Inflammatory bowel disease and the risk of osteoporosis and fracture

Inflammatory bowel disease (IBD) is commonly believed to increase the risk of bone mineral loss, leading to osteoporosis and an increased risk of disabling fractures. In this narrative review, we will presenting a summary of the published medical literature in regards to the relationship between IBD and the development of osteoporosis, bone mineral loss, and fractures. We will explore the epidemiology of metabolic bone disease in IBD, focusing on the prevalence and both the general and IBD-specific risk factors for the development of osteoporosis and of fracture in persons with IBD. We will also examine the role of the inflammatory process in IBD promoting excessive bone mineral loss, as well as the role that low body mass, corticosteroid use, diet, and nutrient malabsorption play in contributing to bone disease. Last, we will discuss our recommendation for: screening for osteoporosis in IBD patients, the use of preventative strategies, and therapeutic interventions for treating osteoporosis in persons with IBD.     

Metabolomic profiling in children with inflammatory bowel disease

Ulcerative colitis (UC) and Crohn's disease (CD) represent inflammatory bowel diseases (IBD) with multifactorial pathogenesis, involving genetic, environmental and microbial factors. Interactions between gut microbiota and immune system result in changes in metabolic pathways. Metabolomics is a comprehensive and quantitative (or semi-quantitative) analysis of metabolites synthetized in human's biological system. It has been shown that metabolic profiling might be used to identify disease biomarkers. Recent findings confirmed alterations in the number of metabolites in patients with IBD. However, most of the studies included adult individuals with ongoing treatment which might have affected the metabolite profiling. Therefore, the aim of our study was to collect the knowledge about metabolomics in paediatric patients with CD or UC based on the currently published literature.     

Induction and maintenance treatment of inflammatory bowel disease: A comprehensive review

Ulcerative colitis (UC) and Crohn's disease (CD) are the two major types of inflammatory bowel disease (IBD). We conducted a comprehensive review of meta-analyses to summarize the reported effectiveness of different drugs for IBD. We performed a literature search and a total of 110 meta-analyses from 66 articles were summarized and re-analyzed (62 in UC and 48 in CD). In summary, 5-ASA was more effective than placebo in both induction and maintenance treatment of UC, but there were conflicting results on the effect of 5-ASA on the induction treatment or relapse of CD. The use of immunomodulatory agents in the induction or maintenance phase of UC and CD using immunomodulators appeared to be more effective than placebo, but the results were impacted by small number of patients, discordant results with the largest study and risk of biases. Anti-TNF-α and anti-integrin therapeutic antibodies in both, induction and maintenance, showed a better efficacy than placebo in a large proportion of patients analyzed. Other agents, such as probiotics, antibiotics, omega-3, were shown to be more effective than placebo, but the same issues arose as stated above with the use of immunomodulatory agents. In conclusion, we performed a comprehensive review of meta-analysis on comparative efficacy of pharmacotherapy used in the management of IBD. Our review will augment our understanding of the treatment of UC and CD by providing a guideline for interpreting the statistically significant findings and discusses the optimal choice for IBD treatment.     

Mouse models of intestinal inflammation as tools to understand the pathogenesis of inflammatory bowel disease

Mouse models of intestinal inflammation resemble aspects of inflammatory bowel disease in humans. These models have provided important insights into mechanisms that control intestinal homeostasis and regulation of intestinal inflammation. This viewpoint discusses themes that have emerged from mouse models of intestinal inflammation including bacterial recognition, autophagy, the IL‐23/Th‐17 axis of inflammation as well as the role of negative regulators. Many of the pathways highlighted by model systems have been identified in recent genome‐wide association studies in human validating the relevance of mouse models to human inflammatory bowel disease. Understanding of the complex biological mechanisms that lead to intestinal inflammation in mouse models may help to define targets for treatment of human diseases.     

