Influence of environmental factors on the onset and course of inflammatory bowel disease

Numerous environmental factors have been linked with inflammatory bowel disease. These include smoking, diet, hygiene, drugs, geographical and psychosocial factors. These factors may either increase the risk of or protect against developing this condition and can also affect the course of illness in a positive or negative manner. A number of studies have examined the influence of environmental factors on inflammatory bowel diseases as a whole as well as on ulcerative colitis and Crohn's disease separately. As there are differences in the pathogenesis of ulcerative colitis and Crohn's disease, the effect of environmental factors on their onset and course is not always similar. Some factors have shown a consistent association, while reports on others have been conflicting. In this article we discuss the current evidence on the roles of these factors on inflammatory bowel disease, both as causative/protective agents and as modifiers of disease course.     

Etiology and pathophysiology of inflammatory bowel disease--environmental factors

Environmental factors play an important role in the pathophysiology of inflammatory bowel disease. There is a strong and consistent association between smoking and Crohn's disease, and between nonsmoking and ulcerative colitis. Despite extensive research, the exact pathophysiological mechanisms for these associations remain unclear. In spite of this, some clinical trials with nicotine-patches showed beneficial effects for the treatment of ulcerative colitis. Associations of Crohn's disease and ulcerative colitis with other environmental factors are weaker like the association with use of oral contraceptives or those less well investigated such as the association with childhood hygiene. Most studies suggesting a potential pathogenetic role of Mycobacterium paratuberculosis or an effect of tuberculostatic therapy in Crohn's disease could not be reproduced by others. Perinatal or childhood infections by viruses like measles are heavily debated, but not proven to be causal for inflammatory bowel disease. Coagulation disorders have been described as protecting from inflammatory bowel disease, suggesting hypercoagulability to be a pathogenetic factor. Some studies described that appendectomy may prevent the onset of ulcerative colitis in man and mice. Other environmental factors such as hydrogen sulfide, tonsillectomy, diet, blood transfusions, and Listeria also require confirmation. There are, however, convincing data from genetic animal models and twin studies that environmental factors as the intestinal bacterial flora interact with susceptible hosts to cause inflammatory bowel disease. Inflammatory bowel diseases have multifactorial etiologies, which require a differentiated approach for treatment and prevention.     

Probiotics in arthralgia and spondyloarthropathies in patients with inflammatory bowel disease. Prospective randomized trials are necessary.

Arthralgias and spondyloarthropathies of the peripheral and axial joints are common in inflammatory bowel disease. Evidence for a strong association between these clinical manifestations and diseases of the joints has been provided by several clinical and epidemiological studies. Immunological studies have shown the presence of shared inflammatory cells both in the gut and the synovium in spondyloarthropathies. Genetic factors play a crucial role in the pathogenesis of spondyloarthropathies and inflammatory bowel disease. The role of the ubiquitous bacterial flora and pathogenic microorganisms present in the intestinal lumen may induce these joint diseases in patients with inflammatory bowel disease. In this review we will focus on the pathogenesis of spondyloarthropathies and arthralgia in patients suffering from inflammatory bowel disease. Based on preliminary clinical observations in patients with arthralgia and IBD, we put forward the hypothesis that probiotics may be helpful in the management of common extraintestinal manifestations such as arthralgia in patients with ulcerative colitis and Crohn's disease.     

Novel susceptibility genes in inflammatory bowel disease

The inflammatory bowel disease, Crohn's disease and ulcerative colitis, are polygenic disorders with important environmental interactions. To date, the most widely adopted approach to identifying susceptibility genes in complex diseases has involved genome wide linkage studies followed by studies of positional candidate genes in loci of interest. This review encompasses data from studies into novel candidate genes implicated in the pathogenesis of inflammatory bowel disease. Novel techniques to identify candidate genes-genome wide association studies, yeast-two hybrid screening, microarray gene expression studies and proteomic profiling, are also reviewed and their potential role in unravelling the pathogenesis of inflammatory bowel disease are discussed.     

Bacteria and inflammatory bowel disease

The cause of inflammatory bowel disease is unknown, but both environmental and genetic factors are implicated. This review presents evidence from recent studies involving both animal models and inflammatory bowel disease patients, which supports a role for bacteria in the aetiology and pathogenesis of Crohn's disease and ulcerative colitis.     

Role of granuloma in the immunopathogenesis of Crohn's disease

Inflammatory bowel diseases (ulcerative colitis and Crohn's disease) are chronic long-lasting inflammatory diseases with yet unknown etiology. Recent advancement revealed that both diseases are associated with genetic predisposition and environmental factors such as luminal microorganisms and antigens. Crohn's disease is associated with histopathologic features such as granuloma formation and longitudinal ulceration. In this article we describe the role of granuloma in the immunopathogenesis of Crohn's disease. Granuloma of Crohn's disease may play crucial roles as antigen-presenting cites to memory type T cells, which leads to activation and proliferation of T cells. Antigens presented at granuloma may be closely related to the disease.     

