Inflammatory bowel disease pathogenesis: Where are we? Claudio Fiocchi*,† *Department of Gastroenterology and Hepatology, Digestive Disease Institute and †Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Key words Crohn’s disease, inflammatory bowel disease, integrome, pathogenesis, ulcerative colitis. Correspondence Claudio Fiocchi, Department of Gastroenterology and Hepatology, Digestive Disease Institute and Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Email: [email protected] The 15th Taishotoyama International Symposium on Gastroenterology, September 26–28, 2013, Tokyo, Japan.

Abstract Inflammatory bowel disease (IBD) is presently one of the most investigated human disorders. Expansion of knowledge of its pathophysiology has helped in developing novel medications to combat gut inflammation with a considerably degree of success. Despite this progress, much more remains to be done in regard to gaining a more profound understanding of IBD pathogenesis, detecting inflammation before it clinically manifests, implementing lifestyle modifications, and developing agents that can modify the natural course of the disease. One of the limitations to achieve these goals is the lack of integration of the major components of IBD pathogenesis, that is the exposome, the genome, the gut microbiome, and the immunome. An “IBD integrome” approach that takes advantage of all functional information derived from the detailed investigation of each single pathogenic component through the use of systems biology may offer the solution to understand IBD and cure it.

Introduction For at least two decades, inflammatory bowel disease (IBD; Crohn’s disease [CD], and ulcerative colitis [UC]) has been the focus of intense attention at the basic science, translational, and clinical level. This attention is explained by an exponential growth in knowledge of its putative predisposing factors, possible cause(s), underlying cellular and molecular mechanisms, as well as the development of biomarkers, more precise diagnostic tools, and innovative therapies. This indisputable progress is due, to a large extent, to a much improved understanding of IBD pathogenesis and the identification of its major components. Currently, there is a general agreement that variations in the patient’s genetic make-up (the genome), broad changes in the surrounding environment (the exposome), alterations in the composition of the gut microbiota (the microbiome), and the reactivity of the intestinal mucosal immune response (the immunome) are at the foundation of IBD pathogenesis. Progress is under way in each of these four components but, unfortunately, to variable degrees and in a rather disjointed and non-integrated fashion, so that knowledge accumulated in one area is not efficiently translated and applied to the benefit of other components. The IBD community is aware of this situation and appreciates the urgent need for and the value of seeking pathophysiological integration, but little effort is actually underway to combine the independent research efforts of various research groups and integrate new discoveries in a bigger IBD picture (the IBD “integrome”), a concept that will be discussed again at the end of the manuscript. This review will, in a succinct way, present some of the established and most relevant information on each component of IBD pathogenesis, highlight the various


degree of interdependence among the components, and try to convince the reader of the fundamental importance of amalgamating knowledge to gain a deeper understanding of IBD pathophysiology with the ultimate goal of developing therapies that can alter the natural history of the disease. To this end, the ome term and concept will be used, whenever appropriate, to reinforce the requirement for integration and globalization, and to conform to increasingly accepted terminologies.

The genome Since the original description of “terminal ileitis” by Crohn and collaborators in 1932, thirty years passed by until Kirsner and Spencer described the observation of familial aggregation in IBD.1 Another 30 years elapsed until the first genome scan uncovered a link of CD with chromosome 16,2 after which, due to technological advances, it took only 5 years until the discovery of the first IBD gene, that is the NOD2/CARD15 gene variants associated with ileal CD.3 After another short 5-year gap, the second gene was discovered, the interleukin (IL)-23 receptor (IL-23R),4 and within five additional years a series of genome-wide association studies were published, bringing the number of associations to > 100 in 2011 and at least 163 in 2012.5 This remarkably fast progress begs the question of how many more genes can be expected to be associated with IBD, but preliminary reports with increasingly fine sequencing power indicate that only a few additional ones remain to be discovered. Of the 163 gene variants associated with IBD, 23 are associated with UC, 30 with CD, and the remaining 110 with both UC and CD.5 The frantic search of genetic associations in IBD is justified not only from a basic research standpoint, but also

