Influence of environmental factors in the development of inflammatory bowel diseases

Idiopathic inflammatory bowel diseases(IBD), Crohn's disease(CD) and ulcerative colitis(UC), are multifactorial diseases that are manifested after disruption of a genetic predisposed individual and its intestinal microflora through an environmental stimulus. Urbanization and industrialization are associated with IBD. Epidemiological data, clinical observations and family/immigrants studies indicate the significance of environmental influence in the development of IBD. Some environmental factors have a different effect on the subtypes of IBD. Smoking and appendectomy is negatively associated with UC, but they are aggravating factors for CD. A westernized high fat diet, full of refined carbohydrates is strongly associated with the development of IBD, contrary to a high in fruit, vegetables and polyunsaturated fatty acid-3 diet that is protective against these diseases. High intake of nonsteroidal antiinflammatory drug and oral contraceptive pills as well as the inadequacy of vitamin D leads to an increased risk for IBD and a more malignant course of disease. Moreover, other factors such as air pollution, psychological factors, sleep disturbances and exercise influence the development and the course of IBD. Epigenetic mechanism like DNA methylation, histone modification and altered expression of miR NAS could explain the connection between genes and environmental factors in triggering the development of IBD.     

Helicobacter pylori and epigenetic mechanisms underlying gastric carcinogenesis

Gastric carcinogenesis is a multistep process triggered by Helicobacter pylori and characterized by accumulation of molecular alterations. Two mechanisms are implicated in cancer-related molecular alterations: genetic and epigenetic. The former includes changes in the DNA sequence, the latter occurs without changes of DNA sequence. However, the most important difference between genetic and epigenetic alterations is that epigenetic changes are potentially reversible by eliminating toxic agents. DNA methylation is the major epigenetic phenomenon of eukaryotic genomes and involves the addition of a methyl group to the carbon 5 position of the cytosine ring within the CpG dinucleotide. DNA methylation is needed for the normal development of cells, whereas aberrant methylation of CpG islands confers a selective growth advantage that results in cancerous growth. The stomach is one of the organs frequently showing aberrant methylation of DNA epithelial cells because of its accessibility to exogenous toxic agents such as H. pylori infection. Aberrant methylation of CpG islands occurs early in gastric carcinogenesis, tends to increase as the process advances and is prevalently related to the infection. In conclusion, gastric cancer is mainly an epigenetic disease and H. pylori, acting through inflammatory mediators, may play a key role in the development of such molecular alterations.     

Accumulation of aberrant DNA methylation during colorectal cancer development

Despite the recent advances in the therapeutic modalities,colorectal cancer(CRC)remains to be one of the most common causes of cancer-related death.CRC arises through accumulation of multiple genetic and epigenetic alterations that transform normal colonic epithelium into adenocarcinomas.Among crucial roles of epigenetic alterations,gene silencing by aberrant DNA methylation of promoter regions is one of the most important epigenetic mechanisms.Recent comprehensive methylation analyses on genome-wide scale revealed that sporadic CRC can be classified into distinct epigenotypes.Each epigenotype cooperates with specific genetic alterations,suggesting that they represent different molecular carcinogenic pathways.Precursor lesions of CRC,such as conventional and serrated adenomas,already show similar methylation accumulation to CRC,and can therefore be classified into those epigenotypes of CRC.In addition,specific DNA methylation already occurs in the normal colonic mucosa,which might be utilized for prediction of the personal CRC risk.DNA methylation is suggested to occur at an earlier stage than carcinoma formation,and may predict the molecular basis for future development of CRC.Here,we review DNA methylation and CRC classification,and discuss the possible clinical usefulness of DNA methylation as biomarkers for the diagnosis,prediction of the prognosis and the response to therapy of CRC.     

