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Background The epidemiology of inflammatory bowel disease (IBD) in developing countries may uncover etiopathogenic factors. We investigated IBD prevalence in Brazil by investigating its geographic, spatial, and temporal distribution, and attempted to identify factors associated with its recent increase. Methods A drug prescription database was queried longitudinally to identify patients and verify population distribution and density, race, urbanicity, sanitation, and Human Development Index. Prevalence was calculated using the number of IBD patients and the population estimated during the same decade. Data were matched to indices using linear regression analyses. Results We identified 162 894 IBD patients, 59% with ulcerative colitis (UC) and 41% with Crohn’s disease (CD). The overall prevalence of IBD was 80 per 100 000, with 46 per 100 000 for UC and 36 per 100 000 for CD. Estimated rates adjusted to total population showed that IBD more than triplicated from 2008 to 2017. The distribution of IBD demonstrated a South-to-North gradient that generally followed population apportionment. However, marked regional differences and disease clusters were identified that did not fit with conventionally accepted IBD epidemiological associations, revealing that the rise of IBD was variable. In some areas, loss of biodiversity was associated with high IBD prevalence. Conclusions When distribution is considered in the context of IBD prevalence, marked regional differences become evident. Despite a background of Westernization, hotspots of IBD are recognized that are not explained by population density, urbanicity, sanitation, or other indices but apparently are explained by biodiversity loss. Thus, the rise of IBD in developing countries is not uniform, but rather is one that varies depending on yet unexplored factors like geoecological conditions.

Background Systems biology is a rapidly advancing field of science that allows us to look into disease mechanisms, patient diagnosis and stratification, and drug development in a completely new light. It is based on the utilization of unbiased computational systems free of the traditional experimental approaches based on personal choices of what is important and what select experiments should be performed to obtain the expected results. Methods Systems biology can be applied to inflammatory bowel disease (IBD) by learning basic concepts of omes and omics and how omics-derived “big data” can be integrated to discover the biological networks underlying highly complex diseases like IBD. Once these biological networks (interactomes) are identified, then the molecules controlling the disease network can be singled out and specific blockers developed. Results The field of systems biology in IBD is just emerging, and there is still limited information on how to best utilize its power to advance our understanding of Crohn disease and ulcerative colitis to develop novel therapeutic strategies. Few centers have embraced systems biology in IBD, but the creation of international consortia and large biobanks will make biosamples available to basic and clinical IBD investigators for further research studies. Conclusions The implementation of systems biology is indispensable and unavoidable, and the patient and medical communities will both benefit immensely from what it will offer in the near future.

Scientific research into the effects and mechanisms of acupuncture for gastrointestinal diseases including inflammatory bowel disease has been rapidly growing in the past several decades. In this review, we discuss the history, theory, and methodology of acupuncture and review potentially beneficial mechanisms of action of acupuncture for managing inflammatory bowel disease. Acupuncture has been shown to decrease disease activity and inflammation via increase of vagal activity in inflammatory bowel disease. Acupuncture has demonstrated beneficial roles in the regulation of gut dysbiosis, intestinal barrier function, visceral hypersensitivity, gut motor dysfunction, depression/anxiety, and pain, all of which are factors that can significantly impact quality of life in patients with inflammatory bowel disease. A number of clinical trials have been performed to investigate the therapeutic effects of acupuncture in ulcerative colitis and Crohn's disease. Although the data from these trials are promising, more studies are needed given the heterogeneous and multifactorial aspects of inflammatory bowel disease. There is also an important need to standardize acupuncture methodology, study designs, and outcome measurements.