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a practical one. In fact, genetic signatures may help identify subgroups of IBD patients who are likely or not to respond to biological therapies,6 and predict medically refractory disease,7 risk of complications, and so on. There is no question that gene variants are implicated in IBD pathogenesis. In fact, recent studies show that the odd ratio for developing UC or CD increases in direct proportion to the number of risk alleles that each patient carries.8 In other words, the greater the burden of IBD-associated genes, the higher the risk of manifesting IBD. Nonetheless, the 163 genes associated with CD or UC only account for approximately 25% of all IBD cases, and even if new associations were to be found, they will not substantially increase this percentage. Thus, what can explain this “genetic vacuum” or “missing heritability” in IBD? One possibility is the interaction among risk genes (gene–gene interaction or epistasis), the other is gene–environment interaction, or most likely a combination of gene–gene and gene–environment interactions. All these options are reasonable and workable, but their investigation poses tremendous technical challenges because of the extreme experimental complexity of biological interaction studies at the functional level, and because only a handful of environmental factors, among the myriad of existing ones, have been firmly associated to CD or UC. So, in answer to the question “IBD pathogenesis: where are we in regard to the genome?” the following can be stated: genetic associations and heterogeneity in IBD are overwhelming, but alone fail to explain IBD; gene–gene and gene–environment interactions must be investigated to better understand IBD pathogenesis.

The exposome The term exposome refers to all that humans are exposed to regardless of the route of contact, all that are spontaneously present in nature, as well as all that are preexisting but humans have artificially modified and all created de novo. Within this broad definition, the microbiome, and the gut microbiota in particular, is also part of the exposome, the only difference being that the gut microbiota is an endogenous component of the exposome, while all the rest represents the exogenous exposome. The importance of the exposome, and even more critical of how the exposome has strikingly and rapidly changed as a result of human evolution, cannot be overemphasized in the pathogenesis of human diseases. A number of illnesses, particularly those of neoplastic and autoimmune/chronic inflammatory nature, including IBD, are unquestionably linked to drastic changes in the exposome. This is clearly demonstrated by the time-dependent increase in the incidence and prevalence of CD and UC throughout the world since World War II, and it is corroborated by the indisputable fact that IBD is here now, but there is essentially no evidence of it a century ago. At that time, the human genetic pool was fundamentally identical to the one of present days, so that genes cannot explain the dramatically greater and still escalating frequency of IBD in essentially all countries.9 Moreover, additional strong evidence for the critical importance of the exposome comes from population migration studies: adults who migrate from low to high IBD incidence areas do not develop the disease, but infants or young people who do such migration or the first generation of the migrants have the same incidence of IBD as the indigenous population of the

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established high-risk area.10 Adult migrants and their offspring share the same genes, yet their risk of IBD is disparate and depends primarily on when and where they migrated to, putting the blame on the environmental factors to which young people or new generations are exposed to. The number and variety of environmental risk factors that have been linked to IBD predisposition are large, ranging from smoking, foods, drugs, xenobiotics, geography, social and educational status, stress, appendectomy, intestinal permeability, and the gut microbiota.11 Some supporting evidence can be found for each of these factors, but reliable epidemiological evidence is only available for smoking in particular, a few drugs (such as contraceptives), appendectomy, and only more recently the gut microbiota and the diet. Many additional factors that have yet to be uncovered or only recently have come under scrutiny certainly exist, for example particulate air pollutants.12

The gut microbiota. Among the innumerous components of the general exposome, the gut microbiota—the microbiome, categorized above as an endogenous exposome—is the one that by far has received the most attention. It is well established that the human gut microbiota is extremely dynamic and undergoes a continuous temporal evolution in both quantity and quality from birth to adulthood, and this evolution is influenced by the genomeand the exposome-derived dietary components and xenobiotics. The composition of the human microbiota is strongly influenced by vaginal versus C-section delivery, and acquires a needed diversity in the early years of development, stabilizes in the adult, and starts declining in the elderly.13 The most critical period of this evolution occurs early in life, when the microbiota is exposed to an increasingly rich array of foods, medications, xenobiotics, etc., and is modified accordingly. This can be defined as the sensitive period, a developmental stage when the type and timing of microbial priming of the intestinal mucosa immune system may result in a healthy gut or a gut prone to developing IBD, a hypothesis paralleling events underlying the pathogenic steps of asthma.14 There is strong evidence indicating that the greater the richness of the microbiota—in number, variety, complexity, and gene expression—the healthier it will be, the more effective it will be in educating the systemic and mucosal immune systems, and the subject carrying it will be less inclined to diseases in general; on the contrary, people with a less rich and diverse microbiota seem to be more prone to disease development. This is the situation in IBD patients, as multiple reports have shown a reproducible association of disease with a loss of microbial diversity, even though it is still to be established whether this is a primary event predisposing to CD or UC, or a finding secondary to the presence of chronic intestinal inflammation. The current keen interest in the gut microbiota in IBD is due to two main factors: the first is experimental and clinical evidence demonstrating the existence of an immune response against it in human and experimental IBD,15 and the second is an increasingly refined identification of its bacterial, viral, and fungal components gathered from individual reports and the results of the Human Microbiome Project.16 In addition to multiple studies in murine models of experimental colitis, there are excellent human studies clearly illustrating how the microbiota incites a rapid immune response in the gut in genetically susceptible individuals, such as

