Immunomodulatory cytokines suppress epithelial nitric oxide production in inflammatory bowel disease by acting on mononuclear cells

Inducible nitric oxide synthase (iNOS) activity in colonic epithelial HT-29 cells is modulated by the T-cell-derived cytokines IL-4 and IL-13, but is not affected by IL-10 despite its effect in models of colitis. We studied the effects of these cytokines on nitric oxide (NO) production by colonic tissue. IL-10 and IL-4 but not IL-13 suppressed the NO production and iNOS expression by inflamed tissue and cytokine-stimulated noninflamed tissue from patients with ulcerative colitis, whereas the three cytokines suppressed NO production in cytokine-stimulated biopsies from controls. To examine why colonic biopsies and HT-29 cells respond differently to immunomodulatory cytokines, a coculture of mixed mononuclear monocytes (MMC) and HT-29 cells was studied. Treatment of HT-29 cells with conditioned medium from IFN-γ/LPS-stimulated MMC produced significant amounts of NO, which suggested the presence of an MMC-derived soluble factor modifying epithelial NO production. Pretreatment of IFN-γ/LPS-stimulated MMC with IL-10 and IL-4 but not IL-13 suppressed NO production by HT-29 cells. Interestingly, pretreatment of HT-29 cells with IL-1 receptor antagonist suppressed the IFN-γ/LPS-stimulated MMC-induced NO production. These results suggest that immunomodulatory cytokines might exert an inhibitory effect on NO up-regulation by colonic epithelium via the inhibition of MMC-derived soluble mediators, such as IL-1.     

益生菌在儿童炎症性肠病中的应用

炎症性肠病（inflammatory bowel disease,IBD）是一种原因不明的慢性非特异性肠道炎性疾病,主要包括溃疡性结肠炎（ulcerative colitis,UC）、克罗恩病（Crohn's disease,CD）和未定型的炎症性肠病（IBD-unclassified,IBDU）。随着对肠道微生物与IBD关系认识的不断加深,许多研究发现肠道菌群的生态失调在IBD的发病中起着重要作用。益生菌在儿童IBD治疗中具有良好前景,但仍缺乏有效的证据来确证益生菌疗效,并指导临床对益生菌的种类和剂量等进行选择。现有研究表明,益生菌对儿童IBD的治疗具有特异性,在诱导和维持UC缓解效果明显,但在诱导CD缓解、维持CD缓解和预防术后并发症及复发方面效果并不理想。     

益生菌在炎症性肠病中的治疗作用

炎症性肠病(inflammatory bowel disease,IBD)包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn’s disease,CD)。随着对肠道微生物群在IBD发病机制中作用的认识不断深入,近年来益生菌广泛应用于IBD治疗。大量临床试验结果表明,益生菌治疗IBD的疗效主要体现在对UC和贮袋炎的治疗,对CD的疗效不明确。益生菌治疗IBD可能通过促进肠道微生物群平衡、改善肠道屏障功能、调节肠道黏膜免疫及营养物质代谢等途径。     

肠内营养支持治疗对炎症性肠病患者肠黏膜屏障功能及炎症反应的影响

目的 探讨早期肠内营养（EN）支持治疗对炎症性肠病（IBD）患者肠黏膜屏障功能及炎症反应的影响。方法 将80例IBD患者按营养支持治疗途径分为EN组（48例）和肠外营养（PN）组（32例）,在常规治疗的基础上分别给予早期EN、PN支持治疗。比较治疗前后2组患者营养学相关指标[白蛋白（ALB）、前白蛋白（PA）、转铁蛋白（TF）]、肠黏膜屏障功能指标（内毒素、D-乳酸）及炎症相关指标[C-反应蛋白（CRP）、降钙素原（PCT）、粪便钙卫蛋白（FCP）]水平。结果 治疗前,2组患者各观察指标水平差异无统计学意义（P>0.05）;治疗后,与治疗前相比,2组患者血清ALB、PA及TF水平均显著升高（P0.05）。结论 在常规治疗的基础上,早期EN支持治疗对IBD患者肠黏膜屏障功能的改善及炎症缓解作用优于PN支持治疗。     

粪菌移植在儿童炎症性肠病中的应用

炎症性肠病（IBD）是一种病因尚不明确的非特异性肠道炎症性疾病。越来越多的证据表明肠道菌群失调与IBD的发生发展密切相关。粪菌移植是通过各种方式将健康捐赠者的粪便菌群移植入患者消化道内,旨在重建患者肠道菌群从而达到对肠道内外疾病治疗的目的。肠道微生物稳态及失调在疾病发生发展中发挥作用,其中包括炎症性肠病（IBD）。越来越多的研究报道了FMT在IBD中的治疗作用,现主要阐述粪菌移植在儿童IBD中的应用。     

