Intestinal Inflammation (intestinal + inflammation)

Distribution by Scientific Domains
Distribution within Medical Sciences

Kinds of Intestinal Inflammation

  • chronic intestinal inflammation


  • Selected Abstracts


    Chronic Intestinal Inflammation and Intestinal Disease in Dogs

    JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2003
    A.J. German
    Normal individuals maintain tolerance to the endogenous bacterial flora residing within their alimentary tract, a phenomenon mediated by the gastrointestinal lymphoid tissue. Loss of this tolerance is a key factor in the development of chronic intestinal inflammation. Manifestations of such uncontrolled inflammation in humans include inflammatory bowel disease and celiac disease. Dogs may similarly be affected, and although the etiopathogenesis is likely similar, the lesions differ. This review includes discussion of the factors involved in breakdown of mucosal tolerance, the immunologic basis of canine enteropathies, and the use of novel immunotherapies for these diseases. [source]


    Characterization of colonic and mesenteric lymph node dendritic cell subpopulations in a murine adoptive transfer model of inflammatory bowel disease

    INFLAMMATORY BOWEL DISEASES, Issue 6 2004
    John Karlis BScHons
    Abstract Ulcerative colitis and Crohn's disease, collectively termed inflammatory bowel diseases (IBD), are chronic inflammatory diseases of the intestine that afflict more than 4 million people worldwide. Intestinal inflammation is characterized by an abnormal mucosal immune response to normally harmless antigens in the gut flora. In Crohn's disease, the pathogenic mucosal immune response is a typical T helper (TH1) type cell response, whereas ulcerative colitis is predominantly associated with a TH2 response. We are interested in the role of dendritic cells in early immunologic events leading to T cell activation and chronic intestinal inflammation. Using a murine adoptive transfer model of IBD, we found an accumulation of dendritic cells in colon and mesenteric lymph nodes during the early stage of IBD before the appearance of epithelial lesions and tissue degradation. In situ immunostaining and flow-cytometric analysis revealed that approximately 50% of colonic dendritic cells were CD11b+ B220, myeloid dendritic cells and 50% expressed the CD11b, B220+ plasmacytoid phenotype. In corresponding mesenteric lymph nodes, approximately 16% were plasmacytoid dendritic cells. Colonic myeloid dendritic cells were shown to express the co-stimulatory molecule CD40. Both, colonic myeloid and plasmacytoid dendritic cells released interferon-, in situ and stimulated T cell proliferation ex vivo. Our results show that dendritic cells can mature in the intestine without migrating to mesenteric lymph nodes. Mature intestinal dendritic cells may form a nucleation site for a local T cell response and play an important role in the pathogenesis of IBD. [source]


    TLR2-independent induction and regulation of chronic intestinal inflammation

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2010
    Olivier Boulard
    Abstract Interactions between the intestinal microflora and host innate immune receptors play a critical role in intestinal homeostasis. Several studies have shown that TLR2 can modulate inflammatory responses in the gut. TLR2 signals enhance tight junction formation and fortify the epithelial barrier, and may play a crucial role in driving acute inflammatory responses towards intestinal bacterial pathogens. In addition, TLR2 agonists can have direct effects on both Th1 cells and Treg. To define the role of TLR2 in the induction and regulation of chronic intestinal inflammation we examined the effects of TLR2 deletion on several complementary models of inflammatory bowel disease. Our results show that TLR2 signals are not required for the induction of chronic intestinal inflammation by either innate or adaptive immune responses. We further show that TLR2,/, mice harbor normal numbers of Foxp3+ Treg that are able to suppress intestinal inflammation as effectively as their WT counterparts. We also did not find any intrinsic role for TLR2 for pathogenic effector T-cell responses in the gut. Thus, in contrast to their role in acute intestinal inflammation and repair, TLR2 signals may have a limited impact on the induction and regulation of chronic intestinal inflammation. [source]


    CCR6 has a non-redundant role in the development of inflammatory bowel disease

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2003
    Rosa Varona
    Abstract Antigen-loaded tissues such as the intestinal mucosa must simultaneously elicit appropriate immune response to innocuous bacteria and food proteins, and to potentially harmful antigens. Impairment of the mechanisms controlling this response may mediate the excessive immune reaction that can lead to tissue destruction and inflammatory intestinal diseases, including inflammatory bowel disease. The intestinal epithelium influences local immune responses through the expression of adhesion molecules, costimulatory factors, cytokines and chemokines. CCL20, a ,-chemokine expressed in epithelia from colon and other intestinal tissue, plays a role in immune responses of intestinal mucosa, as deduced from the defects in intestinal leukocyte homeostasis shown by mice lacking CCR6, the CCL20 receptor. We studied the response of CCR6-deficient mice in two models of inflammatory bowel disease. The data show that absence of CCR6 resulted in less severe intestinal pathology in animals treated with dextran sodium sulfate. Conversely, CCR6 deficiency alters leukocyte homeostasis and the cytokine environment in the intestinal mucosa; these changes are sufficient to confer susceptibility to trinitrobenzene sulfonic acid-induced intestinal inflammation in the otherwise resistant C57BL/6J mouse strain. These results suggest that the CCR6/CCL20 axis has a critical, non-redundant role in the in vivo control of immune responses in the intestine. [source]


