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Background: Butyrate has shown anti‐inflammatory and regenerative properties, providing symptomatic relief when orally supplemented in patients suffering from various colonic diseases. We investigated the effect of a colonic‐delivery formulation of butyrate on the fecal microbiota of patients with inflammatory bowel diseases (IBDs). Methods: In this double‐blind, placebo‐controlled, pilot study, 49 IBD patients (n = 19 Crohn's disease, CD and n = 30 ulcerative colitis, UC) were randomized to oral administration of microencapsulated‐sodium‐butyrate (BLM) or placebo for 2 months, in addition to conventional therapy. Eighteen healthy volunteers (HVs) were recruited to provide a healthy microbiota model of the local people. Fecal microbiota from stool samples was assessed by 16S sequencing. Clinical disease activity and quality of life (QoL) were evaluated before and after treatment. Key Results: At baseline, HVs showed a different microbiota composition compared with IBD patients. Sodium‐butyrate altered the gut microbiota of IBD patients by increasing bacteria able to produce SCFA in UC patients (Lachnospiraceae spp.) and the butyrogenic colonic bacteria in CD patients (Butyricicoccus). In UC patients, QoL was positively affected by treatment. Conclusions and Inferences: Sodium‐butyrate supplementation increases the growth of bacteria able to produce SCFA with potentially anti‐inflammatory action. The clinical impact of this finding requires further investigation. [ABSTRACT FROM AUTHOR]

Background and Aims: Steroid-dependency occurs in up to 30% of patients with ulcerative colitis [UC]. In this setting, few drugs have demonstrated efficacy in inducing steroid-free remission. The aim of this study was to evaluate the efficacy and safety of adding granulocyte/monocyte apheresis [GMA] to oral prednisone in patients with steroid-dependent UC. Methods: This was a randomized, multicentre, open trial comparing 7 weekly sessions of GMA plus oral prednisone [40 mg/day and tapering] with prednisone alone, in patients with active, steroid-dependent UC [Mayo score 4-10 and inability to withdraw corticosteroids in 3 months or relapse within the first 3 months after discontinuation]. Patients were stratified by concomitant use of thiopurines at inclusion. A 9-week tapering schedule of prednisone was pre-established in both study groups. The primary endpoint was steroid-free remission [defined as a total Mayo score ≤2, with no subscore >1] at Week 24, with no re-introduction of corticosteroids. Results: In all 123 patients were included [63 GMA group, 62 prednisone alone]. In the intentionto-treat analysis, steroid-free remission at Week 24 was achieved in 13% (95% confidence interval [CI] 6-24) in the GMA group and 7% [95% CI 2-16] in the control group [p = 0.11]. In the GMA group, time to relapse was significantly longer (hazard ratio [HR] 1.7 [1.16-2.48], P = 0.005) and steroidrelated adverse events were significantly lower [6% vs 20%, P < 0.05]. Conclusions: In a randomized trial, the addition of 7 weekly sessions of GMA to a conventional course of oral prednisone did not increase the proportion of steroid-free remissions in patients with active steroid-dependent UC, though it delayed clinical relapse. [ABSTRACT FROM AUTHOR]

