Molecular fingerprints of neutrophil-dependent oxidative stress in inflammatory bowel disease

Neutrophil accumulation within epithelial crypts and in the intestinal mucosa directly correlates with clinical disease activity and epithelial injury in inflammatory bowel disease (IBD). Current advances have defined the mechanisms by which neutrophils are activated or migrate across endothelial and mucosal epithelial cells. A better understanding of this process will likely provide new insights into novel treatment strategies for IBD. Especially, activated neutrophils produce reactive oxygen and nitrogen species and myeloperoxidase within intestinal mucosa, which induce oxidative stress. Posttranslational modification of proteins generated by these reactive species serves as a “molecular fingerprint” of protein modification by lipid peroxidation-, nitric oxide-, and myeloperoxidase-derived oxidants. Measurement of these modified proteins may serve both as a quantitative index of oxidative stress and an important new biological marker of clinical relevance to IBD. We have succeeded in the clinical development of a novel granulocyte adsorptive apheresis therapy for IBD. In this review, we discuss current advances in defining the role of neutrophil-dependent oxidative stress in IBD.     

Deregulation of intestinal anti-microbial defense by the dietary additive,maltodextrin

Inflammatory bowel disease (IBD) is a complex, multi-factorial disease thought to arise from an inappropriate immune response to commensal bacteria in a genetically susceptible person that results in chronic, cyclical, intestinal inflammation. Dietary and environmental factors are implicated in the initiation and perpetuation of IBD; however, a singular causative agent has not been identified. As of now, the role of environmental priming or triggers in IBD onset and pathogenesis are not well understood, but these factors appear to synergize with other disease susceptibility factors. In previous work, we determined that the polysaccharide dietary additive, maltodextrin (MDX), impairs cellular anti-bacterial responses and suppresses intestinal anti-microbial defense mechanisms. In this addendum, we review potential mechanisms for dietary deregulation of intestinal homeostasis, postulate how dietary and genetic risk factors may combine to result in disease pathogenesis, and discuss these ideas in the context of recent findings related to dietary interventions for IBD.     

Deregulation of intestinal anti-microbial defense by the dietary additive,maltodextrin

Inflammatory bowel disease (IBD) is a complex, multi-factorial disease thought to arise from an inappropriate immune response to commensal bacteria in a genetically susceptible person that results in chronic, cyclical, intestinal inflammation. Dietary and environmental factors are implicated in the initiation and perpetuation of IBD; however, a singular causative agent has not been identified. As of now, the role of environmental priming or triggers in IBD onset and pathogenesis are not well understood, but these factors appear to synergize with other disease susceptibility factors. In previous work, we determined that the polysaccharide dietary additive, maltodextrin (MDX), impairs cellular anti-bacterial responses and suppresses intestinal anti-microbial defense mechanisms. In this addendum, we review potential mechanisms for dietary deregulation of intestinal homeostasis, postulate how dietary and genetic risk factors may combine to result in disease pathogenesis, and discuss these ideas in the context of recent findings related to dietary interventions for IBD.     

炎症性肠病基础研究进展——与临床的联系

炎症性肠病（IBD）包括溃疡性结肠炎（UC）和克罗恩病（CD）,是一组反复发作的非特异性慢性肠道炎症性疾病,其病因尚未完全阐明。近年来随着基因组学、免疫遗传学、分子生物学等的发展以及DNA重组动物模型技术的日趋成熟,IBD病因学和发病机制的研究进展迅猛．取得了巨大的成绩。IBD易感基因的发现,驱动了肠道共生菌与肠上皮屏障相互作用致肠黏膜免疫失衡以及天然性免疫与适应性免疫的相互作用等多方面的进展,对IBD发病机制和疾病本质的揭示起到了重要作用。     

Genetics of ulcerative colitis

Ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic inflammatory bowel diseases (IBDs), with distinct and overlapping susceptibility loci. Recently, hypothesis-free genome-wide association (GWA) studies have revolutionized the field of complex disease genetics. Substantial advances have been achieved in defining the genetic architecture of IBD. To date, over 60 published IBD susceptibility loci have been discovered and replicated, of which approximately a third are associated with both UC and CD, although 21 are specific to UC and 23 to CD. In CD, the breakthrough identification of NOD2 as a susceptibility gene was followed by a rapid phase of gene discovery from GWA studies between 2006 and 2008. Progress in UC was slower; however, by initially testing hits for CD in UC, and later scanning larger UC cohorts, significant new loci for UC have been discovered, with exciting novel insights into disease pathogenesis. Notably, genes implicated in mucosal barrier function (ECM1, CDH1, HNF4α, and laminin B1) confer risk of UC; furthermore, E-cadherin is the first genetic correlation between colorectal cancer and UC. Impaired IL10 signaling has reemerged as a key pathway in intestinal inflammation, and is perhaps the most amenable to therapeutic intervention in UC. Collaborative international efforts with large meta-analyses of GWA studies and replication will yield many new UC genes. Furthermore, a large effort is required to characterize the loci found. Fine-mapping, deep resequencing, and functional studies will be critical to translating these gene discoveries into pathogenic insights, and ultimately into clinical insights and novel therapeutics.     