Background Intestinal fibrosis is a severe complication of inflammatory bowel diseases (IBD) leading to intestinal strictures and need for surgery. No effective anti-fibrotic therapy is available. Cadherin-11 (Cad-11) is an adherens junction protein, which is upregulated in rheumatoid arthritis (RA), idiopathic pulmonary fibrosis (IPF) and skin fibrosis. Inhibition of cadherin-11 has shown beneficial effects in RA and IPF animal models. A phase II clinical trial of cadherin-11 inhibition in RA has shown a good safety profile. Our aim was to evaluate the expression levels and function of Cad-11 in IBD patients using intestinal tissues, primary human intestinal cells, and the murine dextran sulfate sodium (DSS)-induced chronic colitis model. Methods IBD (Crohn’s disease (CD) n=20; Ulcerative colitis (UC) (n=10) and control (n=10) full thickness resected intestinal tissues were procured from adults in accordance with IRB approval. Protein and mRNA were extracted for western blot (WB) and quantitative polymerase chain reaction (qPCR). Distribution of Cad-11 was evaluated by immunofluorescence (IF) and RNA hybridization in frozen and formalin-fixed paraffin-embedded (FFPE) tissue sections, respectively. Primary human intestinal myofibroblasts (HIMF) were used in functional experiments. Recombinant human Fc and Cad-11 extracellular domain (hCAD-11-Fc) was used as activator and siRNA as inhibitor of Cad-11 in HIMF. Murine chronic colitis was induced in wildtype BALB/c mice and cadherin-11 knockout mice by DSS. Anti-Cad-11 monoclonal antibody (H1M1) was used for the treatment of BALB/c mouse colitis. Results Increased gene and protein expression levels of Cad-11 were found in intestinal full thickness IBD tissue compared to controls (45-fold, p Conclusions Cad-11 expression is increased in CD stricture tissues and its blockade reduces profibrotic effects in HIMF in vitro. Inhibition of Cad-11 in vivo reduces clinical severity and fibrosis of experimental colitis.

Small bowel transplant is an acceptable procedure for intractable Crohn’s disease (CD). Some case reports and small series describe the apparent recurrence of CD in the transplanted bowel. This commentary discusses evidence in favor of and against this alleged recurrence and argues that a molecular characterization is needed to prove or disprove that inflammation emerging in the transplanted bowel is a true recurrence of the original CD.

Background Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) displays multiple activities, among which pathogen binding and angiogenesis are particularly prominent. These same functions are also exerted by Toll- and NOD-like receptors (TLRs and NLRs), which are critical mediators of innate immune responses. We investigated whether a functional inter-relationship exists between CEACAM1 and TLRs and NLRs and its potential impact on induction of intestinal angiogenesis. Methods This hypothesis was tested using human intestinal microvascular endothelial cells, a unique cell population exposed to microbial products under physiological and pathological conditions. Results The results show that activation of TLR2/4, TLR4, NOD1, and NOD2 by specific bacterial ligands selectively and differentially upregulates the levels of cellular and soluble CEACAM1 produced by intestinal microvascular endothelial cells. The results also show that CEACAM1 regulates the migration, transmigration, and tube formation of these endothelial cells and mediates vessel sprouting induced by specific TLR and NLR bacterial ligands. Combined, these results demonstrate a close and reciprocal regulatory interaction between CEACAM1 and bacterial products in mediating multiple functions essential to new vessel formation in the gut mucosa. Conclusions A coordinated and reciprocal interaction of CEACAM1 and microbiota-derived factors is necessary to optimize angiogenesis in the gut mucosa. This suggests that a coordination of endogenous and exogenous innate immune responses is necessary to promote intestinal angiogenesis under physiological and inflammatory conditions such as inflammatory bowel disease.

Despite unquestionable progress in the management of inflammatory bowel disease (IBD) and the much improved clinical results achievable today in Crohn's disease (CD) and ulcerative colitis (UC) patients, the overall therapeutic outcome remains far from optimal. The main reason of this partial success is that all current medications only block individual components of a highly complex disease process that results from the integration of multiple and incompletely identified pathogenic components. Thus, if further progress is to be achieved in IBD therapeutics and we want to move from the current success rate to nearly 100%, bold new ideas must be entertained and new approaches put into practice. Both are necessary because in IBD we are dealing with a prototypical complex disease superimposed to the background of the extreme biological diversity of humans in response to injury. An unresolved challenge mandates the adoption of new solutions specifically designed to address the unique features of that challenge. Translated to a disease condition, and IBD in particular, the unresolved challenges of CD and UC demand bold new thinking leading to the conception and implementation of totally innovative therapies. In this article, we propose that one such new thinking is the notion of network medicine for IBD, and that the development of brand new treatments should be based on the identification of the molecular structure of the IBD interactome with the purpose of targeting its controlling elements (central nodes or hubs). This specific targeting of the underlying molecular disease modules will lead to the disruption of the IBD interactome and foster the resolution of intestinal inflammatory process.