The CREM gene is involved in genetic predisposition to inflammatory bowel disease in the Tunisian population

The identification of susceptibility genes for inflammatory bowel disease (IBD) is key to understanding pathogenic mechanisms. Recently, the results of genetic association studies have highlighted many loci that are shared among several autoimmune diseases. We aimed to study the genetic epidemiology of polymorphisms in specific genes previously associated with other autoimmune diseases, namely the CREM, STAT4, STAT5a, Stat5b, and IRF5 genes. Twelve polymorphisms in the CREM, STAT4, STAT5a, Stat5b, and IRF5 genes were genotyped in a cohort of 107 IBD patients (39 Crohn's disease [CD] and 68 ulcerative colitis [UC]) and 162 controls from southern Tunisia. One CREM single nucleotide polymorphism (SNP) displayed evidence for genetic association with IBD (p=8.7×10(-4), odds ratio [OR]=2.84 [1.58; 5.09]). One STAT4 SNP (p=0.026; OR=1.65 [1.06; 2.58]) exhibited a marginal association with UC but not with CD. No significant association was observed with the SNPs in STAT5a, IRF5, and STAT5b. These results suggest that common variants of the CREM gene are involved in the genetic component conferring general susceptibility to IBD, whereas STAT4 appears to be more specifically associated with UC. This work provides motivation for studies aiming to replicate these findings in larger populations.     

Immunopathological characterization of selected mouse models of inflammatory bowel disease: Comparison to human disease

Inflammatory bowel diseases (IBD) are chronic, relapsing conditions of multifactorial etiology. The two primary diseases of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Both entities are hypothesized to occur in genetically susceptible individuals due to microbial alterations and environmental contributions. The exact etiopathogenesis, however, is not known for either disease. A variety of mouse models of CD and UC have been developed to investigate the pathogenesis of these diseases and evaluate treatment modalities. Broadly speaking, the mouse models can be divided into 4 categories: genetically engineered, immune manipulated, spontaneous and erosive/chemically induced. No one mouse model completely recapitulates the immunopathology of CD or UC, however each model possesses particular similarities to human IBD and offers advantageous for specific details of IBD pathogenesis. Here we discuss the more commonly used models in each category and critically evaluate how the immunopathology induced compares to CD or UC, as well as the advantages and disadvantages associated with each model.     

Association among genetic predisposition,gut microbiota,and host immune response in the etiopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn''s disease (CD) and ulcerativecolitis (UC), is a chronic disorder that affects thousands of people around theworld. These diseases are characterized by exacerbated uncontrolled intestinalinflammation that leads to poor quality of life in affected patients. Although theexact cause of IBD still remains unknown, compelling evidence suggests that theinterplay among immune deregulation, environmental factors, and genetic polymorphismscontributes to the multifactorial nature of the disease. Therefore, in this review wepresent classical and novel findings regarding IBD etiopathogenesis. Considering thegenetic causes of the diseases, alterations in about 100 genes or allelic variants,most of them in components of the immune system, have been related to IBDsusceptibility. Dysbiosis of the intestinal microbiota also plays a role in theinitiation or perpetuation of gut inflammation, which develops under altered orimpaired immune responses. In this context, unbalanced innate and especially adaptiveimmunity has been considered one of the major contributing factors to IBDdevelopment, with the involvement of the Th1, Th2, and Th17 effector population inaddition to impaired regulatory responses in CD or UC. Finally, an understanding ofthe interplay among pathogenic triggers of IBD will improve knowledge about theimmunological mechanisms of gut inflammation, thus providing novel tools for IBDcontrol.     

Induction of suppressor cells by Mycobacterium paratuberculosis antigen in inflammatory bowel disease.

We studied the M. paratuberculosis-induced proliferation and suppressor cell generation by peripheral blood lymphocytes from patients with inflammatory bowel disease. Peripheral blood lymphocytes were separated from 33 patients with Crohn's disease, 18 with ulcerative colitis, nine with other intestinal diseases, and five with autoimmune disorders. Proliferation of peripheral blood lymphocytes from normal individuals in response to 10 micrograms/ml of M. paratuberculosis antigen was reduced by depletion of CD4+ T cells. The ability of M. paratuberculosis antigen to suppress concanavalin A-induced proliferation (expressed as a percentage suppression) was reduced by depletion of CD8+ T cells. This suppression was the same whether peripheral blood lymphocytes were from normal individuals, patients with intestinal diseases other than inflammatory bowel disease, or patients with autoimmune disorders (47 +/- 14%, 44 +/- 24%, and 30 +/- 26%, respectively). In contrast, the suppression induced by M. paratuberculosis for patients with Crohn's disease and ulcerative colitis (66 +/- 22% and 67 +/- 22%) was much greater than that for normal individuals (P less than 0.001). In particular, lymphocytes from patients with active Crohn's disease demonstrated little proliferation in response to this antigen but marked suppressor activity (79 +/- 13%). How the immunomodulatory effects of this antigen relate to the pathogenesis of the inflammatory bowel diseases remains to be determined.     

