摘要： The sphingosine-1-phosphate receptor-1 (S1P(1)) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P(1) in intestine using S1P(1)-eGFP mice, the regulation of S1P(1) expression in lymphocytes after administration of dextran sulfate sodium (DSS), after colitis induced by transfer of CD4(+) CD45RB(hi) cells, and by crossing a mouse with TNF-driven ileitis with S1P(1)-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P(1) expression. We found that not only T and B cells express S1P(1), but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P(1) expression, while the enzymes that control tissue S1P levels in mice and humans with inflammatory bowel disease (IBD) were uniformly dysregulated, favoring synthesis over degradation. Finally, we observed that FTY720 reduced T-cell velocity and induced S1P(1) degradation and retention of Naive but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P(1) expression and tissue S1P levels and suggests that the anti-inflammatory properties of S1PR agonists might not be solely due to their lymphopenic effects, but also due to potential effects on DC migration and vascular barrier function.

关键词： Microbiota   Short chain fatty acids   GPCR   IBD  

摘要： Gut microbiota has been well recognized in regulation of intestinal homeostasis and pathogenesis of inflammatory bowel diseases. However, the mechanisms involved are still not completely understood. Further, the components of the microbiota which are critically responsible for such effects are also largely unknown. Accumulating evidence suggests that, in addition to pathogen-associated molecular patterns, nutrition and bacterial metabolites might greatly impact the immune response in the gut and beyond. Short chain fatty acids (SCFA), which are metabolized by gut bacteria from otherwise indigestible fiber-rich diets, have been shown to ameliorate diseases in animal models of inflammatory bowel diseases (IBD) and allergic asthma. Although the exact mechanisms for the action of SCFA are still not completely clear, most notable among the SCFA targets is the mammalian G protein-coupled receptor pair of GPR41 and GPR43. In addition to the well-documented inhibition of histone deacetylases activity mainly by butyrate and propionate, which causes anti-inflammatory activities on IEC, macrophages, and dendritic cells, SCFA has recently been implicated in promoting development of Treg cells and possibly other T cells. In addition to animal models, the beneficial effects have also been reported from the clinical studies that used SCFA therapeutically in controlled trial settings in inflammatory disease, in that application of SCFA improved indices of IBD and therapeutic efficacy was demonstrated in acute radiation proctitis. In this review article, we will summarize recent progresses of SCFA in regulation of intestinal homeostasis as well as in pathogenesis of IBD.

关键词： Pediatric inflammatory bowel disease   Infliximab   Trough level   Antibodies  

摘要： Background/Aims: The clinical use of measuring infliximab (IFX) trough levels (TLs) and antibodies against IFX (ATIs) in patients with pediatric inflammatory bowel disease (IBD) remains unclear. We propose measuring these variables to create individual IFX treatment strategies for patients with pediatric IBD. Methods: This retrospective study was condOcted in pediatric patients with IBD who received IFX from July 2009 to June 2014. Results: Samples were available from 39 patients with pediatric IBD. A significant difference was observed in IFX TLs in 16 patients who were in clinical remission (group A) after IFX therapy (median, 3.99 mu g,/mL;interquartile range [IQR], 0.30 to 21.96) compared to 23 patients who had a poor response to treatment (group B) (median, 0.88 mu g/mL;IQR, 0.00 to 6.80, p=0.002). In group B, 21 patients underwent empiric intensification of IFX treatment. After dose intensification, 17 patients had an improved response to treatment. Four patients still had no response to dose intensification. Therefore, these patients were switched to other biologics. Conclusions: Patients who had poor responses and subtherapeutic IFX TLs had an improved response to dose intensification. Patients who had ATIs were likely to continue to have no response after dose intensification. Therefore, tailoring individual IFX treatments based on IFX TLs, ATIs, and the clinical response should be considered.

关键词： CHOLANGITIS   INFLAMMATORY bowel diseases   PATIENTS   VEDOLIZUMAB  

摘要： A correction to the article 'Efficacy and Safety of Induction Dosing of Vedolizumab for Reducing Biliary Inflammation in Primary Sclerosing Cholangitis (Psc) in Individuals with Inflammatory Bowel Disease' published in the previous issue is presented.