Increased disease activity in eNOS-deficient mice in experimental colitis

Oral dextran sodium sulfate (DSS, 3%) produces experimental colitis with many features of human inflammatory bowel disease (IBD), (leukocyte extravasation, cachexia, and histopathology). Previous studies suggest that the inducible nitric oxide synthase (iNOS) in blood cells or in the endothelium contribute to this injury. However, until now no study has been performed to directly evaluate the role of endothelial nitric oxide synthase (eNOS) in IBD. We compared disease activity in wild-type (eNOS^+/+) and eNOS-deficient (eNOS^−/−) mice in the DSS model of colitis. Administration of DSS induced weight loss, stool blood, and overt histopathology in both mouse strains. Disease activity was dramatically increased in eNOS^−/− mice compared to wild types. Histologically, eNOS-deficient mice had greater leukocyte infiltration, gut injury, and expressed higher levels of the mucosal addressin, MAdCAM-1. These results demonstrate that eNOS plays an important role in limiting injury to the intestine during experimental colitis and altered eNOS content and/or activity may contribute to human IBD.     

益生菌在炎症性肠病治疗中的研究进展

益生菌（Probiotics）是一类能够促进肠道微生物菌群平衡,对宿主健康或生理功能产生有益作用的活性微生物。目前广泛应用于生命健康领域、科学研究、生物工程、工农业以及食品安全。大量国内外研究表明益生菌在降血压、降血糖、降血脂、抗过敏、抗炎、调节免疫、维持肠道菌群平衡等方面具有积极作用。炎症性肠病的病因和发病机制尚未完全明确,现多认为与遗传、环境、感染、免疫以及肠道微生物多因素相互作用有关。益生菌通过多种机制介导,在临床治疗炎症性肠病中扮演着重要角色。     

肠道微生物群落与炎症性肠病关系研究进展

目的炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC）,以持续性肠道非特异性炎症为特征,通常反复发作、迁延不愈,临床上仍无特效性的治疗手段。IBD确切的发病机制尚不清楚,涉及免疫、环境及遗传等因素,这些因素共同诱导肠道炎症、黏膜损伤和修复。肠道微生物群落及其代谢产物、宿主基因易感性及肠道黏膜免疫三方面共同参与了IBD的发病机制。本文从消化道微生态角度出发,对目前IBD相关的肠道微生物群落研究现状、宿主-微生物间免疫应答及益生菌治疗等内容进行探讨。     

炎症性肠病与肠道微生态的研究进展

炎症性肠病(inflammatoryboweldisease,IBD)是一种肠道慢性炎症性疾病,其发病机制尚不清楚。然而,IBD的发病率不断上升给患者及其家属带来了巨大的经济负担,需要找到积极有效的治疗方法来帮助患者。最新的观点认为,宿主和肠道微生物之间的平衡被打破会触发遗传易感个体的免疫炎症反应。肠道菌群失调在炎症性肠病的发病及发展过程中起着重要的作用。临床研究发现,IBD患者肠道菌群失调程度不同,而联合应用益生菌可以改善这些患者的症状。越来越多的研究者密切关注肠道菌群与IBD的关系,并进行了深入的基础和临床研究。本文从肠道菌群对IBD的生理影响以及益生菌和粪便细菌移植等方面进行综述。     

Hypoxia and inflammatory bowel disease

Inflammatory bowel disease (IBD) is a general term to describe inflammatory diseases of the gastrointestinal tract such as Crohn's disease and ulcerative colitis. IBD affects approximately 1 in 200 individuals and exerts a significant health and quality of life burden on patients. Surgical intervention can be curative in ulcerative colitis but there is currently no cure for Crohn's disease. Since this is the case, and the fact that patients are often diagnosed at a young age, IBD exerts a significant financial burden on the health care system, and society as a whole.The underlying pathology of IBD is complex and involves a combination of genetic, environmental and microbial factors. Regardless of the underlying causes of the condition, this disease is universally characterized by disruption to the protective epithelial barrier separating the intestinal lumen above from the mucosal immune system below. Once this barrier becomes compromised a sequence of events ensues, that can occur in repetitive cycles to ensure long-term and serious damage to the gut.The role of hypoxia and hypoxia-dependent signalling pathways are increasingly appreciated to play a role in the physiology and pathophysiology of the intestine. The intestinal epithelium normally exists in a state of physiological hypoxia, with additional tissue hypoxia a feature of active inflammatory disease. Furthermore, recent pre-clinical animal studies have clearly supported the rationale for pharmacologically manipulating the oxygen-sensitive hypoxia-inducible factor (HIF) pathway in models of IBD. Thus, this review will discuss the contribution of hypoxia sensitive pathways in the pathology of IBD. Finally we will discuss the emerging evidence for manipulation of hypoxia-sensitive pathways in the treatment of IBD.     