Tryptophan:A gut microbiota-derived metabolites regulating inflammation

Inflammatory bowel diseases(IBD), which comprise Crohn's disease and ulcerative colitis, are chronic intestinal disorders with an increased prevalence and incidence over the last decade in many different regions over the world. The etiology of IBD is still not well defined, but evidence suggest that it results from per-turbation of the homeostasis between the intestinal microbiota and the mucosal immune system, with the involvement of both genetic and environmental factors. Genome wide association studies, which involve large-scale genome-wide screening of potential polymorphism, have identified several mutations associated with IBD. Among them, Card9, a gene encoding an adapter molecule involved in innate immune response to fungi(via type C-lectin sensing) through the activation of IL-22 signaling pathway, has been identified as one IBD susceptible genes. Dietary compounds, which represent a source of energy and metabolites for gut bacteria, are also appreciated to be important actors in the etiology of IBD, for example by altering gut microbiota composition and by regulating the generation of short chain fatty acids. A noteworthy study published in the June 2016 issue of Nature Medicine by Lamas and colleagues investigates the interaction between Card9 and the gut microbiota in the generation of the microbiota-derived tryptophan metabolite. This study highlights the role of tryptophan in dampening intestinal inflammation in susceptible hosts.     

Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets

The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of nonimmune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct proinflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD.The effects determine pathologic changes,which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes.In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers,research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.     

The genetics of inflammatory bowel disease

The inflammatory bowel diseases (IBD) comprise complex genetic disorders, with multiple contributing genes. Linkage studies have implicated several genomic regions as likely containing IBD susceptibility genes, with some observed uniquely in Crohn's disease (CD) or ulcerative colitis (UC), and others common to both disorders. The best replicated linkage region, IBD1, on chromosome 16q contains the CD susceptibility gene, NOD2/CARD15. NOD2/CARD15 is expressed in peripheral blood monocytes and is structurally related to the plant R proteins, which mediate host resistance to microbial pathogens. Three major coding region polymorphisms within NOD2/CARD15 have been highly associated with CD among patients of European descent. Having one copy of the risk alleles confers a 2-4-fold risk for developing CD, whereas double-dose carriage increases the risk 20-40-fold. All 3 major CD variants exhibit a deficit in NF-kappaB activation in response to bacterial components. Carriage of NOD2/CARD15 risk alleles is associated with ileal location, earlier disease onset, and stricturing phenotype. Other IBD genomic regions include IBD2 on chromosome 12q (observed more in UC), and IBD3, containing the major histocompatibility complex region. A short genomic region has been associated with CD on chromosome 5q, but the precise contributing gene is as yet unidentified. The characterization of additional IBD susceptibility genes could potentially lead to the identification of novel therapeutic agents for IBD, make possible a molecular reclassification of disease, and increase understanding of the contribution of environmental factors (notably, tobacco and the intestinal microbial milieu) to intestinal inflammation.     

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.     

Environment and the inflammatory bowel diseases

Inflammatory bowel diseases (IBD), which consists of Crohn disease and ulcerative colitis, are chronic inflammatory conditions of the gas-trointestinal tract. In genetically susceptible individuals, the interaction between environmental factors and normal intestinal commensal flora is believed to lead to an inappropriate immune response that results in chronic inflammation. The incidence of IBD have increased in the past century in developed and developing countries. The purpose of the present review is to summarize the current knowledge of the association between environmental risk factors and IBD. A number of environmental risk factors were investigated including smoking, hygiene, microorganisms, oral contraceptives, antibiotics, diet, breast-feeding, geographical factors, pollution and stress. Inconsistent findings among the studies highlight the complex pathogenesis of IBD. Additional studies are necessary to identify and elucidate the role of environmental factors in IBD etiology.     

Chemokines in inflammatory bowel disease

Ulcerative colitis (UC) and Crohn’s disease (CD), collectively termed inflammatory bowel diseases (IBD), represent chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract that are charcterized by leukocytic infiltration of the intestinal mucosa and submucosa. In CD, the inflammation is transmural and frequently associated with granuloma formation. Chemokines have emerged as the most important regulators of leukocyte trafficking during infection or inflammation and, therefore, have been implicated in the pathogenesis of IBD. In this review, recent advances on the role of chemokines and their receptors in mucosal immunity and inflammation are discussed, and the potential use of chemokine/chemokine-receptor antagonists as novel therapeutic targets for the treatment of human IBD is highlighted.     

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.     

Fluoride: a risk factor for inflammatory bowel disease?