An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele.

The role of inflammatory T cells in Crohn's disease suggests that inherited variations in major histocompatibility complex (MHC) class II genes may be of pathogenetic importance in inflammatory bowel disease. The absence of consistent and strong associations with MHC class II genes in Caucasian patients with inflammatory bowel disease probably reflects the use of less precise typing approaches and the failure to type certain loci by any means. A PCR-sequence-specific oligonucleotide-based approach was used to type individual alleles of the HLA class II DRB1, DRB3, DRB4, and DRB5 loci in 40 patients with ulcerative colitis, 42 Crohn's disease patients, and 93 ethnically matched healthy controls. Detailed molecular typing of the above alleles has previously not been reported in patients with inflammatory bowel disease. A highly significant positive association with the HLA-DRB3*0301 allele was observed in patients with Crohn's disease (P = 0.0004) but not in patients with ulcerative colitis. The relative risk for this association was 7.04. Other less significant HLA class II associations were also noted in patients with Crohn's disease. One of these associations involved the HLA-DRB1*1302 allele, which is known to be in linkage disequilibrium with HLA-DRB3*0301. These data suggest that a single allele of an infrequently typed HLA class II locus is strongly associated with Crohn's disease and that MHC class II molecules may be important in its pathogenesis.     

Environmental risk factors in Crohn's disease and ulcerative colitis (excluding tobacco and appendicectomy)

A rapid increase in the incidence of Crohn's disease and ulcerative colitis in developed countries, the occurrence of Crohn's disease in spouses, and a lack of complete concordance in monozygotic twins are strong arguments for the role of environmental factors in inflammatory bowel disease (IBD). Research in the field of environmental factors in IBD is based upon epidemiological (geographical and case-control), clinical and experimental studies. The role of two environmental factors has clearly been established in IBD. Smoking is a risk factor for Crohn's disease and a protective factor for ulcerative colitis; appendectomy is a protective factor for ulcerative colitis. Many other environmental factors for IBD have been investigated, including infectious agents, diet, drugs, stress and social status. They are detailed in the present review. Among them, atypical Mycobacteria, oral contraceptives and antibiotics could play a role in Crohn's disease. To date, three hypotheses associate environmental factors with the pathophysiology of IBD (loss of tolerance of intestinal immune system towards commensal bacterial flora): the hygiene, infection and cold chain hypotheses. Much work remains to be done to identify risk factors for IBD. Research identifying environmental factors that might cause a predisposition to IBD is useful. It may lead to disease prevention in subjects who are genetically predisposed and disease improvement in patients.     

Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial function in inflammatory bowel disease

Increasing evidence has emerged that supports an important intersection between 3 fundamental cell biologic pathways in the pathogenesis of inflammatory bowel disease. These include the intersection between autophagy, as revealed by the original identification of ATG16L1 and IRGM as major genetic risk factors for Crohn's disease, and intracellular bacterial sensing, as shown by the importance of NOD2 in autophagy induction upon bacterial entry into the cell. A pathway closely linked to autophagy and innate immunity is the unfolded protein response, initiated by endoplasmic reticulum stress due to the accumulation of misfolded proteins, which is genetically related to ulcerative colitis and Crohn's disease (XBP1 and ORMDL3). Hypomorphic ATG16L1, NOD2, and X box binding protein-1 possess the common attribute of profoundly affecting Paneth cells, specialized epithelial cells at the bottom of intestinal crypts involved in antimicrobial function. Together with their functional juxtaposition in the environmentally exposed intestinal epithelial cell, their remarkable functional convergence on Paneth cells and their behavior in response to environmental factors, including microbes, these 3 pathways are of increasing importance to understanding the pathogenesis of inflammatory bowel disease. Moreover, in conjunction with studies that model deficient nuclear factor-κB function, these studies suggest a central role for altered intestinal epithelial cell function as one of the earliest events in the development of inflammatory bowel disease.     