Increased expression of NKX2.3 mRNA transcribed from the risk haplotype for ulcerative colitis in the involved colonic mucosa

NKX2.3 is a promising candidate for susceptibility genes to inflammatory bowel disease (IBD). The aim of this study was to perform a candidate gene analysis of NKX2.3 in Japanese IBD and to examine how the risk allele (haplotype) affects susceptibility to IBD using allelic expression ratios of NKX2.3 mRNA in the involved colonic mucosa. A total of 344 patients with Crohn's disease (CD), 253 patients with ulcerative colitis (UC), and 243 healthy controls (HCs) were genotyped for 3 tag-single nucleotide polymorphisms (SNPs; rs10883365, rs888208, and rs11596008) around NKX2.3. The allelic expression ratio of NKX2.3-mRNA was examined by TaqMan assay using rs888208 as an allelic (haplotypic) marker. Two SNPs (rs10883365 and rs888208) were significantly associated with UC (p = 7.79 × 10(-4), odds ratio [OR] = 1.54 [95% confidence interval (95% CI) 1.20-1.99], p = 7.70 × 10(-3), OR = 1.41 [95% CI 1.10-1.81], respectively) and 1 SNP (rs10883365) was associated with CD (p = 0.0366, OR = 1.29 [95% CI 1.02-1.63]). Haplotype B formed by the 3 SNPs demonstrated a significant association with UC (p = 6.11 × 10(-4), OR = 1.56 [95% CI 1.21-2.00]). Subgroup analyses indicated that rs10883365 was significantly associated mainly with colonic CD (p = 1.99 × 10(-3), OR = 1.91 [95% CI 1.27-2.88], vs HCs). The allelic expression ratios of NKX2.3 mRNA transcribed from haplotype B (risk haplotype) to haplotype A (the nonrisk haplotype) in the involved mucosa from 10 IBD patients were significantly higher than the allelic ratio of respective genomic DNA (p = 0.00195). We confirmed the association of SNP rs10883365 located in the 5' flanking region of NKX2-3 with Japanese UC and colonic CD and determined the risk haplotype (haplotype B) for UC. The demonstrated allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility to UC through increasing expression of NKX2.3 mRNA in the colonic mucosa.     

Incidence and Prevalence of Inflammatory Bowel Disease across Asia

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn''s disease (CD), are chronic inflammatory disorders of the gastrointestinal tract caused by interactions between genetic, environmental, immunological, and microbial factors. While the incidence and prevalence of IBD in Asian populations were relatively lower than those in Western countries, they appear to be gradually increasing. A Westernized diet, high socioeconomic status, improvement of hygiene, and development of vaccination could affect the increases in IBD incidence and prevalence in Asian countries. This review describes the latest trends in the incidence and prevalence of IBD in Asia. Studying the epidemiology of IBD in Asia may unravel the etiopathogenesis of and risk factors for IBD.     

Differential expression of the TRAIL/TRAIL-receptor system in patients with inflammatory bowel disease

TNF-related apoptosis inducing-ligand (TRAIL) is a potent inducer of apoptosis and plays an important role in immune regulation. To explore the role of TRAIL in inflammatory bowel disease (IBD), we examined the expression of the TRAIL/TRAIL-receptor system in colonic resections from patients with ulcerative colitis and Crohn's disease in comparison to normal colon and appendicitis.     

肥大细胞与炎症性肠病

炎症性肠病（Inflammatoryboweldisease,IBD）包括溃疡性结肠炎（Ulcerativecolitis）和克罗恩病（Crohn’sdisease）,是一种原因不明的慢性非特异性肠道炎症,其发病机制主要和免疫、遗传、感染、应激等多种因素有关。近年来发现其发病与肥大细胞也密切相关。     

Changes in phenotypically distinct mucosal macrophage populations may be a prerequisite for the development of inflammatory bowel disease.