胰腺癌中表观遗传修饰研究进展

胰腺癌的形成受遗传学和表现遗传修饰的影响.基因突变或缺失(遗传学)参与肿瘤的形成,DNA甲基化、组蛋白修饰和RNA干扰等(表观遗传修饰)调节基因表达.随着基因组筛选技术的发展,胰液中DNA甲基化定量检测是诊断胰腺癌的潜在工具,以DNA甲基化和组蛋白乙酰化为基础的表观遗传学是胰腺癌治疗领域中的新靶点.本文对胰腺癌发生发展过程中出现的表遗传修饰异常,以及其生物学和临床意义前景作一介绍.     

DNA methylation in gastric cancer,related to Helicobacter pylori and Epstein-Barr virus

Gastric cancer is a leading cause of cancer death worldwide,and significant effort has been focused on clarifying the pathology of gastric cancer.In particular,the development of genome-wide analysis tools has enabled the detection of genetic and epigenetic alterations in gastric cancer;for example,aberrant DNA methylation in gene promoter regions is thought to play a crucial role in gastric carcinogenesis.The etiological viewpoint is also essential for the study of gastric cancers,and two distinct pathogens,Helicobacter pylori(H.pylori)and Epstein-Barr virus(EBV),are known to participate in gastric carcinogenesis.Chronic inflammation of the gastric epithelium due to H.pylori infection induces aberrant polyclonal methylation that may lead to an increased risk of gastric cancer.In addition,EBV infection is known to cause extensive methylation,and EBV-positive gastric cancers display a high methylation epigenotype,in which aberrant methylation extends to not only Polycomb repressive complex(PRC)-target genes in embryonic stem cells but also non-PRC-target genes.Here,we review aberrant DNA methylation in gastric cancer and the association between methylation and infection with H.pylori and EBV.     

The growing role of gene methylation on endocrine function

DNA methylation is the best studied epigenetic factor, playing a key role in producing stable changes in gene expression, thus defining cell identity and function and adapting cells to environmental changes. DNA methylation has also been recently shown to mediate cell responses to physiological endocrine signals. Moreover, alterations of the normal DNA methylation pattern can also contribute to the development of endocrine and metabolic diseases and can explain the relationship between an individual's genetic background, the environment, and disease. It should be remarked that although DNA methylation and demethylation are active processes, epigenetic changes produced during development can impact adult processes, establishing the idea that endocrine function can be persistently affected by events occurring in early life. Given the complexity of the endocrine system, both genetic and epigenetic processes, including DNA methylation, must be involved in its proper development and functioning. In this study, we summarize the recent knowledge in the field of DNA methylation and endocrinology. Given that DNA methylation can be involved in a number of endocrine and metabolic disorders, understanding and manipulating this modification opens a new door for preventing and treating endocrine diseases.     

Antidepressants can treat inflammatory bowel disease through regulation of the nuclear factor-κB/nitric oxide pathway and inhibition of cytokine production: A hypothesis

Inflammatory bowel disease (IBD) is a group of inflammatory disorders mainly affecting the colon and small intestine. The main types of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). UC is restricted to the large intestine whereas CD can affect any part of the gastrointestinal tract. Treating this disorder depends on the form and level of severity. Common treatment involves an anti-inflammatory drug, such as mesalazine, and an immunosuppressant, such as prednisone. Several signaling pathways, including nuclear factor (NF)-κB and nitric oxide (NO), and genetic and environmental factors are believed to play an important role in IBD. Amitriptyline is a commonly used antidepressant with known anti-inflammatory activities. Amitriptyline also acts on the NF-κB/NO pathway or cytokine production. Therefore, we hypothesize that antidepressants like amitriptyline can be pioneered and considered effective as an innovative and effective therapeutic in the treatment and attenuation of development of IBD in adjusted doses.     