关键词： growth   inflammatory bowel disease   infliximab  

摘要： Background: Growth failure is well-recognized in pediatric inflammatory bowel disease (PIED;<18 years). We aimed to examine whether antitumor necrosis factor (TNF) therapy improves growth in a PIBD population-based cohort. Methods: A retrospective review of all Scottish children receiving anti-TNF (infliximab [IFX] and adalimumab [ADA]) from 2000 to 2012 was performed;height was collected at 12 months before anti-TNF (T-12), start (TO), and 12 (T+12) months after anti-TNF. Results: Ninety-three of 201 treated with IFX and 28 of 49 with ADA had satisfactory growth data;66 had full pubertal data. Univariate analysis demonstrated early pubertal stages (Tanner 1-3 n = 44 vs T4-5 n=22), disease remission, disease duration >= 2 years, and duration of IFX >= 12 months were associated with improved linear growth for IFX;for ADA only improvement was seen in Tanner 1-3. For IFX, Tanner 1-3 median A standard deviation scores for height (Ht SDS) -0.3 (-0.7, 0.2) at T0 changed to 0.04 (-0.5, 0.7) at T+12 (P < 0.001) versus 0.01 (-0.5, 0.9) at T0 in T4-5 changed to 0.01 (-0.4, 0.2) at T+12 (P > 0.05). For IFX disease duration >= 2 year, median A Ht SDS was 0.13 (-0.6, 0.3) at T0 then 0.07 (-0.3, 0.6) at T+12 (P <0.001). Remission improved Delta Ht SDS (median Delta Ht SDS 0.14 [-0.6, 0.3] at T0 to 0.17 [-0.2, 0.7] at T+12 [P < 0.001]). Multiple regression analysis demonstrated corticosteroid usage at T0 predicted improved A Ht SDS at T+12 for IFX and ADA. Conclusions: Anti-TNF therapy is more likely to be associated with growth improvement when used at earlier stages of puberty with remission a key growth-promoting strategy in pediatric Crohn disease.

关键词： High-throughput sequencing   Human gut   Human liver   IBD   PSC   T cell receptor   Ulcerative colitis   Sclerosing cholangitis   Inflammatory bowel disease  

摘要： Background & Aims: Recruitment of gut-derived memory T-cells to the liver is believed to drive hepatic inflammation in primary sclerosing cholangitis (PSC). However, whether gut-infiltrating and liver-infiltrating T-cells share T cell receptors (TCRs) and antigenic specificities is unknown. We used paired gut and liver samples from PSC patients with concurrent inflammatory bowel disease (PSC-IBD), and normal tissue samples from colon cancer controls, to assess potential T cell clonotype overlap between the two compartments. Methods: High-throughput sequencing of TCR beta repertoires was applied on matched colon, liver and blood samples from patients with PSC-IBD (n = 10), and on paired tumor-adjacent normal gut and liver tissue samples from colon cancer patients (n = 10). Results: An average of 9.7% (range: 4.7-19.9%) memory T cell clonotypes overlapped in paired PSC-IBD affected gut and liver samples, after excluding clonotypes present at similar frequencies in blood. Shared clonotypes constituted on average 16.0% (range: 8.7-32.6%) and 15.0% (range: 5.9-26.3%) of the liver and gut memory T-cells, respectively. A significantly higher over lap was observed between paired PSC-IBD affected samples (8.7%, p = 0.0007) compared to paired normal gut and liver samples (3.6%), after downsampling to equal number of reads. Conclusion: Memory T-cells of common clonal origin were detected in paired gut and liver samples of patients with PSCIBD. Our data indicate that this is related to PSC-IBD pathogenesis, suggesting that memory T-cells driven by shared antigens are present in the gut and liver of PSC-IBD patients. Our findings support efforts to therapeutically target memory T cell recruitment in PSC-IBD. Lay summary: Primary sclerosing cholangitis (PSC) is a devastating liver disease strongly associated with inflammatory bowel disease (IBD). The cause of PSC is unknown, but it has been suggested that the immune reactions in the gut and the liver are connected. Our data demon

关键词： Gastroenterology   Inflammatory bowel disease   Japan   Shared decision making   Patient preferences  