    Bifidobacterium longum lysate, a new ingredient for reactive skin

    EXPERIMENTAL DERMATOLOGY, Issue 8 2010
    Audrey Guéniche
    Please cite this paper as: Bifidobacterium longum lysate, a new ingredient for reactive skin. Experimental Dermatology 2010; 19: e1,e8. Abstract:, Reactive skin is characterized by marked sensitivity to physical (heat, cold, wind) or chemical (topically applied products) stimuli and by the impairment of the skin barrier's ability to repair itself. Several lines of evidence suggest that beyond their capacity to positively influence the composition of intestinal microbiota, some probiotic bacteria can modulate the immune system both at local and systemic levels, thereby improving immune defense mechanisms and/or down-regulating immune disorders such as allergies and intestinal inflammation. Several recent human clinical trials clearly suggest that probiotic supplementation might be beneficial to the skin. Using a probiotic lysate, Bifidobacterium longum sp. extract (BL), we demonstrated first in vitro, and then in a clinical trial, that this non-replicating bacteria form applied to the skin was able to improve sensitive skin. The effect of BL were evaluated first on two different models. Using ex vivo human skin explant model we found a statistically significant improvement versus placebo in various parameters associated with inflammation such as a decrease in vasodilation, oedema, mast cell degranulation and TNF-alpha release. Moreover, using nerve cell cultures in vitro, we showed that after 6 h of incubation in culture medium (0.3,1%), the probiotic lysate significantly inhibited capsaicin-induced CGRP release by neurones. Then, a topical cream containing the active extract was tested in a randomized, double-blind, placebo-controlled trial. Sixty-six female volunteers with reactive skin were randomly given either the cream with the bacterial extract at 10% (n = 33) or the control cream (n = 33). The volunteers applied the cream to the face, arms and legs twice a day for two months. Skin sensitivity was assessed by stinging test (lactic acid) and skin barrier recovery was evaluated by measuring trans-epidermal water loss following barrier disruption induced by repeated tape-stripping at D1, D29 and D57. The results demonstrated that the volunteers who applied the cream with bacterial extract had a significant decrease in skin sensitivity at the end of the treatment. Moreover, the treatment led to increase skin resistance against physical and chemical aggression compared to the group of volunteers who applied the control cream. Notably, the number of strippings required to disrupt skin barrier function was significantly increased for volunteers treated with the active cream. Clinical and self-assessment scores revealed a significant decrease in skin dryness after 29 days for volunteers treated with the cream containing the 10% bacterial extract. Since in vitro studies demonstrated that, on one hand, isolate sensitive neurones release less CGRP under capsaicin stimulation in the presence of the bacterial extract and, on the other hand, increased skin resistance in volunteers applying the test cream, we speculate that this new ingredient may decrease skin sensitivity by reducing neurone reactivity and neurone accessibility. The results of this studies demonstrate that this specific bacterial extract has a beneficial effect on reactive skin. These findings suggest that new approaches, based on a bacteria lysate, could be developed for the treatment and/or prevention of symptoms related to reactive skin. [source]


    Regulatory T cells and intestinal homeostasis

    IMMUNOLOGICAL REVIEWS, Issue 1 2005
    Janine L. Coombes
    Summary:, Murine models of inflammatory bowel disease (IBD) are useful tools for the study of the pathogenesis and regulation of intestinal inflammation. Colitis can be induced in immune-deficient mice following transfer of populations of T cells or following infection with Helicobacter hepaticus and other intestinal pathogens. In these situations, colitis occurs as a result of the absence of a specialized population of regulatory cells, as transfer of CD4+CD25+ T cells prevents disease. Importantly, from a clinical perspective, CD4+CD25+ T cells can also reverse an established colitis. CD4+CD25+ T cells proliferate both in the secondary lymphoid organs and at the site of inflammation, suggesting that regulation occurs both locally and systemically. CD4+CD25+ T cells are not only capable of regulating other T cells but are also capable of suppressing components of the innate immune system. Control of colitis is dependent on the presence of the immunosuppressive cytokines interleukin-10 and transforming growth factor-,, although their roles are divergent and complex. Regulatory T cells represent one of the host's mechanisms to prevent immune pathology during chronic immune stimulation. Enhancement of regulatory T-cell activity may be useful to control autoreactive T-cell responses and inhibit harmful inflammatory diseases such as asthma and IBD. [source]