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Background & Aims: In the intestines, Toll-like receptor 2 (TLR2) mediates immune responses to pathogens and regulates epithelial barrier function; polymorphisms in TLR2 have been associated with inflammatory bowel disease phenotype. We assessed the effects of TLR2 signaling on the enteric nervous system (ENS) in mice. Methods: TLR2 distribution and function in the ileal neuromuscular layer of mice were determined by immunofluorescence, cytofluorimetric analysis, immunoprecipitation, and immunoblot analyses. We assessed morphology and function of the ENS in Tlr2 −/− mice and in mice with wild-type Tlr2 (wild-type mice) depleted of intestinal microbiota, using immunofluorescence, immunoblot, and gastrointestinal motility assays. Levels and signaling of glial cell line−derived neurotrophic factor (GDNF) were determined using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and immunoprecipitation analyses. Colitis was induced by administration of dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid to Tlr2 −/− mice after termination of GDNF administration. Results: TLR2 was expressed in enteric neurons, glia, and smooth muscle cells of the intestinal wall. Tlr2 −/− mice had alterations in ENS architecture and neurochemical profile, intestinal dysmotility, abnormal mucosal secretion, reduced levels of GDNF in smooth muscle cells, and impaired signaling via Ret−GFRα1. ENS structural and functional anomalies were completely corrected by administration of GDNF to Tlr2 −/− mice. Wild-type mice depleted of intestinal microbiota had ENS defects and GDNF deficiency, similar to Tlr2 −/− mice; these defects were partially restored by administration of a TLR2 agonist. Tlr2 −/− mice developed more severe colitis than wild-type mice after administration of dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid; colitis was not more severe if Tlr2 −/− mice were given GDNF before dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid. Conclusions: In mice, TLR2 signaling regulates intestinal inflammation by controlling ENS structure and neurochemical coding, along with intestinal neuromuscular function. These findings provide information as to how defective TLR2 signaling in the ENS affects inflammatory bowel disease phenotype in humans. [Copyright &y& Elsevier]

Background: An imbalance in gut microbiota seems to contribute to the development of chronic inflammatory disorders of the gastrointestinal tract, such as ulcerative colitis (UC). Although it has been suggested that probiotic supplementation is an effective approach to colitis, its effects on intestinal flora and on mucosal cytokine balance have never been explored.Aim: To evaluate the effect of Lactobacillus casei (L. casei) DG, a probiotic strain, on colonic-associated microbiota, mucosal cytokine balance, and toll-like receptor (TLR) expression.Methods: Twenty-six patients with mild left-sided UC were randomly allocated to one of three groups for an 8-week treatment period: the first group of 7 patients received oral 5-aminosalicylic acid (5-ASA) alone, the second group of 8 patients received oral 5-ASA plus oral L. casei DG, and the third group of 11 patients received oral 5-ASA and rectal L. casei DG. Biopsies were collected from the sigmoid region to culture mucosal-associated microbes and to assess cytokine and TLR messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (RT-PCR).Results: 5-ASA alone or together with oral L. casei DG failed to affect colonic flora and TLR expression in a significant manner, but when coupled with rectally administered L. casei DG, it modified colonic microbiota by increasing Lactobacillus spp. and reducing Enterobacteriaceae. It also significantly reduced TLR-4 and interleukin (IL)-1β mRNA levels and significantly increased mucosal IL-10.Conclusions: Manipulation of mucosal microbiota by L. casei DG and its effects on the mucosal immune system seem to be required to mediate the beneficial activities of probiotics in UC patients. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Intestinal inflammation is associated with enteric nervous system alterations, at both inflamed and non-inflamed sites. The perception of stimuli from the GI tract is enhanced during inflammatory conditions, but it is unknown whether visceral hypersensitivity is limited to the inflamed area or diffuse throughout the entire GI tract. Moreover, although stress can reactivate inflammatory processes in the gut, it is unknown if this can alter perception from the GI tract. Our aim was to determine if patients with ulcerative colitis (UC) have increased esophageal sensitivity to distention and whether this is modified by experimental stress. METHODS: Ten UC patients and 12 healthy volunteers (HVs) underwent gradual balloon distension of the esophagus to assess their visceral sensitivity. Perceptive and pain thresholds were evaluated in basal conditions and after induction of experimental stress (cold water pressure test) while blood pressure and heart rate were monitored. RESULTS: Patients with UC bad perceptive thresholds to distension similar to HVs (14.08 ± 2.0 ml of air vs 14.5 ± 3.0 ml); in contrast, the volume increment needed to evoke pain was significantly lower in UC patients than in HVs (58.9% vs 149.9%, p < 0.05). Physical stress caused a similar decrease in perceptive thresholds in HVs (- 29.1 ± 8.4%) and patients (- 17.7 ± 9.1%), but pain thresholds were significantly decreased only in HVs (- 28.3 ± 7.1% vs - 11.5 ± 12.3%). CONCLUSIONS: UC is characterized by increased esophageal sensitivity, indicating the existence of diffuse hyperalgesia during intestinal inflammatory processes. This increased sensitivity may account for the frequent upper GI symptoms these patients complain of when in clinical remission. [ABSTRACT FROM AUTHOR]