Small-molecule agents for the treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic, debilitating condition with a significant impact on quality of life. In spite of recent advances with antibody therapies, there remains a significant unmet medical need in IBD. Ongoing research and development efforts aim to identify new therapies that will increase remission rates beyond those achieved with current standard-of-care, while maintaining a high safety margin. This review will provide an overview of the small-molecule agents that are being explored in this regard.     

Prevalence of the factor V Leiden mutation in human inflammatory bowel disease with different activity

BACKGROUND: the developmental mechanism of inflammatory bowel disease (IBD) in patients is unknown, but it may be influenced by different environmental and genetical factors. AIMS of this study were: (1) to classify the IBD patients according the disease activity; and (2) to determine the presence of factor V Leiden mutation in IBD patients. PATIENTS AND METHODS: the observation was carried out in 49 patients with Crohn's disease (CD) and 29 patients with ulcerative colitis (UC). None of them had a history of thrombotic episodes. IBD was diagnosed by conventional clinical, endoscopic, radiological and histological criteria. The factor V Leiden mutation was detected by the polymerase chain reaction (PCR) method. Crohn's disease activity index (CDAI) was evaluated using the method of the National Cooperative Crohn's Disease Study. We determined the UC disease activity according to Truelove-Witts classification. RESULTS: The prevalence of factor V Leiden mutation was increased in both populations of the patients to compare it with healthy persons (14.28 and 27.58% vs. 5.26%, n=7/49 and 8/29 vs. 3/57). The statistical analysis did not show a significant relationship between the CDAI or the Truelove-Witts grade in UC and the presence of Leiden mutation. CONCLUSION: the presence of factor V Leiden mutation probably has a role in the development of IBD. Our results suggest a higher prevalence of this mutation in Central European patients than in Southern, Northern Europe or America, may be due to the genetical differences of these populations.     

MiRNAs and inflammatory bowel disease: An interesting new story

Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory disorder, is caused by a dysregulated and aberrant immune response to exposed environmental factors in genetically susceptible individuals. Despite huge efforts in determining the molecular pathogenesis of IBD, an increasing worldwide incidence of IBD has been reported. MicroRNAs (miRNAs) are a set of noncoding RNA molecules that are about 22 nucleotides long, and these molecules are involved in the regulation of the gene expression. By clarifying the important role of miRNAs in a number of diseases, their role was also considered in IBD; numerous studies have been performed on this topic. In this review, we attempt to summarize a number of studies and discuss some of the recent developments in the roles of miRNAs in the pathophysiology, diagnosis, and treatment of IBD.     

Biological functions of NLRP3 inflammasome: A therapeutic target in inflammatory bowel disease

Cases of inflammatory bowel disease (IBD), a debilitating intestinal disorder with complex pathological mechanisms, have been increasing in recent years, straining the capacity of healthcare systems. Thus, novel therapeutic targets and innovative agents must be developed. Notably, the NLRP3 inflammasome is upregulated in patients with IBD and/or in animal experimental models. As an innate immune supramolecular assembly, the NLRP3 inflammasome is persistently activated during the pathogenesis of IBD by multiple stimuli. Moreover, this protein complex regulates pro-inflammatory cytokines. Thus, targeting this multiprotein oligomer may offer a feasible way to relieve IBD symptoms and improve clinical outcomes. The mechanisms by which the NLRP3 inflammasome is activated, its role in IBD pathogenesis, and the drugs administered to target this protein complex are reviewed herein. This review establishes that the use of inflammasome-targeting drugs are effective for IBD treatment. Moreover, this review suggests that the value and potential of naturally sourced or derived medicines for IBD treatment must be recognized and appreciated.     