Inflammatory bowel disease:Pathogenesis

Inflammatory bowel disease(IBD),including Crohn’s disease and ulcerative colitis,is characterized by chronic relapsing intestinal inflammation.It has been a worldwide health-care problem with a continually increasing incidence.It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut,catalyzed by the genetic susceptibility of the individual.Although the etiology of IBD remains largely unknown,it involves a complex interaction between the genetic,environmental or microbial factors and the immune responses.Of the four components of IBD pathogenesis,most rapid progress has been made in the genetic study of gut inflammation.The latest internationally collaborative studies have ascertained 163susceptibility gene loci for IBD.The genes implicated in childhood-onset and adult-onset IBD overlap,suggesting similar genetic predispositions.However,the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD.Meanwhile,the adaptive immune response has been classically considered to play a major role in the pathogenesis of IBD,as new studies in immunology and genetics have clarified that the innate immune response maintains the same importance in inducing gut inflammation.Recent progress in understanding IBD pathogenesis sheds lights on relevant disease mechanisms,including the innate and adaptive immunity,and the interactions between genetic factors and microbial and environmental cues.In this review,we provide an update on the major advances that have occurred in above areas.     

Epidemiological studies of migration and environmental risk factors in the inflammatory bowel diseases

Inflammatory bowel diseases(IBD)are idiopathic chronic diseases of the gastrointestinal tract well known to be associated with both genetic and environmental risk factors.Permissive genotypes may manifest into clinical phenotypes under certain environmental influences and these may be best studied from migratory studies.Exploring differences between first and second generation migrants may further highlight the contribution of environmental factors towards the development of IBD.There are few opportunities that have been offered so far.We aim to review the available migration studies on IBD,evaluate the known environmental factors associated with IBD,and explore modern migration patterns to identify new opportunities and candidate migrant groups in IBD migration research.     

Genomic and epigenetic instability in colorectal cancer pathogenesis

Colorectal cancer arises as a consequence of the accumulation of genetic alterations (gene mutations, gene amplification, and so on) and epigenetic alterations (aberrant DNA methylation, chromatin modifications, and so on) that transform colonic epithelial cells into colon adenocarcinoma cells. The loss of genomic stability and resulting gene alterations are key molecular pathogenic steps that occur early in tumorigenesis; they permit the acquisition of a sufficient number of alterations in tumor suppressor genes and oncogenes that transform cells and promote tumor progression. Two predominant forms of genomic instability that have been identified in colon cancer are microsatellite instability and chromosome instability. Substantial progress has been made to identify causes of chromosomal instability in colorectal cells and to determine the effects of the different forms of genomic instability on the biological and clinical behavior of colon tumors. In addition to genomic instability, epigenetic instability results in the aberrant methylation of tumor suppressor genes. Determining the causes and roles of genomic and epigenomic instability in colon tumor formation has the potential to yield more effective prevention strategies and therapeutics for patients with colorectal cancer.     

Epigenetic targets of rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic, inflammatory and autoimmune disorder, characterized by chronic arthritis with progressive joint destruction. It has a multifactorial aetiology involving both genetic and environmental factors. Epigenetics can be defined as modifications of DNA that result in altered gene expression. The two main epigenetic mechanisms are post translational modifications to histone tails and DNA methylation. Recent evidence has suggested that epigenetic mechanisms may be an important contributor to RA susceptibility. The aim of this editorial is to present evidence for the role of epigenetic mechanisms in the pathogenesis of RA and the potential to therapeutic target. Several studies targeting histone modification and DNA methylation in animal models of inflammatory arthritis will be reviewed and alterations in the epigenetic signature of genes of key RA related pathways such as pro-inflammatory cytokines, proteases and regulators of cellular proliferation.     

Crucial steps in the natural history of inflammatory bowel disease

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.     