    Lymphoid microenvironment in the gut for immunoglobulin A and inflammation

    IMMUNOLOGICAL REVIEWS, Issue 1 2003
    Robert Chin
    Summary:, Signaling through lymphotoxin , receptor (LT,R) initiates the unfolding of a host of developmental programs ranging from the organogenesis of lymph nodes and Peyer's patches (PPs) to the coordination of splenic microarchitecture. While investigating an alternative pathway to immunoglobulin A (IgA) production, it was uncovered that LT,R signaling in the lamina propria (LP) stroma orchestrates the coordinated expression of key chemokines and adhesion molecules, creation of a cytokine milieu, and stroma development that facilitates robust IgA production independent of secondary lymphoid structures. Simultaneously, this same infrastructure can be commandeered by autoreactive T cells to organize both the acute destruction of the intestinal mucosa and chronic intestinal inflammation via the ligands for LT,R. The ability to modulate LT,R signaling may alternatively permit the suppression of autoimmune responses and augmentation of gut defenses. [source]


    Intestinal dendritic cells: Their role in bacterial recognition, lymphocyte homing, and intestinal inflammation

    INFLAMMATORY BOWEL DISEASES, Issue 10 2010
    S.C. Ng PhD
    Abstract Dendritic cells (DCs) play a key role in discriminating between commensal microorganisms and potentially harmful pathogens and in maintaining the balance between tolerance and active immunity. The regulatory role of DC is of particular importance in the gut where the immune system lies in intimate contact with the highly antigenic external environment. Intestinal DC constantly survey the luminal microenvironment. They act as sentinels, acquiring antigens in peripheral tissues before migrating to secondary lymphoid organs to activate naive T cells. They are also sensors, responding to a spectrum of environmental cues by extensive differentiation or maturation. Recent studies have begun to elucidate mechanisms for functional specializations of DC in the intestine that may include the involvement of retinoic acid and transforming growth factor-,. Specialized CD103+ intestinal DC can promote the differentiation of Foxp3+ regulatory T cells via a retinoic acid-dependent process. Different DC outcomes are, in part, influenced by their exposure to microbial stimuli. Evidence is also emerging of the close interaction between bacteria, epithelial cells, and DC in the maintenance of intestinal immune homeostasis. Here we review recent advances of functionally specialized intestinal DC and their mechanisms of antigen uptake and recognition. We also discuss the interaction of DC with intestinal microbiota and their ability to orchestrate protective immunity and immune tolerance in the host. Lastly, we describe how DC functions are altered in intestinal inflammation and their emerging potential as a therapeutic target in inflammatory bowel disease. (Inflamm Bowel Dis 2010) [source]


    Association between blood flow and inflammatory state in a T-cell transfer model of inflammatory bowel disease in mice

    INFLAMMATORY BOWEL DISEASES, Issue 5 2010
    Norman R. Harris PhD
    Abstract Background: Adoptive transfer of naive T-lymphocyte subsets into lymphopenic mice initiates chronic gut inflammation that mimics several aspects of inflammatory bowel disease (IBD). Patients with IBD can have profound alterations in intestinal blood flow, but whether the same is true in the T-cell transfer model has yet to be determined. Methods: In the current study, chronic intestinal inflammation was induced in recombinase-activating gene-1-deficient (RAG,/,) mice by adoptive transfer of CD4+ T-lymphocytes obtained from interleukin-10 deficient (IL-10,/,) mice. Results: Four weeks later, widespread colonic inflammation was observed in the reconstituted recipients, in contrast to 2 control sets of mice injected with a different subset of lymphocytes or with vehicle alone. We observed that the resulting pathology induced in the reconstituted RAG,/, mice was divided distinctly into 2 subsets: 1 with blood flow near normal with very high inflammation scores, and the other with severely attenuated blood flow but with much lower signs of inflammation. Colonic and ileal blood flow rates in the latter subset of CD4+ mice averaged only ,30% compared to the mice with higher inflammation scores. The lower blood flow rates were associated with greatly reduced red blood cell concentrations in the tissue, suggesting a possible loss of vascular density. Conclusions: In this model of chronic intestinal inflammation, mild inflammation was associated with significant decreases in blood flow. Inflamm Bowel Dis 2009 [source]


    Platelet-activating factor-induced NF-,B activation and IL-8 production in intestinal epithelial cells are Bcl10-dependent

    INFLAMMATORY BOWEL DISEASES, Issue 4 2010
    Alip Borthakur PhD
    Abstract Background: Platelet-activating factor (PAF), a potent proinflammatory phospholipid mediator, has been implicated in inducing intestinal inflammation in diseases such as inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC). However, its mechanisms of inducing inflammatory responses are not fully understood. Therefore, studies were designed to explore the mechanisms of PAF-induced inflammatory cascade in intestinal epithelial cells. Methods: Nuclear factor kappa B (NF-,B) activation was measured by luciferase assay and enzyme-linked immunosorbent assay (ELISA), and interleukin 8 (IL-8) production was determined by ELISA. B-cell lymphoma 10 (Bcl10), caspase recruitment domain-containing membrane-associated guanylate kinase protein 3 (CARMA3), and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) mRNA and protein levels were assessed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. siRNA silencing of Bcl10 was used to examine its role in PAF-induced NF-,B activation and IL-8 production. The promoter region of the Bcl10 gene was cloned with the PCR method and promoter activity measured by luciferase assay. Results: The adaptor protein Bcl10 appeared to play an important role in the PAF-induced inflammatory pathway in human intestinal epithelial cells. Bcl10 was required for PAF-induced I,B, phosphorylation, NF-,B activation, and IL-8 production in NCM460, a cell line derived from normal human colon, and Caco-2, a transformed human intestinal cell line. PAF also stimulated Bcl10 interactions with CARMA3 and MALT1, and upregulated Bcl10 expression in these cells via transcriptional regulation. Conclusions: These findings highlight a novel PAF-induced inflammatory pathway in intestinal epithelial cells, requiring Bcl10 as a critical mediator and involving CARMA3/Bcl10/MALT1 interactions. The proinflammatory effects of PAF play prominent roles in the pathogenesis of IBD and this pathway may present important targets for intervention in chronic inflammatory diseases of the intestine. (Inflamm Bowel Dis 2009;) [source]


