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.     

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。     

Interleukin-6 trans-signaling in inflammatory bowel disease

The pathogenesis of inflammatory bowel disease (IBD) is complex, involving a wide range of molecules including cytokines. Recent investigations support the important role of an interleukin-6 (IL-6) signaling pathway in the development of IBD. However, the molecular mechanisms of this pathway in the intestine remain incompletely understood. The circulating and intestinal levels of IL-6 as well as soluble IL-6 receptor (sIL-6R) are increased in patients with IBD. It is remarkable that the mucosal T cells of IBD patients are extremely resistant to apoptosis and that a large fraction of these cells express membrane-bound gp130 but not IL-6R. The accumulated evidence strongly supports the hypothesis that the development and perpetuation of IBD relies on the increased formation of IL-6/sIL-6R complexes interacting with membrane-bound gp130 on T cells via trans-signaling. These studies suggest that IL-6 trans-signaling may play a role in the development of IBD; they therefore imply the possibility of a selective therapeutic strategy to target this signaling.     

Chronic inflammatory bowel disease in childhood.

The diagnosis of Crohn''s disease in childhood has been facilitated by the use of fibreoptic endoscopy with biopsies, complemented by double-contrast radiology. Clinical suspicion leads initially to several relevant blood tests. These are followed by endoscopy and multiple colonic biopsies or barium follow-through studies depending on whether large-bowel or small-bowel disease is suspected. The present approach to diagnosis is based on corroborative investigative techniques-endoscopy, radiology, and histology, The availability of paediatric colonoscopes of small diameter should make it possible for paediatricians to perform limited examinations, but when more extensive endoscopy is indicated the child should be referred to special centres.     

Leukocyte migration in experimental inflammatory bowel disease

Emigration of leukocytes from the circulation into tissue by transendothelial migration, is mediated subsequently by adhesion molecules such as selectins, chemokines and integrins. This multistep paradigm, with multiple molecular choices at each step, provides a diversity in signals. The influx of neutrophils, monocytes and lymphocytes into inflamed tissue is important in the pathogenesis of chronic inflammatory bowel disease. The importance of each of these groups of adhesion molecules in chronic inflammatory bowel disease, either in human disease or in animal models, will be discussed below. Furthermore, the possibilities of blocking these different steps in the process of leukocyte extravasation in an attempt to prevent further tissue damage, will be taken into account.     

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.     

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.     

Bacteria in the pathogenesis of inflammatory bowel disease

Twin studies have demonstrated the importance of environmental factors in the pathogenesis of inflammatory bowel disease, but progress has been relatively slow in identifying these, with the exception of smoking, which is positively associated with Crohn's disease and negatively associated with ulcerative colitis. Genetic studies have identified risk alleles which are involved in host-bacterial interactions and the mucosal barrier, and evidence is building for a likely pathogenic role for changes in the gut microbiome, with respect to both faecal and mucosa-associated microbiota. Some of these changes may be secondary to inflammation, nevertheless promising new therapeutic targets are beginning to emerge.     

Role of matrix metalloproteinases in inflammatory bowel disease

Recent evidence demonstrates that the increased expression and activity of matrix metalloproteinases (MMPs) may contribute to intestinal tissue injury and inflammation in inflammatory bowel disease, and that MMP inhibition might be a new therapeutic approach to controlling inflammatory response. In addition, MMPs may play a crucial role in physiological and pathophysiological reactions such as leukocyte accumulation into inflamed tissue, cytokine production from inflammatory and epithelial cells, T lymphocyte homing to the intestine, wound healing and proliferation of epithelial cells, and intestinal innate immunity. This review focuses on recent progress in elucidating the biological and pathological roles of MMPs in inflammatory bowel disease.     

The role of obesity in inflammatory bowel disease

In just over a generation overweight and obesity has become a worldwide health concern. The ramifications for this on future health care costs and longevity are consequent, whilst increased adiposity is a harbinger for diabetes, kidney and bone failure, and cancer. An area of intense interest where the role of adiposity is avidly discussed is in inflammatory bowel disease (IBD), which presents mainly as Crohn's disease (CD) and ulcerative colitis (UC). Studies in patients associating IBD with a western diet are divergent. Nevertheless, elegant studies have found gene polymorphisms in humans that in murine models parallel the inflammatory and gut microbiome changes seen in IBD patients. However, an area not to be ignored are the alterations in adipocyte function with ensuing adiposity, in particular and a focus of this review, the dysregulation of the levels of adipocytokines such as leptin and adiponectin. Herein, we present and discuss the known influences of a western diet on IBD in patients and rodent models and how adipocytokines could influence the IBD disease process.     

CEACAM6 gene variants in inflammatory bowel disease

Background

The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) acts as a receptor for adherent-invasive E. coli (AIEC) and its ileal expression is increased in patients with Crohn''s disease (CD). Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD).

Methodology

In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC), and 1,350 healthy, unrelated controls) was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839). In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants.

Conclusions

This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.     

Antilaminaribioside and antichitobioside antibodies in inflammatory bowel disease

Testing antilaminaribioside (ALCA) and antichitobioside (ACCA) antibodies in 89 Crohn's disease (CD), 31 ulcerative colitis (UC) and 50 controls, mean values were 38.6 and 53.0 ELISA units for CD, 34.0 and 32.6 for UC, 34.5 and 36.4 for controls, respectively. There was no significant difference of ALCA values between CD and UC (p = 0.401), CD and control subjects (p = 0.698) or UC and controls (p = 0.898). ACCA were significantly higher in CD compared with UC (p = 0.011) but not with the controls (p = 0.095). No significant difference of ACCA values between UC and controls (p = 0.107) was found. ALCA and ACCA values significantly correlated in CD (r = 0.548, p < 10(-4)) and UC (r = 0.885, p < 10(-4)) but not in controls (r = 0.153, p = 0.287). The positive predictive value for CD was only 20 (ALCA) and 8 % (ACCA), the negative ones (to exclude CD) 25 (ALCA) and 86 % (ACCA). Small and/or large bowel involvement or disease type (i.e. stenosing, perforating or inflammatory) of CD did not differ in the two values. The idea that ALCA and ACCA may be useful either to differentiate between CD, UC and healthy subjects or to stratify CD was not confirmed.