IBD98-M is a delayed-release formulation of mesalamine (mesalazine) and SH with a potential therapeutic role in ulcerative colitis (UC). A total of 51 patients with a modified Ulcerative Colitis Disease Activity Index (UCDAI) score of ≥4 and ≤10, and a modified UCDAI endoscopy subscore ≥1 were randomized for 6 weeks of double-blind treatment with IBD98 0.8 g/day or IBD 1.2 g/day or placebo. The efficacy and safety of IBD98-M in mild to moderate active UC were primarily evaluated. At week 6, 1 (5.9%), 2 (12.5%), and 2 (11.1%) patients receiving IBD98-M 0.8 g, IBD98-M 1.2 g, and placebo, respectively, (p > 0.999) achieved clinical remission. Higher clinical response was seen in IBD98-M 1.2 g (31.3%) versus placebo (16.7%) and endoscopic improvement in IBD98-M 0.8 g (29.4%) versus placebo (22.2%) was seen. Fecal calprotectin levels were reduced in IBD98-M groups versus placebo (p > 0.05). IBD98-M patients achieved significant improvement in physical health summary score component of the SF-36 (p = 0.01 and p = 0.03 respectively) compared to placebo. IBD98-M did not meet the primary end point but had higher clinical response (1.2 g/day) and endoscopic improvement (0.8 g/day) compared to placebo. The safety result shown that IBD98-M treatment was safe and well tolerated in this patient population. No new safety signals or unexpected safety findings were observed during the study. Further trials with different stratification and longer follow-up may be needed to evaluate the efficacy. [ABSTRACT FROM AUTHOR]

Abstract: The incidence of chronic idiopathic inflammatory bowel diseases (IBD) is growing in western countries, making their histological diagnosis an everyday task for all pathologists. Reviews from the literature strongly suggest that such diagnosis cannot be performed on the histological ground alone but requires a clinical-pathological approach. Moreover, bewildering variations can be observed in the terminology employed to report either individual lesions or diagnostic categories. The aim of the present paper is to suggest a practical diagnostic algorithm summarizing the main data from the literature. Particular emphasis has been placed on minimum clinical information required and the accurate definition of individual lesions. Diagnostic categories to employ and to avoid in daily practice have furthermore been stressed. [Copyright &y& Elsevier]

Background: Chronic pouchitis, which can lead to pouch failure, occurs in approximately 5% of patients after restorative proctocolectomy for ulcerative colitis (UC). This work examined the interplay between the microbiota adherent to the ileal pouch mucosa and the mucosal immune system in chronic/relapsing pouchitis. Patients and Methods: Thirty-two consecutive patients attending our surgical gastroenterological department following restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for UC were considered eligible candidates for this study. Biopsy samples of bacteria adherent to the mucosa were collected. TLR4 and TLR2 mucosal expression was measured by Real Time RT-PCR. Serum and mucosal IL-1β, IL-6, and TNF-α levels were assessed using immunometric assays. Fecal lactoferrin concentrations were determined by quantitative ELISA. After a median follow-up of 23 months (IQR 20-24 months) each patient underwent a global assessment of their clinical condition and disease activity status. Results: Six patients were diagnosed with relapsing/chronic pouchitis during the follow-up period. Mucosal TLR2 and TLR4 expression was higher in the chronic/relapsing pouchitis group than in the no or only one episode of pouchitis group (P = 0.036 and P = 0.016, respectively). The number of colony forming units (CFU) of mucosa-associated Clostridiaceae spp. was higher in the former than in the latter group (P = 0.031). Clostridiaceae were associated to a significant risk of chronic/relapsing pouchitis [OR: 14 (95% CI 0.887–224.021), P = 0.045]. Conclusion: Chronic/relapsing pouchitis is associated to higher mucosal TLR2 and TLR4 expression. Mucosal colonization by Clostridiaceae spp seems to play a role in the pathogenesis of chronic/relapsing pouchitis. [ABSTRACT FROM AUTHOR]