关键词： dendritic cells   immunohistochemistry   inflammatory bowel disease   lymph node   mucosa-associated lymphoid tissue   tumor necrosis factor alpha inhibitor  

摘要： Background Antitumor necrosis alpha (TNF alpha) therapy is often used in the management of patients with inflammatory bowel disease (IBD) and may have effects on lymphoid tissue architecture and function. The goal of our study was to characterize the effects of TNF alpha inhibitors on mesenteric lymph node and mucosa-associated lymphoid tissue in patients with IBD. Methods We examined lymphoid tissue morphology in IBD patients treated with TNF alpha inhibitors compared to untreated controls. Intestinal resections from 19 patients (10 anti-TNF alpha treated and 9 controls) were reviewed. Immunohistochemistry for CD21, CD20, and CD3 was performed on ileocecal valve lymphoid tissue and mesenteric lymph nodes from the resection specimens to assess follicular architecture. Results Relative to control groups, TNF alpha-treated groups showed less preserved germinal center architecture, evidenced by lower overall semiquantitative scores for follicular architecture. Likewise, the percentage of secondary follicles to total follicles was decreased in patients treated with TNF alpha blockade. Conclusions Our results suggest that TNF alpha inhibitors may play a role in disruption of lymphoid germinal center architecture in patients with IBD. Awareness of this disrupted lymphoid morphology when examining histologic sections from patients with IBD treated with TNF alpha inhibitors may prevent unnecessary studies to exclude a lymphoproliferative disorder.

关键词： Crohn disease   Inflammatory bowel diseases   Pancreatitis   Ulcerative colitis  

摘要： Background: Idiopathic acute pancreatitis (LAP) in patients with inflammatory bowel disease (IBD) is not well characterized. Our purpose was to better understand this condition and its natural history. Methods: Retrospective cohort study conducted at nine Spanish IBD referral centers. Patients with IBD and a first episode of acute pancreatitis (AP) between 1998 and 2018 were included. Patients with a previous episode of AP or a diagnosis of chronic pancreatitis were excluded. LAP and non-LAP were compared by multivariate logistic regression and survival analysis. Results: We identified 185 patients with IBD (68.7% Crohn's disease) and a first episode of AP. Thirty-eight of those 185 (20.6%) fulfilled criteria for LAP. There were no severe cases of LAP. On multivariate analysis, AP before IBD diagnosis (21.1% vs. 3.4%, p = 0.04) and ulcerative colitis (52.6% vs. 23.1%, p = 0.002) were significantly more common in LAP. Further work-up was performed in 16/38 (42%) LAP patients, and a cause was identified in 6/16 (37.5%). Median time from AP to the end of follow-up was 6.3 years (3.1-10). Five-year risk of AP recurrence was significantly higher in LAP group (28% vs. 5.1%, log-rank p = 0.001), with a median time to first recurrence of 4.4 months (2.9-12.2). Conclusions: LAP represents the second cause of AP in patients with IBD. It is more frequent in ulcerative colitis, and presents a high risk of recurrence. Additional imaging work-up after a first episode of LAP in IBD patients is highly advisable, as it identifies a cause in more than one-third of cases. (C) 2020 LAP and EPC. Published by Elsevier B.V. All rights reserved.

关键词： Parkinson disease (autosomal recessive   early onset) 7 (PARK7)   inflammatory bowel disease (IBD)   apoptosis   p53   epithelial cell   Crohn's disease   DJ-1   intestinal disorder   ulcerative colitis  

摘要： Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1(?/?) mice, DJ-1(?/?)p53(?/?) mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1(?/?) mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.

关键词： Peptides and proteins   Mixtures   Rodent models   Inhibitors   Permeability  

摘要： To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.

关键词： Data processing   Epigenomics  

摘要： Studies of inflammatory bowel disease (IBD) have been inconclusive in relating microbiota with distribution of inflammation. We report microbiota, host transcriptomics, epigenomics and genetics from matched inflamed and non-inflamed colonic mucosa [50 Crohn's disease (CD);80 ulcerative colitis (UC);31 controls]. Changes in community-wide and within-patient microbiota are linked with inflammation, but we find no evidence for a distinct microbial diagnostic signature, probably due to heterogeneous host-microbe interactions, and show only marginal microbiota associations with habitual diet. Epithelial DNA methylation improves disease classification and is associated with both inflammation and microbiota composition. Microbiota sub-groups are driven by dominant Enterbacteriaceae and Bacteroides species, representative strains of which are pro-inflammatory in vitro, are also associated with immune-related epigenetic markers. In conclusion, inflamed and non-inflamed colonic segments in both CD and UC differ in microbiota composition and epigenetic profiles.

关键词： Periodontitis   Inflammatory bowel disease   Meta-analysis  

摘要： Background Periodontitis was reported to be associated with inflammatory bowel disease (IBD). However, the association between them has not been firmly established in the existing literature. Therefore, this meta-analysis was conducted to evaluate the relationship between periodontitis and IBD. Methods Electronic databases were searched for publications up to August 1, 2019 to include all eligible studies. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated to determine the association between periodontal disease and IBD using a random or fixed effects model according to heterogeneity. Results Six eligible studies involving 599 IBD patients and 448 controls were included. The pooled OR between periodontitis and IBD was 3.17 (95% CI: 2.09-4.8) with no heterogeneity observed (I-2 = 0.00%). The pooled ORs were 3.64 (95% CI: 2.33-5.67) and 5.37 (95% CI: 3.30-8.74) for the associations between periodontitis and the two sub-categories of IBD, Crohn' s disease and ulcerative colitis, respectively. Conclusions The results demonstrated that periodontitis was significantly associated with IBD. However, the mechanisms underlying periodontitis and IBD development are undetermined. Further studies are needed to elucidate this relationship.

关键词： Immunology   Amides   Antagonists   Molecules   Inflammation  

摘要： This report deals with the design, the synthesis, and the pharmacological evaluation of pyroglutamide-based P2X7 antagonists. A dozen were shown to possess improved properties, among which inhibition of YO-PRO-1/TO-PRO-3 uptake and IL1 beta release upon BzATP activation of the receptor and dampening signs of DSS-induced colitis on mice, in comparison with reference antagonist GSK1370319A. Docking study and biological evaluation of synthesized compounds has highlighted new SAR, and low toxicity profiles of pyroglutamides herein described are clues for the finding of a usable h-P2X7 antagonist drug. Such a drug would raise the hope for a cure to many P2X7-dependent pathologies, including inflammatory, neurological, and immune diseases.