Previous studies have demonstrated the presence of much more marked macrophage heterogeneity in colonic mucosa affected by the idiopathic inflammatory bowel diseases (ulcerative colitis and Crohn's disease) than in normal mucosa. This study examines the morphology, distribution and phenotypic expression of mucosal macrophage-like cells in biopsies from patients with idiopathic inflammatory bowel disease in comparison with disease control samples from patients with colonic infection or ischaemia. Approximately 80% of macrophage-like cells in histologically normal mucosa co-express the antigens recognized by the monoclonal antibodies RFD1 (an interdigitating cell marker) and RFD7 (a marker for mature tissue macrophages). In idiopathic inflammatory bowel disease, the normal colonic macrophage population is partly replaced by cells staining positively with RFD7 alone, and, to a lesser extent, with RFD1+ dendritic cells. Sections from patients with infections and ischaemia exhibited epithelial HLA-DR positivity and infiltration of the lamina propria by a more heterogeneous population of macrophages than that seen in histologically normal mucosa. However, the displacement of the normal colonic macrophage phenotype by RFD7+ tissue macrophages occurred to a significantly greater extent in idiopathic inflammatory bowel disease than in disease control mucosa. A pathognomonic feature of the ulcerative colitis and Crohn's colitis sections was the clustering of RFD9+ epithelioid cells at the bases of disrupted crypts and adjacent to areas of mucosal damage. It is concluded that a degree of macrophage heterogeneity and macrophage infiltration can occur as a non-specific response to colonic mucosal damage. The distinctive feature of idiopathic inflammatory bowel disease mucosa is the almost complete replacement of the normal colonic mucosal macrophage population by tissue macrophages and epithelioid cells, and this phenomenon may be important in promoting the development of a chronic inflammatory state.     

Diagnostic problems in chronic inflammatory bowel disease related specimens

A diagnosis of inflammatory bowel disease (IBD) carries serious long term implications for patient management and for cost of care. Pathologists must be aware of common mimics of IBD to prevent misdiagnosis. The distinction between ulcerative colitis and Crohn's disease is usually straightforward in resections but cannot be made easily on mucosal biopsies alone. Correlation with clinical and endoscopic findings is needed in the latter instance. The diagnosis of “indeterminate colitis” must be made only in resection specimens using strict diagnostic criteria. This review deals with common problems associated with the diagnosis of IBD and IBD-associated neoplasia.     

Flotillin-2 Expression in the Human Gut: from a Cell Model to Human Tissue in Health and Inflammatory Bowel Diseases

Background and aims: The etiopathogenesis of inflammatory bowel diseases (IBD) remains largely unexplained. Flotillins (flotillin-1 and flotillin-2) are ubiquitous proteins which have been linked to inflammation and regeneration. We hypothesized that alterations in the expression of flotillin-2 in enterocytes may be related to the pathogenesis of IBD as a classical example of an inflammatory disorder of mostly unknown origin.Methods: Cell and tissue localization of flotillin-2 (and -1) were investigated by immunofluorescent staining in 1. polarized and unpolarized CaCo-2w cells as a model of human enterocytes (native and after TNFα stimulation) and 2. intestinal biopsies from controls, patients with ulcerative colitis (UC) and patients with Crohn''s disease (CD). For quantification of flotillin-2, we analyzed its expression in ileal and colonic biopsies from controls, UC patients and CD patients using real-time RT-PCR, Western blot and indirect immunofluorescence.Results: In polarized CaCo-2w cells and human enterocytes in biopsies, flotillins were localized at the basolateral membrane and on subapical vesicles, but not in the apical membrane. Flotillin-2 expression did not differ between UC patients, CD patients and controls. However, it was significantly higher in colonic biopsies compared to ileal biopsies in all groups.Conclusions: By virtue of its abundant expression in enterocytes, flotillin-2 must have an essential function in intestinal physiology, especially in the colon. Yet our data could not link flotillin-2 to the pathogenesis of IBD.     

