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The proper delivery of immune cells throughout the host's various tissues and organs is essential to health, and abnormalities in the type and quantity of leukocyte distribution is usually associated with disease. Because of its size and presence of a very large amount of immunocytes in the mucosa and mesenteric lymph nodes, the gut is the recipient of a constant influx of leukocytes, a process tightly regulated by multiple factors. These include cell adhesion molecules on the leukocytes and their counter-receptors on the microvascular endothelial cells in the bowel wall, a number of chemokines and cytokines that help attracting immune cells, platelets, bacterial products, danger signals, the size of the vascular and lymphatic beds and the process of leukocyte exit and circulation in the blood and lymphatic fluid. The disruption of any of the above regulatory mechanism can lead to inflammation, as is the case for inflammatory bowel disease. Learning how leukocyte and endothelial cells mutually function in health and what goes wrong in inflammation offers the opportunity to intervene therapeutically and re-establish the normal crosstalk between leukocytes and endothelial cells. (C) 2016 S. Karger AG, Basel

Personalized medicine is variably defined as a new system aimed at providing optimal medical care by using comprehensive pathophysiology-based information on all aspects and components of a disease process to prevent, diagnose and treat in ways that are custom-made for the individual patient. The need for personalized medicine derives from the realization that today's most challenging medical conditions are chronic complex diseases with multiple pathogenic components that interact with each other. Complexity and interaction together create unique molecular pathways that are only relevant to certain disease subtypes, but not to the entire population of patients with the same diagnosis. Thus, complex diseases cannot be properly controlled, and much less cured, by modulating single components at sporadic time points in the course of the disease or administering the same treatment to all patients, as we currently do in the management of inflammatory bowel disease (IBD). The implementation of personalized medicine requires entirely novel and methodologically sophisticated bioinformatics-based approaches that use comprehensive and detailed information on the various components (‘omes') of the disease process. This requires identifying the key controllers (‘hubs') of pathogenic pathways in a totally unbiased fashion and discovering highly specific agents that can selectively block or even revert pathogenic events. IBD is a perfect example of a condition with multiple causes and multiple mechanisms, and IBD patients will unquestionably benefit from the adoption of personalized medicine in the near future.

The complexity of IBD is well recognized as are the putative four major components of its pathogenesis, i.e. environment, genetic makeup, gut microbiota and mucosal immune response. Each of these components is extremely complex on its own, and at present should be more appropriately defined by the terms ‘exposome', ‘genome', ‘microbiome' and ‘immunome', respectively, based on the ‘ome' suffix that refers to a totality of some sort. None of these ‘omes' is apparently capable of causing IBD by itself; it is instead the intricate and reciprocal interaction among them, through the so-called ‘IBD interactome', that results in the emergence of IBD, or more appropriately the ‘IBD integrome'. To deal with and understand such overwhelming biological complexity, new approaches and tools are needed, and these are represented by ‘omics', defined as the study of related sets of biological molecules in a comprehensive fashion, such as genomics, transcriptomics, proteomics, metabolomics, and so on. Numerous bioinformatics-based tools are available to explore and take advantage of the massive amount of information that can be generated by the analysis of the various omes and their interactions, aiming at identifying the molecular interactome underlying any particular status of health and disease. These novel approaches are fully applicable to IBD and allow us to achieve the ultimate goal of developing and applying personalized medicine and far more effective therapies to individual patients with Crohn's disease and ulcerative colitis. For the practicing gastroenterologist, an omics-based delivery of healthcare may be intimidating, but it must be accepted and implemented if he or she is to provide the best possible care to IBD patients.

The clinical course of inflammatory bowel disease (IBD) is highly heterogeneous and often unpredictable, with multiple and serious complications that range from stricture formation to bowel obstruction or perforation, fistula formation and the need for surgery. All these problems are manifestations of tissue remodeling, a secondary but universal response to the insults of chronic inflammation. The factors involved in tissue remodeling are several, including the site and duration of inflammation, soluble molecules, the gut microbiota, and the type of mesenchymal cell response. The prototypical and most common type of tissue remodeling in IBD, and Crohn's disease (CD) in particular, is a fibrotic response, and this review will focus on the factors and mechanisms involved in fibrogenesis, and speculate on what is needed for the development of a rational treatment of intestinal fibrosis.

It is becoming increasingly evident that the old paradigm of disease pathogenesis where a given genotype would determine a phenotype and this would lead to a particular disease is no longer acceptable. Many novel components are now recognized to be involved in the predisposition, triggering, progression and outcome of chronic inflammatory diseases like inflammatory bowel disease (IBD). Accordingly, investigation of IBD must recognize this complexity and take all potential components into account, if a full understanding of disease pathophysiology is to be reached and truly effective therapies developed based on this new global understanding. Essential to this approach is the notion of functional integration. Groups of functionally related pathogenic components must be assembled and studied as ‘omes’ like, for instance, the genome and the microbiome; at the same time all relevant ‘omes’ must be functionally and meaningfully integrated into the ‘interactome’, while the ‘epigenome’ should be used to dissect and understand the connections underlying the interactome. This is an ideal but also realistic scenario for the immediate future, as some of the ‘omes’ are already being explored in greater depth and their interactions examined through investigation of gene-gene (GXG) and gene-environment (GXE) interactions. Current knowledge of GXG and GXE and their impact on IBD pathogenesis is the focus of this review.

The rapid accumulation of new knowledge on the genes, gene variations and genetic loci associated with both forms of inflammatory bowel disease (IBD), e.g. Crohn’s disease (CD) and ulcerative colitis (UC), is shedding new light on the immunopathogenic mechanisms underlying these conditions. After the initial report of the association of NOD2 mutations with ileal CD, a large number of additional genetic variants and loci has been found to be associated with both CD and UC, CD alone and, quite recently, UC-associated variants have also emerged. Much of this progress is due to the use of methods such as genome-wide associations (GWA) based on large numbers of reasonably well-characterized patient groups. Among several others, some of the most pathophysiologically relevant associations reported so far are with gene variants related to innate immunity, autophagy, apoptosis, Th1 and Th17 responses, T cell activation, and immunosuppression. Some of these associations have lent further support to previously construed disease mechanisms or disclosed brand new mechanisms, like in the case of the autophagy pathway. While this much progress is obviously welcome, it also brings new challenges. These include the fact that all the gene mutations uncovered so far only account for a minority of all IBD cases, the variable distribution of gene mutations among worldwide IBD populations, and the still unknown effects of gene-gene and gene-environment interactions. Nevertheless, there is no question that genetic information will be quickly utilized not only for a better understanding of IBD pathogenesis, but it will also soon be incorporated into the armamentarium of better diagnostic and therapeutic tools.