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the classical report of D’Haens and collaborators:17 the infusion of luminal contents collected from an ileostomy bag into the diseasefree small bowel of post-ileal resection patients triggers local inflammation in a matter of a few days.17 Also contributing to the notion of an abnormal gut microbiota in both forms of IBD are numerous reports showing a loss of bacterial diversity in active as well as inactive IBD.18 This intense attention to the role of the microbiota in IBD pathogenesis at the investigational level has been accompanied by many different strategies aimed at modulating its composition with variable degrees of success.19 The use of antibiotics has been part of empirical IBD clinical practice for years, followed by studies on probiotics and prebiotics, and currently fecal transplant from healthy donors is being tested in many centers. Clinical trials based on administration of defensins are likely to follow. Even though promising results are reported from time to time, at the moment none of these approaches alone has been proved convincingly successful, and some may even be detrimental. In fact, there is irrefutable epidemiological evidence demonstrating that the earlier and more frequent the use of antibiotics is in the first years of life, the higher the risk of developing IBD, and CD in particular, later on in life.20 Data such as these highlight the crucial importance of promoting a rich and diverse microbiota early in life (the sensitive period) as a way of decreasing the risk of developing IBD, and provide further evidence for a central role of the gut microbiota in IBD pathogenesis.

The diet. As mentioned above, the composition of the gut microbiota is highly susceptible to exposure to all elements present in the external environment, and prime among them are dietary components. In agreement with previous epidemiological evidence that IBD prevalence and incidence increase in parallel with the acquisition of a Western, high-fat, high-sugar, high-calorie diet, as observed for example in Japan,21 more recent studies have shown an indisputable link between the diet and the composition of the gut microbiota. Children from primitive areas of rural Africa have a high bacteroidetes and low firmicutes loads in their stools, while children from European urban centers have the reverse of these proportions.22 In healthy hospital-based volunteers, administration of a diet rich in protein and animal fat promotes the development of Bacteroides, while a carbohydrate-based diet promotes the development of Prevotella in the lumen.23 The worldwide epidemic in obesity provides an additional opportunity to investigate the relationship between diet and IBD. Supplementation of milk-derived saturated fat to the diet of mice enhances the levels of taurocholic acid, which favors the growth of the microbe Bilophila wadsworthia, which in turn triggers inflammation in genetically susceptible IL-10-deficient but not wild-type mice.24 This not only illustrates the power of the diet in conditioning gut inflammation, but also represents a nice example of gene– environment interaction, a concept to be discussed again later on in this review. The potential of an imbalanced diet for the risk of IBD may go beyond its direct effect on the host and may transcend generations. Diet-induced obese ewes give birth to offspring with persistent intestinal inflammation and fibrosis, suggesting that the mother’s behavior during pregnancy impacts on the risk of developing IBD or not in the following generation, and that some individual may already be born with silent IBD that will manifest only later on in life.25 Not only primary food components may 14

increase the risk of IBD, but also a whole series of food additives ubiquitously present in Western diets. A very recent report shows that the sugar substitute maltodextrin increases the adherence of certain Escherichia coli to epithelial surfaces and concomitantly suppresses autophagy in epithelial cells.26 These two effects result in higher colonization and excessive bacterial growth, which can possibly incite an immune response translated into gut inflammation. So, in answer to the question “IBD pathogenesis: where are we in regard to the exposome?” the following can be stated: the emergence of IBD is unequivocally linked to changes in innumerous and complex environmental factors; of these, the intestinal microbiota and the diet appear predominant, and offer the most promising targets for therapeutic intervention.

