Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and these have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis. Second, efforts directed towards the identification of environmental factors implicate commensal bacteria (or their products), rather than conventional pathogens, as drivers of dysregulated immunity and IBD. Third, murine models, which exhibit many of the features of ulcerative colitis and seem to be bacteria-driven, have helped unravel the pathogenesis/mucosal immunopathology of IBD.

Unravelling the pathogenesis of inflammatory bowel disease

Microbial Influences in Inflammatory Bowel Diseases

In the past few years, data obtained from work in animal models, human genetics, basic science and clinical trials, has provided new insights into the mechanisms underlying Crohn's disease and ulcerative colitis. In this review, the author discusses the evidence underlying the disparate theories on the pathogenesis of these diseases and attempts to reconcile them into a coherent hypothesis based on the experimental data. Crohn's disease and ulcerative colitis are idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated. Although their exact etiologies remain uncertain, results from research in animal models, human genetics, basic science and clinical trials have provided important new insights into the pathogenesis of chronic, immune-mediated, intestinal inflammation. These studies indicate that Crohn's disease and ulcerative colitis are heterogeneous diseases characterized by various genetic abnormalities that lead to overly aggressive T-cell responses to a subset of commensal enteric bacteria. The onset and reactivation of disease are triggered by environmental factors that transiently break the mucosal barrier, stimulate immune responses or alter the balance between beneficial and pathogenic enteric bacteria. Different genetic abnormalities can lead to similar disease phenotypes; these genetic changes can be broadly characterized as causing defects in mucosal barrier function, immunoregulation or bacterial clearance. These new insights will help develop better diagnostic approaches that identify clinically important subsets of patients for whom the natural history of disease and response to treatment are predictable.

Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis.

High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease

Two broad hypotheses have arisen regarding the fundamental nature of the pathogenesis of inflammatory bowel diseases (IBDs, which include ulcerative colitis and Crohn disease). The first contends that primary dysregulation of the mucosal immune system leads to excessive immunologic responses to normal microflora. The second suggests that changes in the composition of gut microflora and/or deranged epithelial barrier function elicits pathologic responses from the normal mucosal immune system. Here we examine these hypotheses and conclude that IBD is indeed characterized by an abnormal mucosal immune response but that microbial factors and epithelial cell abnormalities can facilitate this response.

/pdf/the-fundamental-basis-of-inflammatory-bowel-disease-4emb4v4r9c.pdf

The fundamental basis of inflammatory bowel disease

https://www.gastrojournal.org/article/S0016-5085(03)00067-2/pdf

CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells

Interferon-γ Augments CARD4/NOD1 Gene and Protein Expression through Interferon Regulatory Factor-1 in Intestinal Epithelial Cells

Differential regulation of toll-like receptors by pro- and anti-inflammatory cytokines between human intestinal epithelial and monocytic cell lines

Although some intestinal epithelial cell lines are known to respond to lipopolysaccharide (LPS), understanding of the relationship between LPS responsiveness and the expression of LPS receptors or factors regulating LPS responsiveness of intestinal epithelial cell lines is incomplete. In this study, we demonstrate that commonly studied human intestinal epithelial cell lines can be classified into at least three different types on the basis of LPS responsiveness, Toll-like receptor-4 (TLR4) expression, and the effects of gamma interferon (IFN-γ) on LPS responsiveness. The first phenotype, which includes the HCT-116 and Caco-2 cell lines, is characterized by relative hyporesponsiveness to LPS and diminished expression of TLR4 protein. In these cells, IFN-γ does not induce LPS responsiveness. The second phenotype, which includes cell line SW480, exhibits a highly LPS-responsive phenotype and surface expression of TLR4 protein even in unprimed conditions. These lines are functionally similar to cells of monocytic lineage. In the third phenotype, which includes the HT-29 and Colo205 cell lines, TLR4 protein is largely present in the cytoplasmic fraction and the cells are hyporesponsive to LPS in an unprimed condition. However, priming of these cells with IFN-γ can induce LPS responsiveness through augmentation of LPS uptake and expression of MD-2 mRNA and intracellular TLR4 proteins. Finally, these findings suggest that the Th1 cytokine IFN-γ modulates LPS responsiveness through several mechanisms in intestinal epithelial cells and that these cells may comprise different subpopulations with distinct roles in innate immune responses.

https://iai.asm.org/content/iai/71/6/3503.full.pdf

Gamma interferon augments the intracellular pathway for lipopolysaccharide (LPS) recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular Toll-like receptor 4-MD-2 complex.

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CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells

Interferon-γ Augments CARD4/NOD1 Gene and Protein Expression through Interferon Regulatory Factor-1 in Intestinal Epithelial Cells

Differential regulation of toll-like receptors by pro- and anti-inflammatory cytokines between human intestinal epithelial and monocytic cell lines

Gamma interferon augments the intracellular pathway for lipopolysaccharide (LPS) recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular Toll-like receptor 4-MD-2 complex.