关键词： Anemia   Childhood   Hepcidin   Inflammatory bowel disease  

摘要： Anemia is the most common extraintestinal systemic complication of inflammatory bowel disease. Iron deficiency anemia and anemia of chronic disease are among the most frequent types. Intestinal iron absorption is controlled by the activity of ferroportin. Cells with high expression of ferroportin include enterocytes, and also macrophages and hepatocytes. Iron homeostasis is controlled by the hepcidin-ferroportin axis. Hepcidin is a central regulator of iron metabolism and can also serve as a marker of systemic inflammation. During systemic inflammatory response, the synthesis of hepcidin increases, and hepcidin binds to ferroportin and inhibits its activity. Thus, iron is not absorbed from the bowel into the circulation and also remains sequestered in macrophages. Conversely, hepcidin synthesis is suppressed during conditions requiring increased iron intake for enhanced erythropoiesis, such as iron deficiency anemia or hypoxia. Here, ferroportin is not blocked, and iron is actively absorbed into the bloodstream and also released from the stores. Production of hepcidin is influenced by the status of total body iron stores, systemic inflammatory activity and erythropoietic activity. Oral iron therapy is limited in inflammatory bowel diseases due to ongoing gastrointestinal inflammation. It is less effective and may worsen the underlying disease. Therefore, the choice between oral and parenteral iron therapy must be made with caution. Oral iron would be ineffective at high hepcidin levels due to concurrent ferroportin blockage. Contrarily, low levels of hepcidin indicate that oral iron therapy should be successful. An understanding of hepcidin can help in understanding the body's reaction to iron depletion during the inflammatory process.

关键词： Inflammatory bowel disease   Thiopurine   NUDT15  

摘要： The thiopurine drugs azathioprine and 6-mercaptopurine are widely used for the maintenance of clinical remission in steroid-dependent inflammatory bowel disease (IBD). Thiopurines are recommended to be continued throughout pregnancy in IBD patients, but conclusive safety data in pregnant patients remain still insufficient. On the other hand, a strong association between a genetic variant of nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15 ***139Cys) and thiopurine-induced myelotoxicity has been identified. Pharmacokinetic studies have revealed that thiopurine metabolism is altered in pregnant IBD patients and suggested that the fetus may be exposed to the active-thiopurine metabolite, 6-thioguaninetriphosphate, in the uterus. A recent study using knock-in mice harboring the ***138Cys mutation which corresponds to human ***139Cys showed that oral administration of 6-MP at clinical dose induces a severe toxic effect on the fetus harboring the homozygous or heterozygous risk allele. This suggests that NUDT15 genotyping may be required in both women with IBD who are planning pregnancy (or pregnant) and their partner to avoid adverse outcomes for their infant. The risk to the fetus due to maternal thiopurine use is minimal but there are some concerns that are yet to be clarified. In particular, a pharmacogenomic approach to the fetus is considered necessary.

关键词： Inflammatory bowel disease   Nutrition   Dietary intervention   Intestine   Regeneration  

摘要： Recent studies have revealed that calorie restriction is able to modulate immune system and aid in intervention of immune disorders. Inflammatory bowel disease (IBD) is an immune disease in the intestine caused by interplay between genetic susceptibility and environmental factors such as diets. Here we analyzed the therapeutic effect of intermittent calorie restriction with a fasting-mimicking diet (FMD) on dextran sodium sulfate (DSS)-induced chronic IBD model in mice. Two cycles of FMD was administered after IBD symptoms occurred in the mice. FMD administration significantly reduced the score of disease activity index. FMD reversed DSS-mediated shortening of colon length, infiltration of lymphocytes in the crypt of colon, and accumulation of CD4(+) cells in the colon and small intestine. The expression of an inflammation marker NLRP3 was also reduced by FMD administration. The percentage of CD4(+) T cells in both peripheral blood and spleen was also reduced by FMD. In addition, FMD application reversed DSS-mediated reduction in intestinal stem cell marker Lgr5, while the cell proliferation markers Ki67 and PCNA were increased by FMD. Taken together, these results indicate that in the mouse model of IBD, application of the FMD can effectively ameliorate the symptoms and pathogenesis of IBD through reducing the inflammation of intestine and promoting the regeneration and repair of the damaged intestinal epithelium. (C) 2021 Elsevier Inc. All rights reserved.