At the “4th International Meeting on Inflammatory Bowel Diseases: on the Way to New Therapies,” Capri, 2006, genetics, bacteria–host interactions, immunomodulation, and tissue response were discussed deeply in order to understand, rationalize, and develop novel therapies. About genetics, the importance of a better understanding of the nature of known loci and of the putative associations was stressed. It was confirmed that genotype–phenotype associations in inflammatory bowel disease (IBD) have important clinical and therapeutic implications. The importance of the search for dominant bacterial antigens in chronic immune-mediated intestinal inflammation emerged, as well as knowledge of cellular and molecular mechanisms of bacterial–host interactions. It was discussed how innate and adaptive immunity signaling events can perpetuate chronic inflammation. Signal transduction pathways provide an intracellular mechanism by which cells respond and adapt to environmental stress. The identification of these signals have led to a greater understanding of the pathogenesis of IBD and pointed to potential therapeutic targets. It was shown that immune homeostasis is lost in IBD, resulting in a complex tissue response involving the action of immune and nonimmune cells. The nonimmune tissue response in IBD could be regarded as a new target for control of chronic intestinal inflammation. The changing role of biotherapy in IBD was widely discussed and in particular the anti-TNF-α monoclonal antibodies. Granulocyte-colony stimulating factor (GM-CSF) and stem cells therapies were also discussed. The risk-to-benefit ratio of the novel therapies was analyzed in detail. Finally, future directions for basic science and the unmet needs for clinical practice were presented. (Inflamm Bowel Dis 2007)

Inflammatory bowel disease (IBD) is now recognized as a common chronic disease affecting children and adolescents. This article will review recent advances made in the fields of genetics, epidemiology, gut ecology, and immunology regarding the etiopathogenesis of IBD, with particular emphasis on the contributions made by pediatric studies. Areas where further study of the pediatric age group would be beneficial will be highlighted.

Background Increased abdominal visceral adipose tissue (VAT) is associated with systemic inflammation. The influence of VAT on pediatric inflammatory bowel disease (IBD) has not been studied. The objective of this study was to investigate the differences in VAT between pediatric patients with IBD and age-matched controls and identify associations between VAT and Crohn's disease (CD) outcomes. Methods Single-center retrospective cohort study of 114 pediatric patients with IBD (101 CD and 13 ulcerative colitis) who had abdominal computed tomography at diagnosis. VAT volumes were measured from computed tomography images. A control group of 78 age-matched patients without IBD who had abdominal computed tomography was selected for comparison. Results Median VAT was 634 cm (interquartile range, 411-1041) in the IBD group and 659 cm (interquartile range, 394-1015) in the controls. IBD group had 33% higher VAT than controls (95% confidence interval [CI], 11-58) P = 0.002 after adjusting for body mass index and age. In patients with CD, higher VAT was associated with fistulizing or fibrostenotic disease (odds ratio [OR], 1.7; 95% CI, 1.1-2.9; P = 0.03), CD hospitalizations (OR, 1.9; 95% CI, 1.2-3.4; P = 0.01), moderate or severe disease activity scores (OR, 1.8; 95% CI, 1.1-3.1; P = 0.02), and shorter intervals from diagnosis to surgery (hazard ratio, 1.4; 95% CI, 1.0-2.0; P = 0.05) after adjusting for body mass index and age. Conclusions At diagnosis, pediatric patients with IBD have higher adjusted VAT volumes than age- and body mass index-matched controls. Higher VAT volumes in pediatric patients with CD predicted more hospitalizations, increased likelihood of complicated disease, shorter interval from diagnosis to surgery, and higher disease activity scores at diagnosis.

Chronic intestinal inflammation and impaired tissue repair leading to intestinal fibrosis are a commonly observed complication in inflammatory bowel disease. This is particularly true for small bowel Crohn's disease. However, the development of fibrosis in ulcerative colitis has remained largely unexplored. This is surprising, given knowledge about its prevalence for decades, well described histopathologic features of fibrotic and stricturing ulcerative colitis, the relevance of the extracellular matrix for intestinal inflammation and fibrosis, and the clinical impact of fibrosis on stricture formation, motility, and the necessary discrimination from colonic malignancy. This systematic review summarizes the current knowledge of ulcerative colitis-related fibrosis, including epidemiology, basic mechanisms, histopathology, and clinical implications.