间充质干细胞治疗炎症性肠病的应用及前景

炎症性肠病（IBD）是一种慢性非特异性肠道炎性疾病,其病因未明,有终生复发倾向,重症者迁延不愈。早期治疗以药物为主,部分重症患者后期需要手术干预。近年来,间充质干细胞（MSCs）由于具有多向分化潜能、免疫调节及组织修复功能已被广泛应用于IBD治疗的临床前基础研究中,具有一定理论基础。在已开展的MSCs治疗IBD的临床试验中,尚未有严重并发症的报道。虽然目前MSCs治疗不是IBD的标准治疗方案,但今后可能会成为一种新的治疗选择,特别是对于难治性或合并肛瘘的IBD患者。本文就MSCs的概况及其在IBD治疗的作用机制和应用前景作一综述。     

An analysis of genetic factors related to risk of inflammatory bowel disease and colon cancer

Background and aimsPatients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer than the general population. Genome-wide association studies have identified and replicated several loci associated with risk of IBD; however, it is currently unknown whether these loci are also associated with colon cancer risk.MethodsWe selected 15 validated SNPs associated with risk of either Crohn's disease, ulcerative colitis, or both in previous GWAS and tested whether these loci were also associated with colon cancer risk in a two-stage study design.ResultsWe found that rs744166 in STAT3 was associated with colon cancer risk in two studies; however, the direction of the observation was reversed in TP53 mutant tumors possibly due to a nullification of the effect by mutant p53. The SNP, which lies within intron 1 of the STAT3 gene, was associated with lower expression of STAT3 mRNA in TP53 wild-type, but not mutant, tumors.ConclusionsThese data suggest that the STAT3 locus is associated with both IBD and cancer. Further understanding the function of this variant in relation to TP53 could possibly explain the role of this gene in autoimmunity and cancer. Furthermore, an analysis of this locus, specifically in a population with IBD, could help to resolve the relationship between this SNP and cancer.     

Enhanced platelet adhesion induces angiogenesis in intestinal inflammation and inflammatory bowel disease microvasculature

Although angiogenesis is viewed as a fundamental component of inflammatory bowel disease (IBD) pathogenesis, we presently lack a thorough knowledge of the cell type(s) involved in its induction and maintenance in the inflamed intestinal mucosa. This study aimed to determine whether platelet (PLT) adhesion to inflamed intestinal endothelial cells of human origin may favour angiogenesis. Unstimulated or thrombin‐activated human PLT were overlaid on resting or tumour necrosis factor (TNF)‐α‐treated human intestinal microvascular endothelial cells (HIMEC), in the presence or absence of blocking antibodies to either vascular cell adhesion molecule (VCAM)‐1, intercellular adhesion molecule (ICAM)‐1, integrin α_vβ₃, tissue factor (TF) or fractalkine (FKN). PLT adhesion to HIMEC was evaluated by fluorescence microscopy, and release of angiogenic factors (VEGF and soluble CD40L) was measured by ELISA. A matrigel tubule formation assay was used to estimate PLT capacity to induce angiogenesis after co‐culturing with HIMEC. TNF‐α up‐regulated ICAM‐1, α_vβ₃ and FKN expression on HIMEC. When thrombin‐activated PLT were co‐cultured with unstimulated HIMEC, PLT adhesion increased significantly, and this response was further enhanced by HIMEC activation with TNF‐α. PLT adhesion to HIMEC was VCAM‐1 and TF independent but ICAM‐1, FKN and integrin α_vβ₃ dependent. VEGF and sCD40L were undetectable in HIMEC cultures either before or after TNF‐α stimulation. By contrast, VEGF and sCD40L release significantly increased when resting or activated PLT were co‐cultured with TNF‐α‐pre‐treated HIMEC. These effects were much more pronounced when PLT were derived from IBD patients. Importantly, thrombin‐activated PLT promoted tubule formation in HIMEC, a functional estimate of their angiogenic potential. In conclusion, PLT adhesion to TNF‐α‐pre‐treated HIMEC is mediated by ICAM‐1, FKN and α_vβ₃, and is associated with VEGF and sCD40L release. These findings suggest that inflamed HIMEC may recruit PLT which, upon release of pro‐angiogenic factors, actively contribute to inflammation‐induced angiogenesis.     