Giant cell arteritis and inflammatory bowel disease – Is there a connection? Results from a population-based study

Background

Giant cell arteritis (GCA) is an autoimmune disorder which primarily affects large vessels, whilst inflammatory bowel diseases (IBD) mainly target the gut. Co-existence of the two maladies has been reported sporadically in the literature; therefore the purpose of this study was to assess the authenticity of such an association in a large, cross-sectional study.

炎症性肠病的致病机理和治疗研究进展

炎症性肠病（IBD）,主要指克隆病（CD）和溃疡性结肠炎（UC）,同时也包括一些其它非传染性的肠道炎症,是一类以免疫应答失调导致持续性肠道炎症为特征的疾病。IBD的病因和确切的发病机制目前还并不明确,一般认为是在遗传易感性的个体身上,由于环境因素,遗传因素,以及免疫因素等各方面的综合作用,肠道粘膜免疫系统对肠道微生物菌群发生了过度的免疫反应而最终导致了肠道炎症。IBD传统的治疗方法并没有很好的效果并常常伴随着强烈的副作用。近些年来随着对免疫因素在IBD发病中所起作用的研究日益深入,不断出现着一些针对IBD发病机制的新的疗法。     

Absence of a role for interleukin‐13 in inflammatory bowel disease

IL‐13 has been implicated in the pathogenesis of ulcerative colitis (UC), and may have a role in animal models of gut fibrosis. We studied the involvement of IL‐13 in inflammation and fibrosis in UC and Crohn's disease (CD). Intestinal biopsies and anti‐CD3/CD28‐ or anti‐CD2/CD28‐stimulated lamina propria mononuclear cells from UC and CD patients and control subjects were cultured, and IL‐13, IL‐4, IL‐5, IL‐17A and IFN‐γ production was measured. Mucosal IL‐13‐producing cells were characterised by flow cytometry. Gut explants from strictured CD, non‐strictured CD and healthy donors were cultured ex vivo, and secreted IL‐13, IL‐1β and collagen were measured. IL‐13 production by mucosal explants and activated lamina propria mononuclear cells did not differ between CD, UC and control subjects, and was at least a log lower than IFN‐γ and IL‐17A. IL‐13‐producing cells, and in particular natural killer T cells, were uniformly low in all groups. IL‐4 and IL‐5 were undetectable in culture supernatants. Explants of CD strictures produced low amounts of IL‐13, whereas IL‐1β and collagen were elevated. We could not confirm that UC or strictured CD are associated with elevated IL‐13 production. These data suggest that an anti‐IL‐13 Ab would not be an appropriate therapeutic strategy in inflammatory bowel disease.     

Identification of serum and tissue micro‐RNA expression profiles in different stages of inflammatory bowel disease

The altered expression of micro‐RNA (miRNA) has been associated with Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to establish specific miRNA expression patterns in the serum and mucosa of inflammatory bowel disease (IBD) patients (UC and CD with colonic involvement) at different stages of the disease. Serum and biopsies from nine active CD (aCD), nine inactive CD (iCD), nine active UC (aUC) and nine inactive UC (iUC) and serum from 33 healthy subjects were collected. Up to 700 miRNAs were evaluated by the TaqMan® human miRNA array. The ΔCt values were obtained using the mean expression values of all expressed miRNAs in a given sample as a normalization factor for miRNA real‐time quantitative polymerase chain reaction data. The levels of serum miRNAs in CD and UC patients were different to healthy subjects. Thirteen serum miRNAs were expressed commonly in CD and UC patients. Two miRNAs were higher and four miRNAs were lower in the serum of aCD than iCD. No serum miRNA was regulated exclusively in aUC compared with iUC patients. Four miRNAs were higher and three miRNAs were lower in the mucosa of aCD than iCD. Two miRNAs were higher and three miRNAs were lower in the mucosa of aUC than iUC. No serum miRNAs coincided with tissue miRNAs in aCD and aUC patients. Our results suggest the existence of specific miRNA expression patterns associated with IBD and their different stages and support the utility of miRNA as possible biomarkers. This pilot study needs to be validated in a large prospective cohort.