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.     

New cytokine therapeutics for inflammatory bowel disease

Conventional therapy for inflammatory bowel diseases rely on corticosteroids and 5-aminosalicylates combined with immunosuppressive agents for maintenance. These drugs are not always effective and may inflict serious side effects. Other therapies are therefore awaited. Infliximab, a monoclonal antibody against the pro-inflammatory cytokine TNF-alpha has been successfully applied as a treatment for Crohn's disease. The mechanism of action of this drug extends beyond the level of TNF-alpha scavenging and includes induction of apoptosis of effector cells. Numerous anti-TNF antibodies have been developed and are currently evaluated in clinical trials. Other targets for monoclonal antibodies include integrins and cytokines involved in T-cell differentiation and activation. Likewise recombinant proteins that moderate TNF bioactivity and lymphocyte function have been developed. The therapeutic effect of recombinant interleukin-10 seems to be dependent on local delivery of the protein. Antisense therapy targeting lymphocyte migration has also been tested in IBD. Finally, the conventional drug thalidomide and possibly MAP-kinase inhibitors may become novel treatment entities for IBD.     

多巴胺能系统与炎症性肠病

多巴胺(dopamine,DA)是一种儿茶酚胺类的神经递质.多项研究表明多巴胺能信号通路是促进中枢神经系统和免疫系统之间平衡的关键因素,某些免疫细胞自身可以产生和释放DA.DA受体广泛表达于多种免疫细胞,DA能系统受损可能影响免疫稳态,从而影响自身免疫性疾病的发生和进展.这使得DA和炎症性肠病(inflammatory...     

Pregnancy and inflammatory bowel disease.

Conclusions about the relationship between the pathophysiology and treatment of inflammatory bowel disease and the physiology and management of pregnancy are based on the results of several large physician surveys and retrospective chart reviews. Patients with active disease fare worse than those with inactive disease. There is little evidence that pregnancy affects the course of inflammatory bowel disease or that inactive inflammatory bowel disease affects the course of pregnancy. Judicious medical therapy is effective in controlling inflammatory bowel disease during pregnancy. Sulfasalazine or steroid therapy should not be withdrawn in a patient who needs it to achieve or maintain a quiescent state of inflammatory bowel disease during the course of pregnancy. Immunosuppressive therapy should be avoided. Aggressive medical therapy with total parenteral nutrition in a team approach with a gastroenterologist, surgeon, and perinatologist usually avoids the need for surgical intervention during pregnancy with a good fetal outcome in a patient whose disease is active. Contraception against pregnancy need only be considered in those patients whose disease is so severe that operative therapy is imminent.     

Design of nanozymes for inflammatory bowel disease therapy

Science China Life Sciences -     

Somatostatin in inflammatory bowel disease

Intestinal inflammation is controlled by various immunomodulating cells, interacting by molecular mediators. Neuropeptides, released by enteric nerve cells and neuroendocrine mucosa cells, are able to affect several aspects of the general and intestinal immune system, with both pro- as well as anti-inflammatory activities. In inflammatory bowel disease (IBD) there is both morphological as well as experimental evidence for involvement of neuropeptides in the pathogenesis. Somatostatin is the main inhibitory peptide in inflammatory processes, and its possible role in IBD is discussed.     

Cytokines in inflammatory bowel disease

Over the past decade, much has been learned regarding the role of various cytokines in the pathogenesis of inflammatory bowel disease. Several cytokine 'knockout' models in mice have been shown to develop colitis, while alterations in the production of various cytokines has been documented in human Crohn's disease and ulcerative colitis. In recent years, attempts have been made to treat these diseases through modulation of cytokine production or action. This review focuses on the cytokines that have been implicated in the pathogenesis of inflammatory bowel disease. The evidence for and against a role for particular cytokines in intestinal inflammation is reviewed, as is the experimental and clinical data suggesting that cytokines are rational targets for the development of new therapies.     

Nematode modulation of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic disease arising due to a culmination of genetic, environmental, and lifestyle-associated factors and resulting in an excessive pro-inflammatory response to bacterial populations in the gastrointestinal tract. The prevalence of IBD in developing nations is relatively low, and it has been proposed that this is directly correlated with a high incidence of helminth infections in these areas. Gastrointestinal nematodes are the most prevalent parasitic worms, and they efficiently modulate the immune system of their hosts in order to establish chronic infections. Thus, they may be capable of suppressing unrelated inflammation in disorders such as IBD. This review describes how nematodes, or their products, suppress innate and adaptive pro-inflammatory immune responses and how the mechanisms involved in the induction of anti-nematode responses regulate colitis in experimental models and clinical trials with IBD patients. We also discuss how refinement of nematode-derived therapies should ultimately result in the development of potent new therapeutics of clinical inflammatory disorders.     

炎症性肠病生物检测器的构建与调试

利用工程改造过的肠道微生物进行无创、便宜便捷的肠道炎症检测、治疗可有效应用于医药行业。肠道炎症通常伴随着肠道中硫代硫酸盐和连四硫酸盐的增加,双组分系统ThsSR和TtrSR是两套分别检测这两种小分子的生物感受器系统。采用荧光蛋白作为指示剂需要复杂的测试仪器,不适用于家用检测环境,而肉眼可见的色素蛋白和有色小分子作为指示剂将可能扩大ThsSR和TtrSR的应用前景。两套系统分别被转入大肠杆菌EscherichiacoliTop10和益生菌E. coli Nissle 1917中,sfGFP信号表达效果证明了这两套系统可用。考虑实际应用,sfGFP被一系列色素蛋白和显色小分子替换,在E. coli Top10中,一系列色素蛋白和紫色杆菌素前体protoviolaceinic acid的显色效果明显,表明了该系统具有用于实际肠道炎症检测的可行性。结果表明,改进后的ThsSR和TtrSR系统能够针对不同浓度的肠道炎症标记物作出相应程度的反应,具备用于家庭环境人体肠道炎症检测的潜力。     