Associations between chronotype,sleep disturbances and seasonality with fatigue and inflammatory bowel disease symptoms

Growing number of studies suggests link between circadian rhythms and inflammatory bowel diseases (IBD) manifestation. We hypothesize that: 1) IBD are associated with increased eveningness and sleep disturbances; 2) eveningness and sleep disturbances are related to more severe IBD symptoms. In total, 129 participants were enrolled to this study, divided into three groups: 34 Crohn’s disease (CD) patients, 38 ulcerative colitis (UC) patients and 57 healthy controls (HC) group. They all fulfilled a questionnaire, consisting of the Composite Scale of Morningness (CSM), Seasonal Pattern Assessment Questionnaire (SPAQ), Pittsburgh Sleep Quality Index, Inflammatory Bowel Disease Questionnaire (IBDQ) and Multidimensional Fatigue Inventory (MFI). Multiple regression models controlled for age and sex revealed that in CD group higher eveningness measured with CSM was associated with higher general fatigue, physical fatigue, mental fatigue and reduced motivation measured by MFI. Lower CSM morning affect is associated with greater general fatigue, physical fatigue and more reduced activity. Greater seasonality scores are associated with increased physical fatigue and more reduced activity and motivation. Lower sleep quality measured with PSQI is associated with higher physical fatigue and more reduced activity. Correlational analysis revealed that higher seasonality and lower sleep quality are associated with increased systemic and bowel symptoms and decreased emotional and social functions measured with IBDQ. In UC group, eveningness is associated with greater general fatigue, physical fatigue and more reduced activity. Higher CSM morning affect is associated with decreased general fatigue, physical fatigue and less reduced activity. Higher CSM circadian preference scores are associated with decreased general and physical fatigue, and less reduced activity. Increased seasonality is associated with more physical fatigue. Lower sleep quality is associated with greater general and physical fatigue. To our best knowledge this is the first study evaluating associations between chronotype and sleep disturbances with IBD symptoms. We have found that chronotype preferences, whose role in IBD has been until now overlooked, may be one of the important factors contributing to fatigue in this clinical group.     

不同途径下MIMP对 炎症性肠病小鼠肠道菌群结构的影响

目的通过葡聚糖硫酸钠诱导小鼠炎症性肠病(IBD)模型并观察不同途经下乳杆菌微小膜蛋白(MIMP)对炎症性肠病小鼠的紧密连接蛋白及菌群结构的影响。方法 C57BL/6小鼠24只根据DSS和MIMP不同干预组合将其分为4组:MIMP腹腔注射组(n=6)、MIMP灌胃组(n=6)、诱导肠炎组(n=6)和健康对照组(n=6),利用Western blot对各组小鼠肠道中紧密连接蛋白(Occludin、JAM-1和ZO-1)的表达进行检测,采用16SrRNA测序技术检测V4区鉴定细菌,并进行菌群差异分析。结果 MIMP腹腔注射及灌胃均可显著提高IBD小鼠肠道中紧密连接蛋白的表达水平,灌胃组效果更为显著;MIMP干预后小鼠肠道中拟杆菌门(Bacteroidetes)丰度增高、厚壁菌门(Firmicutes)及变形菌门(Proteobacteria)丰度降低,LEfSe分析、PCoA分析和PCA分析提示4组小鼠肠道菌群结构差异显著。结论不同途径下MIMP均可显著提高IBD小鼠肠道中紧密连接蛋白的表达水平,改善肠黏膜屏障功能,纠正小鼠肠道菌群结构紊乱。     

Chemokine and cytokine levels in inflammatory bowel disease patients

Crohn’s disease (CD) and ulcerative colitis (UC), two forms of inflammatory bowel disease (IBD), are chronic, relapsing, and tissue destructive lesions that are accompanied by the uncontrolled activation of effector immune cells in the mucosa. Recent estimates indicate that there are 1.3 million annual cases of IBD in the United States, 50% of which consists of CD and 50% of UC. Chemokines and cytokines play a pivotal role in the regulation of mucosal inflammation by promoting leukocyte migration to sites of inflammation ultimately leading to tissue damage and destruction. In recent years, experimental studies in rodents have led to a better understanding of the role played by these inflammatory mediators in the development and progression of colitis. However, the clinical literature on IBD remains limited. Therefore, the aim of this study was to evaluate systemic concentrations of key chemokines and cytokines in forty-two IBD patients with a range of disease activity compared to levels found in ten healthy donors. We found a significant increase in an array of chemokines including macrophage migration factor (MIF), CCL25, CCL23, CXCL5, CXCL13, CXCL10, CXCL11, MCP1, and CCL21 in IBD patients as compared to normal healthy donors (P < 0.05). Further, we also report increases in the inflammatory cytokines IL-16, IFN-γ, IL-1β and TNF-α in IBD patients when compared to healthy donors (P < 0.05). These data clearly indicate an increase in circulating levels of specific chemokines and cytokines that are known to modulate systemic level through immune cells results in affecting local intestinal inflammation and tissue damage in IBD patients. Blockade of these inflammatory mediators should be explored as a mechanism to alleviate or even reverse symptoms of IBD.