    Bifidobacterium animalis causes extensive duodenitis and mild colonic inflammation in monoassociated interleukin-10-deficient mice

    INFLAMMATORY BOWEL DISEASES, Issue 7 2009
    James P. Moran PhD
    Abstract Background: We recently showed that Bifidobacterium animalis is more prevalent within the colons of interleukin (IL)-10-deficient (,/,) mice than in wildtype (WT) animals colonized with the same specific pathogen-free (SPF) fecal contents. Here we tested the ability of this organism to cause T-cell-mediated intestinal inflammation by introducing it into germ-free (GF) IL-10,/, mice. Methods: GF IL-10,/, or WT mice were monoassociated with Bifidobacterium animalis subsp. animalis ATCC (American Type Culture Collection, Manassas, VA) 25527T or with B. infantis ATCC 15697T. Inflammation was measured by blinded histologic scores of the duodenum, cecum, and colon and by spontaneous secretion of IL-12/IL-23 p40 from colonic explants. Bacterial antigen-specific CD4+ mesenteric lymph node (MLN) T-cell recall responses were measured in response to antigen-presenting cells (APC) pulsed with bacterial lysates. Results:B. animalis caused marked duodenal inflammation and mild colitis in monoassociated IL-10,/, mice, whereas the intestinal tracts of WT animals remained free of inflammation. B. infantis colonization resulted in mild inflammation in the duodena of IL-10,/, mice. CD4+ MLN T cells from B. animalis monoassociated IL-10,/, mice secreted high levels of IFN-, and IL-17 in response to B. animalis lysate. B. animalis equally colonized the different intestinal regions of WT and IL-10,/, mice. Conclusions:B. animalis, a traditional probiotic species that is expanded in experimental colitis in this model, induces marked duodenal and mild colonic inflammation and TH1/TH17 immune responses when introduced alone into GF IL-10,/, mice. This suggests a potential pathogenic role for this commensal bacterial species in a susceptible host. (Inflamm Bowel Dis 2009) [source]


    Prebiotics in chronic intestinal inflammation

    INFLAMMATORY BOWEL DISEASES, Issue 3 2009
    Mirjam A.C. Looijer, Van Langen MD
    Abstract Prebiotics are nondigestible fermentable fibers that are reported to have health benefits for the host. Older as well as more recent studies show beneficial effects in experimental colitis and lately also in human inflammatory bowel diseases (IBD), such as Crohn's disease, ulcerative colitis, and chronic pouchitis. In this review we give an overview of the benefits of prebiotics in rodent IBD models and in IBD patients and discuss their possible protective mechanisms. Commensal intestinal bacteria induce and perpetuate chronic intestinal inflammation, whereas others are protective. However, most of the current medications are directed against the exaggerated proinflammatory immune response of the host, some of them toxic and costly. Feeding prebiotics changes the composition of the intestinal microflora toward more protective intestinal bacteria and alters systemic and mucosal immune responses of the host. Therapy for IBD targeting intestinal bacteria and their function is just emerging. Prebiotics have the promise to be relatively safe, inexpensive, and easy to administer. Unraveling their protective mechanisms will help to develop rational applications of prebiotics. However, the initial promising results with dietary prebiotics in preclinical trials as well as small studies in human IBD will need to be confirmed in large randomized controlled clinical trials. (Inflamm Bowel Dis 2008) [source]


    Acute experimental colitis and human chronic inflammatory diseases share expression of inflammation-related genes with conserved Ets2 binding sites

    INFLAMMATORY BOWEL DISEASES, Issue 2 2009
    Tineke C.T.M. van der Pouw Kraan PhD
    Abstract Background: Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by chronic inflammation of the gastrointestinal tract, with overlapping clinical characteristics and unknown etiology. We reasoned that in intestinal inflammation the initial activation of the innate immune response fails to resolve, finally resulting in uncontrolled chronic inflammatory bowel disease. Methods: To identify the early inflammatory events in colitis that remain active in human chronic colitis, we analyzed the changes of the colonic transcriptome during acute experimental colitis and compared the outcome with previously published profiles of affected tissues from patients with UC and CD, and as a control for intestinal inflammation in general, tissues from celiac disease patients. Rheumatoid arthritis synovial tissues were included as a nonintestinal inflammatory disease. The expression profiles of each disease were analyzed separately, in which diseased tissues were compared to unaffected tissues from the same anatomical location. Results: Gene ontology analysis of significantly regulated genes revealed a marked activation of immunity and defense processes in all diseases, except celiac disease, where immune activation is less prominent. The control region of upregulated genes contained an increase in Ets2 binding sites in experimental colitis, UC, and rheumatoid arthritis, and were associated with upregulated immune activity. In contrast, upregulated genes in celiac disease harbored the transcription factor binding site GLI, which binds to the Gli family of transcription factors involved in hedgehog signaling, affecting development and morphogenesis. Conclusion: Ets2 may be an important transcription factor driving inflammation in acute as well as chronic inflammatory disease. (Inflamm Bowel Dis 2008) [source]