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。     

Genes, diet and inflammatory bowel disease

Inflammatory bowel disease (IBD) arises in part from a genetic predisposition, through the inheritance of a number of contributory genetic polymorphisms. These variant forms of genes may be associated with an abnormal response to normal luminal bacteria. A consistent observation across most populations is that any of three polymorphisms of the Caspase-activated recruitment domain (CARD15) gene are more prevalent in IBD patients as compared with unaffected controls. Similar aberrant responses to bacteria are associated with variants in Autophagy-related 16-like 1 (ATG16L1) and human defensin (HBD-2, -3 and -4) genes. The defective bacterial signal in turn leads to an excessive immune response, presenting as chronic gut inflammation in susceptible individuals. Inconsistent population reports implicate the major histocompatability complex (MHC), that encodes a number of human leukocyte antigens (HLA), MHC class I chain-related gene A (MICA) or cytokines, such as tumour necrosis factor-alpha (TNF-alpha). Toll-like receptors encoded by the TLR4 or TLR9 genes may also play a role. Recent whole genome scans suggest that a rare variant in the interleukin-23 receptor (IL23R) gene may actually protect against IBD. Other implicated genes may affect mucosal cell polarity (Drosophila discs large homologue 5, DLG5) or mucosal transporter function (sodium dependent organic cation transporters, SLC22A4 and SLC22A5). A variant in ABCB1 (ATP-binding cassette subfamily B member 1) may be especially associated with increased risk of UC. While pharmacogenetics is increasingly being used to predict and optimise clinical response to therapy, nutrigenetics may have even greater potential. In many cases, IBD can be controlled through prescribing an elemental diet, which appears to act through modulating cytokine response and changing the gut microbiota. More generally, no single group of dietary items is beneficial or detrimental to all patients, and elimination diets have been used to individualise dietary requirements. However, recognising the nature of the genes involved may suggest a more strategic approach. Pro- or prebiotics will directly influence the microbial flora, while immunonutrition, including omega-3 fatty acids and certain polyphenols, may reduce the symptoms of gut inflammation. The expression of gut transporters may be modulated through various herbal remedies including green tea polyphenols. Such approaches would require that the gene of interest is functioning normally, other than its expression being up or down-regulated. However, new approaches are being developed to overcome the effects of polymorphisms that affect the function of a gene. A combination of human correlation studies with experimental models could provide a rational strategy for optimising nutrigenetic approaches to 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.     

Lipoxin biosynthesis in inflammatory bowel disease

BACKGROUND AND AIMS: Lipoxins are anti-inflammatory lipid mediators that are produced in gut mucosa, which serve to limit and resolve persistent inflammation. The purpose of this study was to evaluate colonic lipoxin biosynthesis in patients with ulcerative colitis (UC) to establish a possible biochemical basis for persistent inflammation in UC. METHODS: Colonic mucosa from patients with UC or organ donors (controls) was placed into tissue culture for 90 min. The conditioned media was assayed (ELISA) for lipoxin A4 (LXA) and the biologically active isomer 15-epi-LXA4 (aspirin triggered lipoxin, ATL). Mucosal tissue 15-lipoxygenase protein was determined by Western blot. RESULTS: Patient colonic mucosa produced significantly lower (12-fold) amounts of LXA, relative to organ donors. This occurred irregardless of patient steroid treatment. However, patient tissue responded to in vitro aspirin by synthesizing biologically active ATL. For the first time, human colonic mucosa was found to synthesize 15-lipoxygenase-2, an epithelial-derived isoenzyme used for lipoxin synthesis. These levels were significantly lower in UC patients compared to the control tissue. Finally, mice chronically treated with a putative selective 15-lipoxygenase inhibitor (PD 146176) experienced significantly worse intestinal function during experimental colitis, relative to untreated mice. CONCLUSION: Colonic mucosa from UC patients demonstrated defective lipoxin biosynthesis, which may contribute to the inability of these patients to resolve persistent colonic inflammation.     

The genetics and immunopathogenesis of inflammatory bowel disease

Genome-wide association studies efficiently and powerfully assay common genetic variation. The application of these studies to Crohn's disease has provided insight into the immunopathogenesis of this disease, implicating a role for genes of the innate and adaptive immune systems. In this Review, I discuss our current understanding of the genetics and immunopathogenesis of Crohn's disease and ulcerative colitis. Crohn's disease, but not ulcerative colitis, is associated with genetic variation in NOD2 and an autophagy gene, ATG16L1, both of which affect the intracellular processing of bacterial components. By contrast, variation in the gene encoding the interleukin-23 (IL-23) receptor subunit, as well as in the IL12B, STAT3 and NKX2-3 gene regions, is associated with both Crohn's disease and ulcerative colitis. Comparative analyses of gene associations between these two inflammatory bowel diseases reveal common and unique mechanisms of their immunopathogenesis.     

Microbiological and immunological strategies for treatment of inflammatory bowel disease.

Chronic inflammatory bowel diseases such as Crohn's disease or ulcerative colitis, affect around 1 in every 1000 individuals in western countries. They probably result from an inappropriate reaction towards the commensal microflora and are currently treated with anti-inflammatory drugs or surgery. Novel strategies aim at blocking lymphocyte recruitment and activation, improved targeting of therapeutics and modification of gut microflora.