The immunome Until recently, the investigation of IBD pathogenesis had been almost exclusively centered on the study of pro-inflammatory immune-mediated events. This is obviously justified, but it is now evident that this is not enough to fully comprehend the mechanisms of tissue damage in CD and UC, and that investigation of immune responses in IBD has to be evaluated in the context of exposomeand microbiome-derived effects. An important evolution in the study of the immunome in IBD has been the realization that innate immune responses may be more directly relevant to disease pathogenesis than adaptive responses, even though both occur at the same time but are likely triggered at different phases in the course of the disease. An additional key notion is based on clear evidence that in health the control of intestinal immune homeostasis depends on the reciprocal and active regulation between the microbiota in the lumen and a variety of immune and non-immune cells in the mucosa.27 Epithelial cells, Paneth cells, dendritic cells, and T and B cells secrete a whole host of soluble factors that regulate the quality and quantity of microbes in the lumen; as a counterpart, different microbes in the lumen control and determine the development of lymphoid follicles, production of antibodies, and effector and regulatory T cells in the mucosa.27 Consequently, any alteration on either side of the luminal interface may lead to a dysregulation of the balance and trigger inflammation. We still do not understand how IBD is initiated, what starts the initial immune response, and what keeps it going, but environmental and genetic factors must concomitantly contribute to it. Despite this knowledge gap, the patterns of immune response have been relatively well characterized: in CD there is a predominant Th1 and Th17 response, translated by the elevated production of IL-12, interferon (IFN)-γ, and IL-17A,28 while in UC there is an atypical Th2 response defined by elevated production of IL-5 and IL-13 and low IL-4.29 This distinction is, to some degree, artificial as all cytokines are always present in the inflamed mucosa, and differences are quantitative rather than qualitative. Nevertheless, this paradigm has been useful in the study of each form of IBD and has helped in the development of new form of therapy based on the above cytokine profiles. In addition to these adaptive immune responses, much has been learned about the defects of innate immunity in IBD, and particularly CD. Numerous reports have described variants in genes controlling innate immunity recognition and processing of bacterial components, including NOD2, TLR4, TLR5, ATG16L1, and IRGM.30 In addition, functional defects of

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macrophage function have been reported in CD patients, suggesting that the acute inflammatory response is faulty in this form of IBD and may be the cause of granuloma formation and persistent inflammation.31 The abnormal immune reactivity that mediates inflammation and tissue damage in IBD is likely to be highly complex and possibly variable with the course of the disease, but both innate and adaptive pathways are certainly involved. Another aspect that needs to be considered in regard to the immune response in IBD is the evolution that immune-mediated diseases have experienced in the last few decades. In the 1980s and 1990s, immunology was almost exclusively focused on T and B cells and their products, in the 2000s the focus started to shift to innate immune cells, such as epithelial cells, dendritic cells, macrophages, and NK cells, and currently most other tissue cells are also being appreciated as players of immunity and inflammation, including mesenchymal and endothelial cells, keratinocytes and platelets, as well as the acellular extracellular matrix. With the adoption of the expanded view of what is “immune” or what mediates inflammation, and especially chronic inflammation, there is a need to recognize the crucial importance of and understand biological interactions, particularly with components of the microbiome. In regard to IBD, its pathophysiology can no longer be viewed as depending exclusively on the response of traditional immune cells to microbial elements, but also of epithelial, mesenchymal, endothelial, and neural cells, and it is this global tissue response that determines the acute or chronic nature of the gut inflammatory response and its associated tissue-modifying events, such as angiogenesis, lymphangiogenesis, wound healing, and fibrosis. So, in answer to the question “IBD pathogenesis: where are we in regard to the immunome?” the following can be stated: the tissue response in IBD involves more components than previously anticipated; both immune and non-immune cells participate in innate and adaptive responses, and both should be evaluated in detail and eventually considered as potential therapeutic targets.