关键词： Inflammatory bowel disease   Surgery   COVID-19  

摘要： Outcomes of inflammatory bowel disease (IBD) patients requiring surgery during the outbreak of Coronavirus disease 19 (COVID-19) are unknown. Aim of this study was to analyse the outcomes depending on the COVID-19 status of the centre. Patients undergoing surgery in six COVID-19 treatment and one COVID-free hospitals (five countries) during the first COVID-19 peak were included. Variables associated with risk of moderate-to-severe complications were identified using logistic regression analysis. A total of 91 patients with Crohn's disease (54, 59.3%) or ulcerative colitis (37, 40.7%), 66 (72.5%) had surgery in one of the COVID-19-treatment hospitals, while 25 (27.5%) in the COVID-19-free centre. More COVID-19-treatment patients required urgent surgery (48.4% vs. 24%, p = 0.035), did not discontinue biologic therapy (15.1% vs. 0%, p = 0.039), underwent surgery without a SARS-CoV-2 test (19.7% vs. 0%, p = 0.0033), and required intensive care admission (10.6% vs. 0%, p = 0.032). Three patients (4.6%) had a SARS-CoV-2 infection postoperatively. Postoperative complications were associated with the use of steroids at surgery (Odds ratio [OR] = 4.10, 95% CI 1.14-15.3, p = 0.03), presence of comorbidities (OR = 3.33, 95% CI 1.08-11, p = 0.035), and Crohn's disease (vs. ulcerative colitis, OR = 3.82, 95% CI 1.14-15.4, p = 0.028). IBD patients can undergo surgery regardless of the COVID-19 status of the referral centre. The risk of SARS-CoV-2 infection should be taken into account.

关键词： Medicine/Public Health   general   Pediatrics   Pediatric Surgery  

摘要： BACKGROUND: The aim of this study was to assess PA patterns among children and adolescents with inflammatory bowel disease (IBD). METHODS: Sixty participants with IBD (42 Crohn's disease [CD], 10 ulcerative colitis [UC], and 8 IBD-unclassified [IBD-U], 30 male patients) in remission (n = 45) or with mild disease (n = 15) were compared with 60 healthy age- and sex-matched controls. Each participant wore a triaxial accelerometer during 4 consecutive days for objective daily PA quantification. Results: Overall, there was no significant difference in daily PA patterns between patients with IBD and healthy controls, with 31.7% of patients with IBD and 38.3% of healthy controls fulfilling the recommendation of 60 min of moderate-to-vigorous physical activity (MVPA) daily (NS). Male patients with IBD spent significantly less time in MVPA compared with matched healthy controls (mean difference, 16.2 min day(-1);p < 0.05). No difference was observed for female patients with IBD. No difference in sedentary pattern between male patients with IBD and controls was found. Conclusions Children and adolescents with inactive or mildly active IBD have similar PA patterns compared with healthy controls, except for male patients who have reduced moderate-to-vigorous PA. By far, most patients with IBD do not fulfill the MVPA recommendations for health benefits. Impact There is few data on PA patterns in pediatric patients with IBD. Methodological issues to assess PA limit the strengths of these studies. Pediatric IBD patients with inactive or mildly active IBD have similar physical activity patterns compared with healthy controls, except for male patients who have reduced moderate-to-vigorous PA. Most patients with IBD do not fulfill the MVPA recommendations for health benefits.

关键词： innate lymphoid cell   innate lymphoid cells   mucosal-associated invariant T   microbiota   very early-onset inflammatory bowel disease  

摘要： Objectives: Very early-onset inflammatory bowel disease (VEO-IBD) arises in children less than 6 years old, a critical time for immunologic development and maturation of the intestinal microbiome. Non-conventional lymphocytes, defined here as mucosal-associated invariant T cells and innate lymphocytes, require microbial products for either development or expansion, aspects that could be altered in very early-onset inflammatory bowel disease. Our objective was to define conventional leukocyte and non-conventional lymphocyte populations in controls and patients using multiparameter flow cytometry to test the hypothesis that their frequencies would be altered in a chronic inflammatory state associated with significant dysbiosis. Methods: Multiparameter flow cytometry was used in a control cohort of 105 subjects to define age-effects, not previously comprehensively examined for these cell types in humans. Differences were defined between 263 unique age-matched patients with VEO-IBD and 105 controls using Student t-test. Subjects were divided into two age groups at the time of sampling to control for age-related changes in immune composition. Results: Intermediate monocytes were consistently decreased in patients with VEO-IBD compared to controls. Mucosal-associated invariant T cells were significantly lower in patients with long-standing disease. Levels were less than half of those seen in the age-matched control cohort. The innate lymphoid cells type 2 population was expanded in the youngest patients. Conclusion: Mucosal-associated invariant T cells are diminished years after presentation with inflammatory bowel disease. This durable effect of early life intestinal inflammation may have long-term consequences. Diminished mucosal-associated invariant T cells could impact host defense of intestinal infections.