    Suppression of experimental colitis in mice by CD11c+ dendritic cells

    INFLAMMATORY BOWEL DISEASES, Issue 2 2009
    Joseph E. Qualls PhD
    Abstract Background: The innate immune system serves a critical role in homeostasis of the gastrointestinal (GI) tract. Both macrophages (MØs) and dendritic cells (DCs) have been shown to have pathogenic roles in animal models of inflammatory bowel disease. However, studies by several labs have established that resident MØs and DCs within the normal GI tract maintain an immunosuppressive phenotype compared to that seen in other peripheral sites. Recent studies by our lab demonstrated that the depletion of both MØs and DCs before the initiation of dextran sodium sulfate (DSS)-induced colitis resulted in exacerbation of disease, partly caused by increased neutrophil influx. Methods/Results: In this current report, DSS-induced colitis was shown to be significantly more severe when DCs were selectively depleted in mice as indicated by changes in weight loss, stool consistency, rectal bleeding, and histopathology. In contrast to enhanced colitis in MØ/DC-depleted mice, which was associated with increased neutrophil influx, increased colitis in DC-depleted mice was not associated with an increase in neutrophils in the colon, as shown by CXCL1 chemokine levels and myeloperoxidase (MPO) activity. However, increased IL-6 gene and protein expression in colon tissues correlated positively with increased colitis severity in DC-depleted mice compared to colitis in DC-intact mice. Conclusions: This study demonstrates that resident DCs can suppress the severity of acute DSS colitis and that regulation of IL-6 production may contribute to DC-mediated control of intestinal inflammation. (Inflamm Bowel Dis 2008) [source]


    Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti-TNF-alpha therapy for Crohn's disease

    INFLAMMATORY BOWEL DISEASES, Issue 10 2008
    Taina Sipponen MD
    Abstract Background: Fecal calprotectin and lactoferrin are promising noninvasive biomarkers for intestinal inflammation. In Crohn's disease (CD), during anti-TNF-alpha (TNF-,) treatment, the clinical significance of these markers has, however, been insufficiently explored. Methods: Among CD patients receiving anti-TNF-, therapy we assessed the role of fecal calprotectin and lactoferrin as surrogate markers for mucosal healing. Before and 3 months after the beginning of anti-TNF-, induction, 15 patients underwent ileocolonoscopy with scoring of the Crohn's Disease Index of Severity (CDEIS). Fecal samples for calprotectin and for lactoferrin measurements were collected and the Crohn's Disease Activity Index (CDAI) was calculated at the time of the endoscopies and 2 and 8 weeks after the first treatment. Results: The median CDEIS fell from 13.0 to 4.8 (P = 0.002) and CDAI from 158 to 68 (P = 0.005). Accordingly, the median fecal calprotectin concentration fell from 1173 ,g/g to 130 ,g/g (P = 0.001) and fecal lactoferrin from 105.0 ,g/g to 2.7 ,g/g (P = 0.001). Of the 15 patients, 11 (73%) showed an endoscopic response to treatment and 5 of these achieved endoscopic remission (CDEIS < 3). In those 5 patients the fecal calprotectin concentration declined from 1891 ,g/g (range 813,2434) to 27 ,g/g (13,130) and lactoferrin from 92.4 ,g/g (35.5,235.6) to 1.9 ,g/g (0.0,2.1). Conclusions: Compared to pretreatment values, concentrations of fecal calprotectin and lactoferrin after the anti-TNF-, treatment were significantly lower. During anti-TNF-, therapy these fecal neutrophil-derived proteins may thus be useful surrogate markers for mucosal healing. (Inflamm Bowel Dis 2008) [source]


    Fecal calprotectin is useful in predicting disease relapse in pediatric inflammatory bowel disease