New pathogenic mechanisms Although the immunome is unquestionably the primary effector arm of inflammation in CD and UC, it is unlikely that it acts alone and independently of other biological processes that unfold at the same time or determine propensity to inflammation at earlier stages of the disease. An example of the first process is what is called “sterile inflammation.”32 Under normal circumstances, cells die by apoptosis, a physiological and active death process in which the cells implode and retain all its intracellular components, to be then cleared by macrophages. In contrast, in many pathological conditions, cells die by necrosis (in various forms called necroptosis, pyroptosis, etc.) and release a number of products and molecules that are not normally found free in the tissue microenvironment and consequently not recognized, including DNA, RNA, ATP, nuclear proteins like HMGB1, uric acid, and fragments of the extracellular matrix.33 Collectively, these factors are named damage-associated molecular patterns (DAMPs). All of them can then incite a “sterile” inflammatory reaction, so defined because it is independent on the presence of pathogen-associated molecular patterns, which incite the traditional microbial inflammation. Tissue damage is intrinsic to IBD, particularly if severe as in the case of

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ulcer formation and bleeding, and elements that trigger sterile inflammation are unquestionably released in actively inflamed IBD mucosa.34 A hypothesis has been advanced that all forms of chronic inflammation, as typically observed in IBD, actually involve a combination of traditional microbial inflammation as well as sterile inflammation, which are together responsible for what has been named “unresolving inflammation.”35 This new concept makes special sense in IBD, and it must be seriously taken into consideration. An additional example of another biological process that needs more investigation is the role of the inflammasome in IBD pathogenesis. Human data are still missing, but the inflammasome has been investigated in IBD animal models with contrasting results.36 An example of factors that must be involved in IBD pathogenesis is the epigenome. Epigenetic modifications start in utero and continue throughout life, including maternal factors and behavior, nutrition, microbes, drugs, xenobiotics, illnesses, and aging, and together determine whether health or disease will be the final outcome. The epigenome includes all events associated with chromatin modifications that regulate multiple DNA-based processes, including the critical step of gene transcription.37 Therefore, it is obvious that epigenetic events should reveal new insights into IBD pathogenesis by acting as fine tuners of gene expression. Chromatin modifications are mediated by a number of enzymes that modulate histone modifications and DNA methylation status; these are the ultimate controllers of gene expression after an antigen has triggered a downstream cascade of events leading to gene activation.37 Thus, the degree of an inflammatory response is regulated by epigenetic events, and this is clearly of major importance in conditions, like IBD, where inflammatory gene expression is at the center of the pathogenic process. The study of the epigenome in IBD has barely started, but the identification of the major exposome-derived epigenome components and events, and the identification of the epigenetic steps controlling gene expression in IBD mucosa, will undoubtedly become vital to understand IBD pathogenesis. So, in answer to the question “IBD pathogenesis: what are its new components?” the following can be stated: additional components of IBD pathogenesis are being constantly recognized, such as sterile inflammation, the inflammasome, and the epigenome; they need to be investigated de novo, and new pathophysiologybased molecular approaches must be developed to possibly target these new components

Time-dependent evolution of IBD Both CD and UC are lifelong conditions, and there is increasingly solid evidence that pathogenic events underlying both forms of IBD vary with disease evolution. What is detected at an early, intermediate, or late stage of IBD may or may not be the same response unless placed in the context of timing of disease. IBD is certainly present at the mucosal level well before the initial clinical symptoms and manifestations (the life before IBD that includes the sensitive period previously mentioned), and continues after the clinical diagnosis is made with an unpredictable disease course (the life after IBD that includes a less sensitive period): thus, there are early and late stages of IBD, a concept corroborated by studies of pediatric IBD.38 The demonstration of well-defined disease stages in human patients is practically unfeasible because of the ethical and logistic impossibility of studying patients for years and

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years of disease evolution, but this can be accomplished in animal models. Studies in IL-10-deficient mice that spontaneously develop colitis show that the early stages of colitis are mediate by high levels of IL-12 and IFN-γ, a typical Th1 pattern, while in the late stages of disease there is a switch to a Th2 pattern mediated primarily by high IL-4 and IL-13.39 Importantly, blockade of IL-12 and IFN-γ is therapeutically efficacious in early but not late colitis, while blockade of IL-4 and IL-13 is needed to improve colitis in late disease. These findings have important implications for humans, and in fact clinical trials show a differential response to anti-tumor necrosis factor-α therapy in early versus late disease, with better and more prolonged response when the biologic is administered in recently diagnosed subjects.40 Therefore, from a pathogenesis perspective, IBD can be perceived as resulting from primary factors that include the exposome, genome, microbiome, and immunome in the early stages of disease, and then persisting in the late stages under the influence of modifying secondary

factors, such as the epigenome, DAMPs, adiposity, neural, and endocrine factors, as well as many others. So in answer to the question “IBD pathogenesis: what is the importance of time-dependent evolution?” the following can be stated: IBD can no longer be seen as a condition with a fixed set of pathogenic events and clinical manifestations; on the contrary, IBD is a dynamic condition with a time-dependent evolution of disease mechanisms and clinical expression.