Although the association between inflammatory bowel disease (IBD) and oral hygiene has been noticed before, there has been little research on prolonged fluoride exposure as a possible risk factor. In the presented cases, exposure to fluoride seems indirectly associated with higher incidence of IBD. Fluoride toxicology and epidemiology documents frequent unspecific chronic gastrointestinal symptoms and intestinal inflammation. Efflux genes that confer resistance to environmental fluoride may select for IBD associated gut microbiota and therefore be involved in the pathogenesis. Together these multidisciplinary results argue for further investigation on the hypothesis of fluoride as a risk factor for IBD.     

New pathophysiological insights and modern treatment of IBD

Inflammatory bowel disease (IBD), which comprises two main types, namely, Crohn’s disease and ulcerative colitis, affects approximately 3.6 million people in the USA and Europe, and an alarming rise in low-incidence areas, such as Asia, is currently being observed. In the last decade, spontaneous mutations in a diversity of genes have been identified, and these have helped to elucidate pathways that can lead to IBD. Animal studies have also increased our knowledge of the pathological dialogue between the intestinal microbiota and components of the innate and adaptive immune systems misdirecting the immune system to attack the colon. Present-day medical therapy of IBD consists of salicylates, corticosteroids, immunosuppressants and immunomodulators. However, their use may result in severe side effects and complications, such as an increased rate of malignancies or infectious diseases. In clinical practice, there is still a high frequency of incomplete or absent response to medical therapy, indicating a compelling need for new therapeutic strategies. This review summarizes current epidemiology, pathogenesis and diagnostic strategies in IBD. It also provides insight in today’s differentiated clinical therapy and describes mechanisms of promising future medicinal approaches.     

MICROBIOTA INSIGHTS IN CLOSTRIDIUM DIFFICILE INFECTION AND INFLAMMATORY BOWEL DISEASE

ABSTRACT

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation that includes Crohn´s disease (CD) and ulcerative colitis (UC). Although the etiology is still unknown, some specific factors have been directly related to IBD, including genetic factors, abnormal intestinal immunity, and/or gut microbiota modifications. Recent findings highlight the primary role of the gut microbiota closely associated with a persistent inappropriate inflammatory response. This gut environment of dysbiosis in a susceptible IBD host can increasingly worsen and lead to colonization and infection with some opportunistic pathogens, especially Clostridium difficile. C. difficile is an intestinal pathogen considered the main cause of antibiotic-associated diarrhea and colitis and an important complication of IBD, which can trigger or worsen an IBD flare. Recent findings have highlighted the loss of bacterial cooperation in the gut ecosystem, as well as the pronounced intestinal dysbiosis, in patients suffering from IBD and concomitant C. difficile infection (CDI). The results of intestinal microbiota studies are still limited and often difficult to compare because of the variety of disease conditions. However, these data provide important clues regarding the main modifications and interrelations in the complicated gut ecosystem to better understand both diseases and to take advantage of the development of new therapeutic strategies. In this review, we analyze in depth the gut microbiota changes associated with both forms of IBD and CDI and their similarity with the dysbiosis that occurs in CDI. We also discuss the metabolic pathways that favor the proliferation or decrease in several important taxa directly related to the disease.     

Evolving paradigms in the pathogenesis of IBD

The pathogenesis of all immune-mediated inflammatory diseases has been carefully studied over the past several decades, but it is only recently that we have come to appreciate common pathways and genes. This is especially true for the inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis, where a keener appreciation of the contributions of genetics, environment, and immune response have been dissected. In fact, in many ways, IBD has become the model for studying such disorders. The complex nature of interactions is continuing to be defined, and novel therapies targeting defects in these interactions have been developed and are being tested in the clinic. The era of bench to bedside has finally matured, and cures for debilitating diseases are now in sight. This review describes our current state of knowledge of each component of IBD pathogenesis. What has evolved is a clearer picture and novel targets for therapy.     

Genetics of inflammatory bowel diseases: A comparison between Western and Eastern perspectives

Inflammatory bowel disease (IBD) is a chronic relapsing intestinal inflammatory disorder with unidentified causes. Currently, studies indicate that IBD results from a complex interplay between various genetic and environmental factors that produce intestinal inflammation. However, these factors may differ for Asians and Caucasians. Thus, differences in epidemiology, genetic variants, and clinical phenotypes of IBD have been observed between the two populations. Understanding the discrepancies between data from populations with different genetic backgrounds and environmental factors may reveal fundamental aspects of IBD pathogenesis. Accordingly, this review will summarize the current knowledge of IBD genetics studied in Asian countries and compare it with that from Western countries, with special focus on innate bacterial sensing, autophagy, and the interleukin‐23 receptor‐T helper cell 17 pathway. The epigenetic nature of IBD pathogenesis as well as the pharmacogenetics related to the use of immunomodulators will also be briefly covered.