Nutritional modulation of the inflammatory bowel response

Crohn's disease and ulcerative colitis represent distinct phenotypic forms of inflammatory bowel disease and continue to be a common cause of morbidity. The corticosteroids and the immunomodulatory drugs, which are the basis of treatment for the inflammatory bowel diseases, do not assure always satisfactory outcomes. Nutrition has been used in order to modify the inflammatory response of various chronic inflammatory diseases, including Crohn's disease and ulcerative colitis. In the pathogenesis of inflammatory bowel diseases, the intestinal microflora and the intestinal mucosal disorders play a crucial role. Also, the release of reactive oxygen species is a significant factor of initiation and preservation of the inflammatory reaction in these diseases. The advantages of the nutritional treatment derive from the sequestration of intraluminal agents which may promote the inflammatory bowel response or, alternatively, nutrition is able to modify the immune response, reducing the uncontrolled inflammatory reaction. Furthermore, nutrition can enhance the mucosal barrier function and consists a significant source of antioxidants. This review focuses on certain nutritional components that modulate the inflammatory response of the bowel and aims to present a rational thesis regarding the use of nutritional agents in the management of inflammatory bowel diseases.     

Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities

Ulcerative colitis (UC) and Crohn's disease (CD), the primary constituents of inflammatory bowel disease (IBD), are precipitated by a complex interaction of environmental, genetic, and immunoregulatory factors. Higher rates of IBD are seen in northern, industrialized countries, with greater prevalence among Caucasians and Ashkenazic Jews. Racial gaps are closing, indicating that environmental factors may play a role. IBD is multigenic, with the most clearly established genetic link between certain NOD2 variants and CD. Regardless of the underlying genetic predisposition, a growing body of data implicates a dysfunctional mucosal immune response to commensal bacteria in the pathogenesis of IBD, especially CD. Possible triggers include a chronic inflammatory response precipitated by infection with a particular pathogen or virus or a defective mucosal barrier. The characteristic inflammatory response begins with an infiltration of neutrophils and macrophages, which then release chemokines and cytokines. These in turn exacerbate the dysfunctional immune response and activate either TH1 or TH2 cells in the gut mucosa, respectively associated with CD and, less conclusively, with UC. Elucidation of immunological and genetic factors indicate multiple points at which the inflammatory cascade may be interrupted, yielding the possibility of precise, targeted therapies for IBD.     

Genotype-phenotype correlations: how many disorders constitute inflammatory bowel disease?

Various chromosomal loci transfer susceptibility to the development of Crohn's disease and/or ulcerative colitis. The disease-causing gene on one of these loci (IBD1) has been identified as CARD15/NOD2 and certain loss-of-function mutations were linked to the development of Crohn's disease. The recent data from association studies of CARD15/NOD2 mutations with certain phenotypes of Crohn's disease are reviewed. These mutations link to early onset ileal and fibrostenotic disease corresponding to the A1/L1 or L3/B2 subgroup of the Vienna classification. The present data on variations in HLA or cytokine genes suggest that these genes are disease modifying rather than disease predisposing. Certainly, inflammatory bowel diseases consist of more than two genotypes and phenotypes. At this stage, predictions on the number of disease causing genes, mutations or environmental factors are impossible.     

Role of cytokines and platelet-activating factor in inflammatory bowel disease

BACKGROUND: Platelet-activating factor (PAF) and cytokines, such as interleukins, tumor necrosis factor, and others, are thought to play a role in the inflammatory process involving gastrointestinal disorders such as Crohn's disease, ulcerative colitis, ischemic colitis, or antibiotic-associated colitis. PURPOSE: This study was undertaken to review the latest literature on the role of PAF and cytokines in the genesis of inflammatory bowel disease and implications for therapy and management. RESULTS: PAF is an endogenous phospholipid involved in hypersensitivity and inflammatory reactions such as platelet and neutrophil aggregation, vasodilation, increased vascular permeability, and leukocyte adhesion, which have been associated with inflammatory processes. Cytokines are peptides that regulate and coordinate inflammatory and immunologic responses. Increased production of cytokines has been reported during Crohn's disease and ulcerative colitis and is correlated with disease activity. CONCLUSIONS: Because PAF and cytokines may have an important role in the pathogenesis of inflammatory bowel disease, their inhibition by specific antagonists, mediators, or other agents such as steroids may have a potential therapeutic benefit in treatment and management of these inflammatory diseases in the near future.     

Phagocyte dysfunction and inflammatory bowel disease

Inflammatory bowel diseases are common chronic inflammatory disorders. The majority are idiopathic and can be broadly divided into Crohn's disease and ulcerative colitis. Their cause is unknown, but most hypotheses focus on a primary role for T-cell dysfunction. Conversely, there is a collection of congenital disorders of phagocyte function that result not only in immunodeficiency but also in noninfectious inflammatory bowel disease. In all cases, the latter is strikingly reminiscent of the clinical and pathological features of Crohn's disease. This coincides with recent work demonstrating that despite previous emphasis on adaptive immune dysfunction, patients with Crohn's disease actually possess an unusually weak acute innate inflammatory response. This review consolidates the literature on inflammatory bowel disease in congenital immunodeficiencies and considers the role of phagocyte dysfunction in Crohn's disease. Concepts about pathogenesis and treatment that can be carried across these disorders are also discussed.     