The IBD “integrome” The goal of achieving a true understanding of IBD pathogenesis has roots in the very practical necessity of improving current therapeutic approaches to IBD. If one looks at the evolution of IBD treatments from the 1940s, when the benefits of sulfasalazine in UC patients were first recorded, until the present, when combination therapies and biologics have become a routine and effective


Epidemiological associations

Epigenetic modifications Diet


Human studies



Animal models


Animal models GWAS

Clinical observations GWAS

Gut microbiome

Figure 1 Schematic representation of the “IBD integrome” concept. The four “ome” ovals represent the currently accepted major components of IBD pathogenesis, that is, the exposome, the genome, the gut microbiome, and the immunome. The exposome oval is larger than the others to translate the authors’ view that the exposome is the primary originator and most important component of IBD pathogenesis. The direction of the arrows indicates the main functional relationships among the pathogenic components, and they are sided by the available epidemiological, experimental, and clinical evidence supporting the portrayed relationship. GWAS, genome-wide association studies; IBD, inflammatory bowel disease.


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way to manage IBD, there is no question that giant steps have been taken for the better. Nevertheless, results are far from ideal, particularly in regard to rather predictable recurrence of disease, the most difficult challenge that patients and doctors alike constantly face in their lives. Based on the continuous expansion of knowledge of IBD pathophysiology, most of the molecules identified as direct or indirect mediators of inflammation have been or are being targeted by the pharmaceutical industry, resulting in a long list of antibodies or small compounds directed at highly specific molecular targets.41 All the agents developed with this approach make theoretical sense, but in clinical practice even some of the most promising new agents fail the test of controlling gut inflammation; a glaring example is the case for secukinumab, a human anti-IL17A, which actually worsened the course of CD,42 the form of IBD where the Th17 response is supposed to be central to tissue damage and inflammation. The lessons derived from this failure are several and are of fundamental importance. First, the function of Th17 cells and IL-17 is clearly not understood in IBD pathophysiology; second, we obviously do not understand whether Th17 cells mediate damage or protection, or they do so under different circumstances; and third, blockade of IL-17 is very effective in psoriasis, a disease sharing commonalities with CD, so that efficacy in one chronic inflammatory condition does not imply efficacy in another, even related, disease. Therefore, when we look at the 25 drugs developed in the last decade and tested in IBD clinical trials, nine are or appear to be effective, two show promise, and the remaining 18 have failed.41 This poses the obvious question of why even rationally developed drugs fail to work. We suggest that one of the main, if not the single most important, reasons is because they essentially target exclusively the immunome, with disregard of the other components of IBD pathogenesis: the exposome, the genome, and the gut microbiome. Thus, if IBD is indeed the result of a complex integration of these components, a truly effective therapy can only be achieved if an “IBD integrome” approach is implemented, as alluded to in the introduction (Fig. 1). The challenges of doing so are enormous but not insurmountable. Individual and separate approaches to each “ome” involved in IBD is impractical, too costly, and too time-consuming, but a comprehensive and concomitant approach, like the one that systems biology can offer, seems a reasonable, feasible, and practical alternative. Biobanking is becoming a reality in all major medical centers, and this allows the collection of vast amounts of molecular data from genomic, proteomic, and microbiomic arrays; specific “ome” signatures that can be matched with carefully analyzed phenotypic information from properly selected patient subgroups can then be obtained; from the combination of molecular data and omic signatures, models that generate improved patient classifications, predict clinical course, select the most logical treatment forms, and anticipate outcome can be developed.43 This seemingly “futuristic” approach to IBD therapy is closer than what appears to be, and considering the incredible technological progress of today and its increasing speed as time goes by it will become routine within less than two decades.

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Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 12–18 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

Inflammatory bowel disease pathogenesis: where are we?

Inflammatory bowel disease (IBD) is presently one of the most investigated human disorders. Expansion of knowledge of its pathophysiology has helped i...
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