI on the gastric type proton pump of the inner ear, cannot be ruled out. Another possible effect could depend upon vasomotor activity enabling better peripheral perfusion without significantly modifying blood pressure values, thus contributing to the stabilization of inner ear oxygenation. Additionally, a certain degree of anti-inflammatory effect could yield another kind of non-specific favourable influx. In conclusion, even if the supposed benefit deriving from the use of PPI in treating inner ear affections of unknown origin is still unclear with regard to its significance and limits, the reported results demonstrate that longitudinal studies could be useful in order to verify the possibility of a new therapeutic perspective. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Immune activation may be involved in the pathogenesis of irritable bowel syndrome (IBS). However, the relative magnitude of this immune component and its correlation with gender and gastrointestinal complaints in IBS patients remains poorly elucidated.METHODS:We enrolled 48 IBS patients, with either diarrhea or constipation, 12 patients with microscopic colitis, 20 patients with ulcerative colitis, and 24 healthy controls. Colonic immunocytes were identified with quantitative immunohistochemistry on mucosal biopsies. Gastrointestinal symptoms were assessed using a validated questionnaire.RESULTS:IBS patients showed a significant 72% increase in mucosal immune cells compared to controls (P<0.001). Further analyses showed that increased immune cells were present in 50% of the IBS patients. The magnitude of the immune infiltrate in IBS was significantly lower than that of microscopic colitis or ulcerative colitis (42% and 124% increases vs. IBS, respectively; P<0.001). Compared with controls, IBS patients had increased numbers of CD3+, CD4+, and CD8+ T cells and mast cells (P<0.001). Compared to male IBS patients, female IBS patients had greater numbers of mast cells (P=0.066), but lower numbers of CD3+ and CD8+ T cells (P=0.002 and <0.001, respectively). Mucosal mast cell infiltration of IBS patients was significantly associated with abdominal bloating frequency (P=0.022) and with symptoms of dysmotility-like dyspepsia (P=0.001), but not ulcer-like dyspepsia.CONCLUSIONS:A large subset of IBS patients shows gender-dependent mucosal infiltration of immunocytes that correlates with abdominal bloating and dysmotility-like dyspepsia. These results provide the rationale for considering immune mechanisms as a pathophysiological component in a subset of IBS patients.Am J Gastroenterol 2009; 104:392–400; doi:10.1038/ajg.2008.94; published online 13 January 2009 [ABSTRACT FROM AUTHOR]

Background: Gastroparesis is a digestive syndrome characterized by delayed gastric emptying (GE) and by symptoms that are suggestive of gastroduodenal motor disorders. There are three grades of gastroparesis of increasing severity: (a) mild gastroparesis; (b) compensated gastroparesis; and (c) gastric failure. GE abnormalities are partially related to symptom type and severity, and other mechanisms may be involved. Aim: To investigate enteric dysmotility (ED) in patients with suspected gastroparesis. Methods: Patients with symptoms suggestive of gastroparesis were consecutively included in the study and underwent a 13C‐octanoic acid GE breath test and small bowel manometry (SBM). Clinical features were recorded using predefined, validated questionnaires at entry. Key Results: The study enrolled 88 patients (71 women; mean age: 37.8 ± 14.3 years). Gastric emptying was delayed in 25 patients (28.4%), and 70 patients (79.5%) presented small bowel motor abnormalities including bursts, abnormal activity fronts, inability to respond to meal ingestion, and hypocontractility. Gastric emptying was delayed in 24 of the 70 patients with ED (34.3% vs 5.5% of patients with normal SBM). Enteric dysmotility was detected in 24 of 25 patients (96%) with delayed GE. Patients with and without delayed GE showed similar moderate/severe gastroparesis manifestations, but patients with ED significantly more often had moderate/severe gastroparesis manifestations than patients with normal SBM (grade 1:14% vs 39%, grade 2:62% vs 56%, grade 3:24% vs 5%, respectively). Conclusions and Inferences: Enteric dysmotility was more frequent than delayed GE in patients with symptoms suggestive of gastroparesis. Gastroparesis severity was associated with small bowel motor abnormalities but not with delayed GE. [ABSTRACT FROM AUTHOR]