About one-half century ago inflammatory bowel disease (IBD) was a true “Cinderella” of the autoimmune/chronic inflammatory disease cluster, with probably the most inadequate and least dependable amount of information on what might be causing Crohn’s disease (CD) or ulcerative colitis (UC), what could be leading to them, and what the mechanisms underlying inflammatory tissue damage might be.1 This situation is dramatically reversed at the beginning of the 21st century, and it is fair to state that more progress has been achieved in IBD than in any other condition characterized by chronic inflammation of a specific target organ. At present, the IBD research community is satisfied, if not convinced, with the general notion that both CD and UC are closely related to 4 fundamental components that explain their pathogenesis: broad environmental changes, genetic predisposition, the enteric commensal flora, and the immune system.2,3 Progress in each of these areas has not been necessarily even, which is primarily due to logistic difficulties intrinsic to large-scale studies, limits on financial means, variable technological progress, and the availability of enough “hands and brains” to perform basic studies or implement laborious and time-consuming experiments at the bench. Let us briefly analyze each of the above 4 pathogenic components. To further expand our understanding of the contribution of environmental changes to IBD pathogenesis obviously cannot be done at the bench. To generate strong solid evidence in support of the “hygiene hypothesis,”4,5 which links environmental changes to an inappropriate immune reactivity at the systemic or intestinal levels, massive, expensive, longterm prospective studies of diverse populations in various parts of the world would be needed. No single investigator or even groups of investigators alone will ever be able to gather the financial and logistic resources needed to properly carry out these studies, which should be relegated to international governmental agencies. Since this is highly improbable to occur, the lack of adequate IBD epidemiologic studies will continue to hinder efforts to better understand the impact of the environment on the emergence of IBD worldwide. Quite an opposite situation has taken place in the field of IBD genetics. The recent development of technologies that can generate a comprehensive portrait of the human genome, methods that allow rapid sequencing of DNA from preselected and reasonably well-defined patient and control populations, coupled with the creation of genetic consortia in the USA, Europe, and elsewhere have allowed the performance of massive genome-wide association (GWA) studies.6 These are not necessarily “bench-based” activities, but combined they have yielded 2 critical pieces of information: the first is the discovery of novel, numerous, strong links between genetic variations and IBD, particularly in CD; the second is the essentially irrefutable proof that genetic predisposition is required to develop IBD.7 This is an excellent example of how long-held intuitions about disease mechanisms based only on clinical and laboratory experience are transformed into reality because of technological advances. While the progress in the field of IBD genetics has been impressive, as is often the case, new challenges are created by new knowledge. At the moment 30 genetic variations have been reported in IBD, but they explain 30% of all IBD cases. How many more variations are to be expected? If the ones described so far represent the most frequent because they are the easiest to detect by GWA, will we uncover an even greater number of variations in unyielding numbers of small subsets of CD and UC patients?8 If so, this is a disheartening and daunting perspective, and one that may keep investigators very busy for quite some time unless additional screening tools become available.9 The long-lasting emphasis put on immunological studies during several decades has caused the field of microbiology to be relatively neglected. Scientists are now suffering from this gap in knowledge, which has become far more acute after the discovery that that the human genome contains “only” 20,000 genes—instead of the predicted 100,000—and the realization that essential functions needed for health depend on complementary functions codified by genes of the human microbiota.10 This is particularly true in the gastrointestinal tract, whose function is almost entirely dependent on the presence of the enteric commensal flora. Lack of adequate knowledge of the enteric microbiota has become a pressing issue for IBD pathogenesis after the realization that gut flora appears to be the target of the aberrant immune response driving inflammation and tissue damage in the gut of CD and UC patients.11,12 To alleviate our ignorance, the recently established Human Microbiome Project and the increasingly widespread use of DNA-based rather than culture-based techFrom the Department of Gastroenterology & Hepatology, Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio, USA. Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20659 Published online in Wiley InterScience (www.interscience.wiley.com).