Etiology and pathogenesis of inflammatory bowel disease

Despite of scientific efforts during the last decades, etiology and pathogenesis of the two major inflammatory bowel diseases, namely Crohn's disease and ulcerative colitis, remain rather unclear. According to the results of multiple studies it is accepted that the development of either disease is the result of an exaggerated or insufficiently suppressed immune response to a hitherto undefined luminal antigen, probably derived from the microbial flora. This inflammatory process leads to the well-known mucosal damage and therefore a further disturbance of the epithelial barrier function, resulting in an increased influx of bacteria into the intestinal wall, even further accelerating the inflammatory process. However, these immunological disturbances that have been investigated extensively during the past years have to be considered on the genetic background of the individual patient and the environmental factors the patient is exposed to. In this review we will attempt to summarize the current knowledge about risk factors for inflammatory bowel diseases, genetic and environmental factors of IBD and focus on the immunological alterations of innate and acquired immune system underlying Crohn's disease and ulcerative colitis.     

Viruses, autophagy genes, and Crohn's disease

The etiology of the intestinal disease Crohn's disease involves genetic factors as well as ill-defined environmental agents. Several genetic variants linked to this disease are associated with autophagy, a process that is critical for proper responses to viral infections. While a role for viruses in this disease remains speculative, accumulating evidence indicate that this possibility requires serious consideration. In this review, we will examine the three-way relationship between viruses, autophagy genes, and Crohn's disease and discuss how host-pathogen interactions can mediate complex inflammatory disorders.     

Lipoprotein (a), thrombophilia and inflammatory bowel disease.

Thrombophilia in inflammatory bowel disease may be due to several risk factors, such as a dysbalanced haemostasis with a hypercoagulative state, thrombocytosis, hyperfibrinogenaemia and hyperhomocysteinaemia. In addition, increased concentrations of lipoprotein (a), a modified form of low-density lipoprotein particles, have been associated with a higher risk of thrombotic vascular disease, probably due to inhibition of (local and endothelial) fibrinolysis. The mechanisms regulating the plasma concentration of lipoprotein (a) have not yet been elucidated completely, but genetic factors are involved. Dietary factors seem to play a minor role. In this issue of the journal, Koutroubakis et al. report that lipoprotein (a) concentration is elevated in patients with Crohn's disease, but not in patients with ulcerative colitis. Several other (apo)lipoproteins have a different pattern in patients with inflammatory bowel disease than in a control population of healthy subjects from Crete. These findings add up to the multifactorial nature of thrombophilia in inflammatory bowel disease patients, especially in patients with Crohn's disease, and give rise to speculations about the clinical significance of the observed different lipoprotein metabolism in patients with inflammatory bowel disease.     

Thrombosis and inflammatory bowel disease.

Interaction between thrombosis and inflammation is increasingly recognized. With this, interest has arisen in the role of thrombosis in inflammatory conditions, including the inflammatory bowel diseases. Although the association between active inflammatory bowel disease and thromboembolic complications has long been known, there has been a resurgence in research into the role of thrombosis and the hemostatic system in the pathogenesis of both ulcerative colitis and Crohn's disease. Here we review the increased frequency of thromboembolic complications occurring in patients with inflammatory bowel disease; whether thrombosis might play a part in the initiation and maintenance of inflammation in inflammatory bowel disease; abnormalities of the coagulation system found in patients with inflammatory bowel disease; platelet dysfunction in inflammatory bowel disease; the mechanisms by which hemostatic processes might be proinflammatory in inflammatory bowel disease; and how these interactions might impact not only on the prevention of complications, but also on the treatment of the underlying inflammation in inflammatory bowel disease.     

Exogenous factors in Crohn's disease. A critical review.

The etiology of Crohn's disease remains elusive. Though there may be a genetic predisposition to the disease, epidemiologic evidence suggests that environmental factors are important. The role of dietary components and enhanced intestinal permeability deserve more attention. From this review of past studies, this investigator believes that ingested compounds may play an important role in the pathogenesis of Crohn's disease. Silica and various silicates provide models of how dietary factors might cause the disease and explain some of its features.     

胶囊内镜在小肠Crohn病的应用

小肠Crohn病是一种节段性、全壁层炎症性病变,其病因不明,临床表现多样,病理改变无特异性,误诊率高.对于小肠Crohn病,胶囊内镜是一种有价值的诊断方法.此文综述了胶囊内镜的应用原理、诊断小肠Crohn病的临床应用情况及存在的问题,并且探讨了今后的研究领域.