    INFLAMMATORY BOWEL DISEASES, Issue 5 2008
    Dorota Walkiewicz MD
    Abstract Background: Fecal calprotectin (FC) has been proposed as a noninvasive surrogate marker to determine the degree of intestinal inflammation and predicting relapse in patients with inflammatory bowel disease (IBD). The aim was to compare FC levels in IBD and healthy controls, to correlate FC levels with clinical disease activity, and to assess whether FC levels can be used to predict clinical relapse in children with IBD. Methods: Enzyme-linked immunosorbent assay (ELISA) determined levels of FC were measured in more than 1 stool samples (n) from 32 IBD patients (n = 97) and from 34 healthy controls (n = 37). Disease activity was assessed by the Harvey,Bradshaw index in Crohn's disease (CD) and by Physician's Global Assessment (PGA) in both CD and ulcerative colitis (UC). Clinical events were recorded up to 9 months following stool collection in CD patients. Wilcoxon rank sum test and Fisher's exact tests were used to compare FC levels in IBD patients and in control. Kaplan,Meyer analysis was used to determine a risk of clinical relapse in relation to FC levels. Results: The IBD group had higher FC levels (range 17,7500 g/g) compared with control (16,750 g/g, P < 0.0001). FC levels were higher during relapse (CD, 3214 ± 2186; UC, 2819 ± 1610) compared to remission (CD, 1373 ± 1630; UC, 764 ± 869; P < 0.0001). Among those with clinical relapse, 90% had FC levels more than 400 ,g/g in CD. Eighty-nine percent of CD encounters with FC levels less than 400 ,g/g remained in clinical remission. Conclusions: FC levels differentiate active IBD from controls. Among children with CD and in remission, FC levels may be useful in predicting impending clinical relapse. (Inflamm Bowel Dis 2008) [source]


    Campylobacter and IFN, interact to cause a rapid loss of epithelial barrier integrity

    INFLAMMATORY BOWEL DISEASES, Issue 3 2008
    Louisa E.N. Rees PhD
    Abstract Background: The intestinal epithelium is a single layer of polarized cells and is the primary barrier separating foreign antigen and underlying lymphoid tissue. IFN, alters epithelial barrier function during inflammation by disrupting tight cell junctions and facilitating the paracellular transport of luminal antigens. The aim of this work was to determine whether Campylobacter infection of cells exposed to IFN, would lead to greater disruption of cell monolayers and hence increased bacterial translocation. Methods: Monolayers were polarized on Transwell polycarbonate membranes for 14 days and then cultured in the presence or absence of 100 U/mL IFN,. Campylobacter was added to the apical side of the monolayer at an MOI of 30. Transepithelial electrical resistance (TEER) was recorded and bacteria in the basal well counted every 2 hours. Cells were stained for occludin, actin, and nuclear DNA, and cell viability determined by measurement of apoptosis. Results: In the presence of IFN,, TEER dropped significantly after 18 hours, indicating a reduction in barrier function. A further significant decrease was seen in the presence of both IFN, and Campylobacter, indicating a synergistic effect, and cellular morphology and viability were affected. Bacterial translocation across the monolayer was also significantly greater in the presence of IFN,. Conclusions: These combined effects indicate that Campylobacter infection concomitant with intestinal inflammation would result in a rapid and dramatic loss of epithelial barrier integrity, which may be a key event in the pathogenesis of Campylobacter -mediated colitis and the development of bloody diarrhea. (Inflamm Bowel Dis 2007) [source]


    Dual-association of gnotobiotic Il-10,/, mice with 2 nonpathogenic commensal bacteria induces aggressive pancolitis

    INFLAMMATORY BOWEL DISEASES, Issue 12 2007
    Sandra C. Kim MD
    Abstract Background: Monoassociating gnotobiotic IL-10-deficient (,/,) mice with either nonpathogenic Enterococcus faecalis or a nonpathogenic Escherichia coli strain induces T-cell-mediated colitis with different kinetics and anatomical location (E. faecalis: late onset, distal colonic; E. coli: early onset, cecal). Hypothesis: E. faecalis and E. coli act in an additive manner to induce more aggressive colitis than disease induced by each bacterial species independently. Methods: Germ-free (GF) inbred 129S6/SvEv IL-10,/, and wildtype (WT) mice inoculated with nonpathogenic E. faecalis and/or E. coli were killed 3,7 weeks later. Colonic segments were scored histologically for inflammation (0 to 4) or incubated in media overnight to measure spontaneous IL-12/IL-23p40 secretion. Bacterial species were quantified by serial dilution and plated on culture media. Mesenteric lymph node (MLN) CD4+ cells were stimulated with antigen-presenting cells pulsed with bacterial lysate (E. faecalis, E. coli, Bacteroides vulgatus) or KLH (unrelated antigen control). IFN-, and IL-17 levels were measured in the supernatants. Results: Dual-associated IL-10,/, (but not WT) mice developed mild-to-moderate pancolitis by 3 weeks that progressed to severe distal colonic-predominant pancolitis with reactive atypia and duodenal inflammation by 7 weeks. NF-,B was activated in the duodenum and colon in dual-associated IL-10,/, × NF-,BEGFP mice. The aggressiveness of intestinal inflammation and the degree of antigen-specific CD4+ cell activation were greater in dual- versus monoassociated IL-10,/, mice. Conclusion: Two commensal bacteria that individually induce phenotypically distinct colitis in gnotobiotic IL-10,/, mice act additively to induce aggressive pancolitis and duodenal inflammation. (Inflamm Bowel Dis 2007) [source]


    Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells

    INFLAMMATORY BOWEL DISEASES, Issue 10 2007
    Renata Stepankova PhD
    Abstract Background: The aim was to analyze the influence of intestinal microbiota on the development of intestinal inflammation. We used the model of chronic inflammation that develops spontaneously in the colon of conventional severe combined immunodeficiency (SCID) mice restored with the CD45 RBhigh subset of CD4+T cells isolated from the spleen of normal BALB/c mice. Methods: A CD4+CD45RBhigh subpopulation of T cells was purified from the spleen of conventional BALB/c mice by magnetic separation (MACS) and transferred into immunodeficient SCID mice. Germ-free (GF) SCID mice or SCID mice monoassociated with Enterococcus faecalis, SFB (segmented filamentous bacteria), Fusobacterium mortiferum, Bacteroides distasonis, and in combination Fusobacterium mortiferum + SFB or Bacteroides distasonis + SFB were used as recipients. SCID mice were colonized by a defined cocktail of specific pathogen-free (SPF) bacteria. Mice were evaluated 8,12 weeks after the cell transfer for clinical and morphological signs of inflammatory bowel disease (IBD). Results: After the transfer of the CD4+CD45RBhigh T-cell subpopulation to SCID mice severe colitis was present in conventional animals and in mice colonized with a cocktail of SPF microflora plus SFB. Altered intestinal barrier in the terminal ileum of mice with severe colitis was documented by immunohistology using antibodies to ZO-1 (zona occludens). Conclusions: Only SFB bacteria together with a defined SPF mixture were effective in triggering intestinal inflammation in the model of IBD in reconstituted SCID mice, while no colitis was detected in GF mice or in mice colonized either with SPF microflora or monoassociated only with SFB or colonized by Bacteroides distasonis + SFB or Fusobacterium mortiferum + SFB. (Inflamm Bowel Dis 2007) [source]


    Epithelial barrier disruption allows nondisease-causing bacteria to initiate and sustain IBD in the IL-10 gene-deficient mouse,

    INFLAMMATORY BOWEL DISEASES, Issue 8 2007
    Beate C. Sydora PhD
    Abstract Background: In the IL-10 gene-deficient mouse model, development of intestinal inflammation is associated with a defect in epithelial barrier integrity that is thought to allow sufficient passage of bacteria or bacterial antigens to initiate a mucosal immune response. Microbial monoassociation experiments into axenic animals have shown that some, but not all, endogenous bacteria will initiate an intestinal inflammatory response. For instance, Bacteroides vulgatus does not initiate intestinal inflammation in axenic IL-10 gene-deficient mice. We investigated whether B. vulgatus requires concomitant disruption of the intestinal epithelial barrier integrity in order to initiate an inflammatory response. Methods: We first identified a dose of the indomethacin that would cause a primary disruption of the epithelial barrier without causing intestinal inflammation. IL-10 axenic mice were then administered this dose of indomethacin in their drinking water for 7 days and concomitantly monoassociated, by oral gavage, with B. vulgatus. Results: Indomethacin treatment (2 ,g/g/d) for 7 days resulted in disruption of epithelial barrier integrity, but it caused neither a systemic inflammatory response nor a mucosal inflammatory response in the colon or cecum. Monoassociation with B. vulgatus alone did not lead to a mucosal inflammatory response, despite a measurable systemic response. In contrast, administration of indomethacin plus B. vulgatus -monoassociation resulted in a marked intestinal inflammatory response in colon and cecum. Conclusions: Our data show that, in a genetically predisposed animal model, the nondisease-causing endogenous bacteria, B. vulgatus, is able to cause an intestinal inflammatory response provided that disruption of the intestinal epithelial barrier has occurred. (Inflamm Bowel Dis 2007) [source]


    CD4+ T lymphocytes mediate colitis in HLA-B27 transgenic rats monoassociated with nonpathogenic Bacteroides vulgatus

    INFLAMMATORY BOWEL DISEASES, Issue 3 2007
    Frank Hoentjen MD
    Abstract Background: HLA-B27/,2 microglobulin transgenic (TG) rats develop spontaneous colitis when raised under specific pathogen-free (SPF) conditions or after monoassociation with Bacteroides vulgatus (B. vulgatus), whereas germ-free TG rats fail to develop intestinal inflammation. SPF HLA-B27 TG rnu/rnu rats, which are congenitally athymic, remain disease free. These results indicate that commensal intestinal bacteria and T cells are both pivotal for the development of colitis in TG rats. However, it is not known if T cells are also required in the induction of colitis by a single bacterial strain. The aim of this study was therefore to investigate the role of T cells in the development of colitis in B. vulgatus,monoassociated HLA-B27 TG rats. Methods: HLA-B27 TG rnu/rnu and rnu/+ rats were monoassociated with B. vulgatus for 8,12 weeks. CD4+ T cells from mesenteric lymph nodes (MLNs) of B. vulgatus,monoassociated rnu/+ TG donor rats were transferred into B. vulgatus,monoassociated rnu/rnu TG recipients. Results:B. vulgatus,monoassociated rnu/+ rats showed higher histologic inflammatory scores and elevated colonic interferon-, mRNA, cecal myeloperoxidase, and cecal IL-1, levels compared to those in rnu/rnu TG rats that did not contain T cells. After transfer of CD4+ cells from colitic B. vulgatus,monoassociated rnu/+ TG donor rats, B. vulgatus,monoassociated rnu/rnu TG recipients developed colitis that was accompanied by B. vulgatus- induced IFN-, production by MLN cells in vitro and inflammatory parameters similar to rnu/+ TG rats. Conclusions: These results implicate CD4+ T cells in the development of colitis in HLA-B27 TG rats monoassociated with the nonpathogenic bacterial strain B. vulgatus. (Inflamm Bowel Dis 2007) [source]