关键词： Inflammatory bowel disease   Relapse   Top-down therapy   Step-up therapy  

摘要： Purpose The therapeutic effect of top-down therapy for inflammatory bowel disease (IBD) has not been fully evaluated in real-world clinical settings. We compared the effectiveness of top-down and step-up therapies for IBD. Methods We retrospectively evaluated patients who were admitted with IBD (Crohn's disease [CD] or ulcerative colitis [UC]) between 2012 and 2019 using the nationwide Japan Diagnosis Procedure Combination database. Patients who received immunomodulators or biologic agents at the start of observation were assigned to the top-down group and those who did not were enrolled in the step-up group. Relapse was the primary outcome, a composite outcome defined as surgery, new steroid or immunomodulator use, hospitalization, a new biologic agent, or switching biologic agents. Results We analyzed 6715 patients (CD, N = 3643;UC, N = 3072). Relapse occurred in 1982 CD cases (54.4%). The cumulative CD relapse incidence was 32.9% at 1 year and 61.3% at 5 years in the top-down group and 30.7% at 1 year and 58.6% at 5 years in the step-up group. Relapse occurred in 2032 UC cases (47.8%). The cumulative relapse incidence was 33.5% at 1 year and 50.0% at 5 years in the top-down group and 35.2% at 1 year and 51.6% at 5 years in the step-up group. No clinical factors associated with relapse were identified in patients with CD or UC. Conclusion Compared with step-up therapy, top-down therapy was not associated with a decreased relapse risk in a real-world population of patients with CD or UC.

关键词： feelings   patients   patients reported outcomes   perception of surgery   quality of life   stoma acceptance  

摘要： Aim Surgery is indicated in selected patients with inflammatory bowel disease (IBD). However, due to a negative perception, surgery may be delayed, leading to possible unfavourable outcomes. The aim of this work was to investigate patients' perceptions of surgery and the impact on reported outcomes. Method An international multilingual online survey was used to query IBD patients' experiences of surgery, information sources, expectations and concerns, quality of life (QoL) and feelings. Results The survey was completed by 425 of 510 participants. Crohn's disease was more frequent (61%) than ulcerative colitis (36%). Most patients primarily learned about surgery from their gastroenterologist and were informed of the risks and benefits by the surgeon. In almost one-third of patients indication for surgery was not a shared decision between gastroenterologist and surgeon. Seventy per cent of patients naive to surgery were not aware of any surgical options. The majority of patients (80%) perceived surgery as the last option after many medical treatments rather than an alternative therapeutic option (20%). Sixteen per cent of patients obtained their primary information from the Internet, while 82.4% used the Internet to obtain additional information. Fear of surgical complications was cited by 73% of patients, while relief from symptoms was indicated by 31%. Most patients coped with their stoma better than expected or as they expected. Negative feelings decreased after surgery, while a lasting improvement in positive feelings and QoL was reported. Conclusion Despite the negative perception of surgery and the delayed involvement of surgeons as a source of information and in the decision-making process, the majority of respondents experienced positive outcomes from surgery, including improvement QoL and acceptance of the stoma.

关键词： colitis   dysregulated immune response   epigenetics   histone modification   IBD   macrophage  

摘要： Background and Aim Epigenetic modification is an important part of the pathogenesis of inflammatory bowel disease (IBD). Some studies proved that p62 was involved in inflammatory response and upregulated in IBD patients, and histone modification plays an important role in regulating p62 expression. SETD8, a histone H4K20 methyltransferase, has been reported downregulated in some inflammatory diseases. Here, we investigated the role of SETD8 in the development of IBD and its underlying mechanisms. Methods An inflammatory cell model was established to elucidate whether SETD8 involved in inflammatory response in macrophages. Three percent dextran sodium sulfate-induced colitis murine model injection with SETD8 inhibitor was used in our study to investigate whether SETD8 inhibition can affect the progress of IBD. The expression of SETD8 and p62 was measured by qRT-PCR and western blot. The mRNA level of inflammatory cytokines was analyzed by qRT-PCR. In addition, chromatin immunoprecipitation-PCR was performed to identify the mechanism by which SETD8 regulates p62. Results SETD8 expression obviously decreased in vitro, in vivo models and in IBD patients. In lipopolysaccharide-activated RAW264.7 cells, knockdown of SETD8 significantly increased the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-alpha, IL-6, IL-1 beta, and MCP-1. Based on the dataset, we verified that p62 was a target gene of SETD8 and chromatin immunoprecipitation-PCR assay identified that silence of SETD8 distinctly decreases the H4K20me1 enrichment in the promoter of p62. Moreover, silencing of p62 partly reverses the SETD8 inhibition-mediated pro-inflammatory effect in vitro. Finally, SETD8 pharmacological inhibitor (UNC0379) aggravated the disease progression in dextran sodium sulfate-induced murine colitis. Conclusion Our findings elucidate an epigenetic mechanism by which SETD8 regulates the p62 expression and restrains the inflammatory response in colitis. Our result sug