食管癌转移的表观遗传学改变研究进展

食管癌的发生发展是基因变异和环境因素共同作用的结果,表观遗传学变化常受环境等后天因素调控,是食管癌复发和转移的关键驱动因素之一。本文综述参与食管癌发生和演进的表观遗传学变化,包括DNA甲基化、组蛋白修饰与染色质重塑、miRNA、长链非编码RNA等,分析总结表观遗传学变异在食管癌转移中的关键作用,为食管癌治疗提供新的思路和策略。     

Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults

Inflammatory bowel diseases(IBDs) are a group of chronic inflammatory conditions mainly of the colon and small intestine. Crohn's disease(CD) and ulcerative colitis(UC) are the most frequent types of IBD. IBD is a complex disease which arises as a result of the interaction of environmental, genetic and immunological factors. It is increasingly thought that alterations of immunological reactions of the patients to their own enterable bacteria(microfilm) may contribute to inflammation. It is characterized by mucosal and sub mucosal inflammation, perpetuated by infiltration of activated leukocytes. CD may affect the whole gastrointestinal tract while UC only attacks the large intestine. The therapeutic goal is to achieve a steroidfree long lasting remission in both entities. UC has the possibility to be cured by a total colectomy, while CD never can be cured by any operation. A lifelong intake of drugs is mostly necessary and essential. Medical treatment of IBD has to be individualized to each patient and usually starts with anti-inflammatory drugs. The choice what kind of drugs and what route administered(oral, rectal, intravenous) depends on factors including the type, the localization, and severity of the patient's disease. IBD may require immune-suppression to control symptoms such as prednisolone, thiopurines, calcineurin or sometimes folic acid inhibitors or biologics like TNF-α inhibitors or anti-integrin antibodies. For both types of disease(CD, UC) the same drugs are available but they differ in their preference in efficacy between CD and UC as 5-aminosalicylic acid for UC or budesonide for ileocecal CD. As therapeutic alternative the main mediators of the disease, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via two apheresis systems(Adacolumn and Cellsorba) in steroid-refractory or dependent cases. Extracorporeal photopheresis results in an increase of regulatory B cells, regulatory CD8~+ T cells and T-regs Type 1. Both types of apheresis were able to induce clinical remission and mucosal healing accompanied by tapering of steroids.     

Epigenetic changes and liver carcinogenesis

The molecular mechanisms involved in liver carcinogenesis are poorly understood. Over the past decade, epigenetic changes (DNA methylation) have received increasing attention for their potential involvement in the development of hepatocarcinoma. The DNA methylation level is influenced by environmental factors (folate and methionine diet), as well as by genetic factors (methylenetetrahydrofolate reductase/MTHFR polymorphisms). These findings provide new insight into the understanding of liver carcinogenesis. Interventional studies are now required to determine the role of folate supplementation in the development of liver tumors in targeted patients.     

Role of epigenetic changes in hematological malignancies

Inactivation of tumor suppressor genes is an important event contributing to the development of neoplasia. In addition to the classic genetic mechanisms of deletion or inactivating point mutations, growth regulatory genes can be functionally inactivated without alterations of the primary sequence by methylation of cytosine residues in the promoter regions of the genes. After introducing epigenetic phenomena in general and the molecular basis of DNA methylation in more detail, this review will present the broad spectrum of alterations in DNA methylation patterns found in hematopoietic malignancies. In addition, the implications for therapy and prognosis will be discussed.Grant numbers and sources of support: Deutsche Krebshilfe, grant 10-1842-Le I     

DNA methylation in hepatocellular carcinoma

As for many other tumors, development of hepatocellular carcinoma （HCC） must be understood as a multistep process with accumulation of genetic and epigenetic alterations in regulatory genes, leading to activation of oncogenes and inactivation or loss of tumor suppressor genes （TSG）. In the last decades, in addition to genetic alterations, epigenetic inactivation of （tumor suppressor） genes by promoter hypermethylation has been recognized as an important and alternative mechanism in tumorigenesis. In HCC, aberrant methylation of promoter sequences occurs not only in advanced tumors, it has been also observed in premalignant conditions just as chronic viral hepatitis B or C and cirrhotic liver. This review discusses the epigenetic alterations in hepatocellular carcinoma focusing DNA methylation.