摘要： Introduction: Recent studies have indicated that patients are showing increased interest in playing a larger role in making decisions regarding their medical treatment. Inflammatory bowel disease (IBD) is a chronic disease that manifests either as Crohn's disease (CD) or ulcerative colitis (UC). IBD treatment is multifaceted and dependent on patient-specific factors. The selection of treatment options is mostly driven by physicians, and it is unclear to what degree patients are involved in shared decision-making (SDM). The objective of the current study is to assess preferences among Japanese patients with IBD in regard to SDM during their treatment for IBD. Methods: A nationwide web-based survey was performed in Japan during February 2016. The patients were asked for their basic clinical characteristics, socioeconomic status, medical history, treatment details, and preferences regarding SDM in IBD treatment. Differences were analyzed by chi-square, t tests, a multiple regression analysis, and ordered logistic regression analysis. Results: In response to the screening survey, a total of 1068 Japanese nationals met the inclusion criteria for this study of being patients diagnosed with IBD who are currently receiving treatment. Of these, 235 had CD and 800 UC;33 were not specified. Overall, the majority of these patients felt that SDM was very important. Furthermore, interest in SDM was strongly associated with certain disease comorbidities, surgical history, and current treatment, although there were some differences in the results between CD and UC. Conclusion: The present study found that the majority of IBD patients in Japan wanted to have a role in their treatment plan. The results indicate that the patient's preference in regard to SDM was driven by their perception of the severity or progression of their disease.

关键词： Thymic stromal lymphopoietin   Immuno-pathogenesis   Inflammatory bowel disease   Gene-to-gene network   Protein-to-protein network  

摘要： Proinflammatory cytokines are thought to modulate pathogeneses of various inflammatory bowel diseases (IBDs). Thymic stromal lymphopoietin (TSLP), which has been studied in various allergic diseases such as asthma, atopic dermatitis (AD) and eosinophilic esophagitis (EoE), has been less considered to be involved in IBDs. However, mucosal dendritic cells (DCs) induced by various cytokines including TSLP were reported to cause polarization of T cell toward Th2 response, the differentiation of regulatory T-cell (Treg), and secretion of IgA by B cells. In this review, we discuss the concept that decreased TSLP has the potential to accelerate the development of Thl response dominant diseases such as the Crohn's disease (CD) while increased TSLP has the potential to lead to a development of Th2 cell dominant diseases such the ulcerative colitis (UC). To examine TSLP's role as a potential determining factor for differentiating UC and CD, we analyzed the effects of other genes regulated by TSLP in regards to the UC and CD pathogeneses using data from online open access resources such as NetPath, GeneMania, and the String database. Our findings indicate that TSLP is a key mediator in the pathogenesis of IBDs and that further studies are needed to evaluate its role. (C) 2016 Elsevier B.V. All rights reserved.

关键词： MYCOBACTERIUM tuberculosis   INFLAMMATORY bowel diseases   ULCERATIVE colitis   DISEASE risk factors   CROHN'S disease  

摘要： Background The low incidence of Mycobacterium tuberculosis infection and lack of adequate controls have prevented researchers from estimating tuberculosis (TB) risk in inflammatory bowel disease (IBD) patients. Aim To evaluate the risk of incident TB among IBD patients. Methods Using the 2011-2013 data of the South Korean National Health Insurance (NHI) system, we calculated the incidence rates (IRs), standardised incidence ratio (SIR) and number needed to screen (NNS) for incident TB in IBD patients compared to the general population in terms of subtype, age, gender and IBD medications. Results The IR, SIR and NNS for TB in IBD patients were 223.9/100 000 person-years, 2.64 (2.30-3.01) and 446.6 (392.8-517.6), respectively. The TB IR in Crohn's disease (CD) patients was significantly higher than that in ulcerative colitis (UC) patients (340.1/100 000 person-years vs. 165.5/100 000 person-years, respectively;P < 0.001). The SIR and NNS for TB among CD patients were 4.00 (3.59-4.45) and 604.2 (506.1-749.6), respectively;those among UC patients were 1.95 (1.66-2.27) and 294.0 (246.9-363.4). The TB IRs in IBD patients did not differ significantly by age or gender (Ptrend = 0.505 and P = 0.861, respectively). The TB IRs among IBD patients prescribed 5-ASA, corticosteroids, immunomodulators and anti-TNF-alpha were 143.5, 208.5, 284.6 and 554.1 per 100 000 person-years, respectively. Among IBD patients treated using anti-TNF-alpha, the TB IR was significantly higher than that among all IBD patients (P < 0.001);the SIR and NNS for TB were 6.53 (5.99-7.09) and 180.5 (144.6-240.1) respectively. Conclusion Clinicians should be aware of the increased risk of active tuberculosis in patients with IBD who are receiving anti-TNF-alpha therapy.