BACKGROUND Genome-wide association studies have identified at least 71 Crohn's disease (CD) genetic risk loci, but the role of gene-gene interactions is unclear. The value of genetic variants in clinical practice is not defined because of limited explained heritability. METHODS We examined model predictability of combining the 71 CD risk alleles and genetic interactions in an ongoing inflammatory bowel disease genome-wide association study. The Wellcome Trust Case Control Consortium inflammatory bowel disease genome-wide association study was used as a replicate cohort. We used logic regression, an adaptive regression methodology, to search for high-order binary predictors (e.g., single-nucleotide polymorphism [SNP] interactions). RESULTS The combined 71 CD SNPs had good CD risk predictability (area under the curve of 0.75 and 0.73 in the 2 cohorts). Higher cumulative allele score predicted higher CD risk, but a relatively small difference in cumulative allele scores was observed between CD and controls (49 versus 47, P < 0.001). Through LR, we identified high-order genetic interactions and significantly improved the model predictability (area under the curve, from 0.75 to 0.77, P < 0.0001). A genetic interaction model, including NOD2, ATG16L1, IL10/IL19, C13orf31, and chr21q loci, was discovered and successfully replicated in the independent Wellcome Trust Case Control Consortium cohort. The explained heritability of the 71 CD SNPs alone was 24% and increased to 27% after adding the genetic interactions. CONCLUSIONS A novel approach allowed the identification and replication of genetic interactions among NOD2, ATG16L1, IL10/IL19, C13orf31, and chr21q loci. CD risk can be predicted by a model of 71 CD loci and improved by adding genetic interactions.

In this study the TCR-Vβ repertoire expressed in T cells of lamina propria mononuclear cells (LPMC) and peripheral blood mononuclear cells (PBMC) was examined using a reverse transcription-PCR (RT-PCR) technique for TCR-Vβ mRNA. Using a qualitative RT-PCR method, LPMC of patients with IBD and control individuals were shown to contain mRNA for each of 20 TCR-Vβ families, indicating that IBD is not associated with a major deletion or expansion of any TCR-Vβ family. Subsequently, using a quantitative method for four frequently expressed TCR-Vβ families, it was shown that the pattern of TCR-Vβ expression was different in PBMC and LPMC of both IBD patients and control individuals. In addition, it was shown that the LPMC/PBMC ratio of mean mRNA values for TCR-Vβ2, but not for TCR-Vβ6, 7, and 14 was lower in IBD patients than control individuals. These results show that the TCR-Vβ repertoire in PBMC and LPMC is different both in IBD patients and control individuals. In addition, they show that the TCR-Vβ repertoire is altered in IBD, possibly due to an immune response to disease specific antigens, superantigens or neoantigens.

The gastrointestinal tract is unique when compared to other organs of the body because is in direct contact with the external environment and continuously exposed to antigens derived from foods and the enteric flora. To provide a balanced response (homeostasis) to these massive antigenic challenges and still allow the selective absorption of essential nutrients, the intestine has developed a series of powerful defense mechanisms that comprise both physical and biological controls. Physical controls include peristalsis, mucus secretion, and an uninterrupted monolayer of epithelial cells regulated by tight junctions. Biological controls include secretion of antibacterial molecules like defensins, lactoferrin, and lysozyme, trafficking of immune cells in and out of the gut, and a highly specialized immunological system that utilizes both innate and adaptive immune components. The integrated response of these combined defense systems is reflected by the accumulation of an enormous amount of immune cells that are scattered all along the mucosal surface of the gastrointestinal tract, distributed as either organized structures (Peyer’s patches in the small bowel and lymphoid follicles in the colon) or diffusely in the epithelium and lamina propria (intraepithelial lymphocytes and lamina propria mononuclear cells, respectively).1 Thus, when examined histologically, the intestinal mucosa appears to be “inflamed” compared to other mucosal surfaces that are devoid of immune cells or sparsely populated by them. Hence, the term “physiological” intestinal inflammation has been coined.2 Three obvious questions follow this definition of physiological intestinal inflammation: What are the mechanisms underlying its existence? What is its functional significance? What happens when physiological inflammation goes awry? During the last decade major advances in our understanding of the cellular, molecular, and functional mechanisms of physiological intestinal inflammation have occurred. Most of these advances are due to a substantially improved appreciation of the interactions between the normal commensal flora and the mucosal immune system.3 For a long time it has been known that animals kept in a germ-free environment only develop a very rudimentary mucosal immune system, a phenomenon primarily due to the lack of antigenic exposure to the bacteria that normally reside in the intestinal lumen. We know now that bacterial antigens are sampled by mucosal dendritic cells, critical antigen-presenting cells that initiate and control innate immune responses.4 There is recognition that bacterial antigen is mediated by Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-1-like receptors (RLRs)5,6 that discriminate between molecular patterns expressed by commensal or pathogenic bacteria, with subsequent presentation to and activation of effector cells of the adaptive immune system, primarily T and B cells, and development of an immune response that maintains mucosal immune homeostasis. Anatomically, the establishment of this homeostasis is translated by the presence of physiological intestinal inflammation. The functional significance of developing physiological inflammatory reactions in the gut is that they enable the body to recognize foreign and bacterial commensal antigens, and mount an appropriate immune response that is highly regulated and “controlled.” This way, intestinal tissue damage is prevented. The ability of responding to an antigenic challenge without causing injury or disease is what is defined as “tolerance,” or “oral tolerance” in the case of the gastrointestinal tract, and endows the essential ability of continuously adapt to the surrounding environment by creating a limited degree of inflammation that does not cause disease.7 The balance that controls intestinal homeostasis is delicate but, in most individuals, sturdy enough to withstand the challenges of qualitative or quantitative changes of dietary and microbial antigens, and physiological intestinal inflammation is preserved. If an acute infection occurs, as in salmonellosis or shigellosis, physiological inflammation transforms into pathological inflammation, which, however, is self-limited and followed by complete resolution. In contrast, in individuals destined to develop inflammatory bowel disease (IBD), the transformation of physiological into pathological inflammation never results in complete resolution, and overt chronic intestinal inflammation ensues, as typically observed in patients with Crohn’s disease (CD) or ulcerative colitis (UC).8,9 In individuals with an enhanced genetic risk of developing gut inflammation, like first-degree relatives of CD patients, there is a high prevalence of subclinical intestinal inflammation,10 which could be viewed as an intermediate From the Departments of Pathobiology and Gastroenterology & Hepatology, The Cleveland Clinic Foundation, Ohio, USA. Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20618 Published online in Wiley InterScience (www.interscience.wiley.com).

Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of chronic inflammatory bowel disease (IBD), are characterized by mucosal immune cell activation that is driven by a cytokine imbalance. Several cytokines involved in IBD act through the activation of the signal transducers and activators of transcription (STAT) family. We investigated the activation of STAT3 in the mucosa of CD and UC patients, and evaluated whether this event is specific for IBD patients. Using immunofluorescence and immunoblotting, total and phosphorylated STAT3 levels were assessed in biopsy specimens, isolated lamina propria mononuclear cells, and peripheral blood mononuclear cells from patients with CD, UC, other forms of intestinal inflammation, and control subjects. Immunoblotting revealed phosphorylated STAT3 in mucosal biopsy specimens from patients with CD, UC, celiac disease, and acute self-limited colitis, but not in the normal mucosa of control subjects. In IBD patients, STAT3 activation was confined to actively inflamed areas. Accordingly, activated STAT3 was detected in isolated lamina propria mononuclear cells from inflamed IBD tissues, but not in peripheral blood mononuclear cells from control subjects or IBD patients. Immunofluorescence demonstrated that the sources of activated STAT3 were macrophages and T lymphocytes, but not neutrophils. STAT3 activation also was detected in T cells infiltrating the duodenal mucosa of celiac disease patients. We conclude that STAT3 signaling occurs in both CD and UC, where it is strictly confined to areas of active inflammation and is limited to infiltrating macrophages and T cells. The occurrence of STAT3 signaling in other acute and chronic intestinal inflammatory conditions suggests that, rather than a specific feature of IBD, it represents a fundamental signaling pathway that is shared by multiple forms of gut inflammation.

Intestinal epithelial cells are actively involved in the pathogenesis of inflammatory bowel disease resulting in an altered functional phenotype. The modulation of epithelial gene expression may occur as a consequence of proliferative, metabolic, immune, inflammatory, or genetic abnormalities. Differential screening of epithelial-cell-derived cDNA libraries (from control, ulcerative colitis, and Crohn's disease epithelial cells) and differential display of mRNA were used for investigation of disease-associated gene expression and modulation. Intestinal epithelial gene expression was successfully analyzed by both approaches. Using differential screening with clones encoding mitochondrial genes, quantitative overexpression was observed in both ulcerative colitis and Crohn's disease, while a unique expression of small RNA was noticed in Crohn's disease cells using Alu-homologous clones. Differential display demonstrated that several genes were differentially displayed among control, ulcerative colitis, and Crohn's disease epithelial cells. This was confirmed by immunohistochemical staining of pleckstrin, desmoglein 2 and voltage-dependent anion channel in control and inflammatory bowel disease mucosal samples. In summary, several inflammatory bowel disease-related associations were found. Since both differential screening and display have advantages and limitations, the combination of both techniques can generate complementary information, facilitate search for novel genes, and potentially identify genes uniquely associated with inflammatory bowel disease.