    Bacterial antigens alone can influence intestinal barrier integrity, but live bacteria are required for initiation of intestinal inflammation and injury

    INFLAMMATORY BOWEL DISEASES, Issue 6 2006
    Beate C. Sydora PhD
    Abstract Intestinal flora plays a critical role in the initiation and perpetuation of inflammatory bowel disease. This study examined whether live fecal bacteria were necessary for the initiation of this inflammatory response or whether sterile fecal material would provoke a similar response. Three preparations of fecal material were prepared: (1) a slurry of live fecal bacteria, (2) a sterile lysate of bacterial antigens, and (3) a sterile filtrate of fecal water. Each preparation was introduced via gastric gavage into the intestines of axenic interleukin-10 gene-deficient mice genetically predisposed to develop inflammatory bowel disease. Intestinal barrier integrity and degrees of mucosal and systemic inflammations were determined for each preparation group. Intestinal barrier integrity, as determined by mannitol transmural flux, was altered by both live fecal bacterial and sterile lysates of bacterial antigens, although it was not altered by sterile filtrates of fecal water. However, only live fecal bacteria initiated mucosal inflammation and injury and a systemic immune response. Fecal bacterial antigens in the presence of live bacteria and sterile fecal bacterial antigens have different effects on the initiation and perpetuation of intestinal inflammation. [source]


    CD4+CD25+ cell depletion from the normal CD4+ T cell pool prevents tolerance toward the intestinal flora and leads to chronic colitis in immunodeficient mice

    INFLAMMATORY BOWEL DISEASES, Issue 6 2006
    Claudia Veltkamp MD
    Abstract Background: CD4+CD25+ regulatory T cells have been shown to prevent immune-mediated colitis in mice; however, it is unclear whether the absence of CD4+CD25+ in the normal CD4+ T cell pool is responsible for the development of chronic colitis. Using the T cell-deficient Tg,26 mouse model, we show that CD4+CD25, cells but not CD4+CD25+ cells induce a severe intestinal inflammation. Transfer of CD4+CD25+ cells, together with CD4+CD25, cells, ameliorated intestinal inflammation, and reconstitution with the whole mesenteric lymph node cell pool did not induce colitis in recipients. Transferred CD4+CD25, cells were found mainly in the mesenteric lymph nodes, where they showed an activated TH1-like phenotype. In the absence of regulatory CD4+CD25+ T cells, recipient CD4+ cells secreted IFN-, in response to stimulation with intestinal bacterial antigen that was prevented in vivo and in vitro by regulatory CD4+CD25+ cells. These studies suggest that CD4+CD25, cells have a strong colitogenic effect in the Tg,26 colitis model and that CD4+CD25+ cells may be the main regulators that prevent or downregulate the proinflammatory effect of colitogenic T cells in the Tg,26 mouse model. [source]


    Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody

    INFLAMMATORY BOWEL DISEASES, Issue 1 2006
    Ivan J Fuss MD
    Abstract Background: Interleukin (IL)-12p70 and IL-23 are key T helper-1 (TH1) cytokines that drive the inflammation seen in numerous models of intestinal inflammation. These molecules contain an identical p40 chain that is bound to a p35 chain in IL-12 and a p19 chain in IL-23, making both potentially susceptible to modulation by an anti-IL-12p40 monoclonal antibody (mAb). Methods: In the present study, we sought to determine whether active inflammation in Crohn's disease (CD) is associated with the increased synthesis of both of these cytokines and whether patients treated with an anti-IL-12p40 mAb down-regulate IL-23 as well as IL-12p70 as previous reported. Results: To this end we initially determined that IL-12p70 secretion by control and CD antigen-presenting cells (macrophages) in lamina propria mononuclear populations is optimized by stimulation with CD40L and interferon-,. In subsequent studies using these stimulation conditions we found that patients with CD manifested both increased IL-12p70 and IL-23 secretion before anti-IL-12p40 mAb treatment and normal levels of secretion of these cytokines following cessation of treatment. Antigen-presenting cells in lamina propria mononuclear cells from ulcerative colitis patients, in contrast, produced only baseline levels of IL-23. Finally, we found that IL-23-induced T cell production of IL-17 and IL-6 are also greatly reduced after antibody treatment. The latter data are parallel to those from previous studies showing that anti-IL-12p40 down-regulates IFN-, and tumor necrosis factor-, secretion. Conclusions: We conclude that CD but not ulcerative colitis is associated with high levels of both IL-12p70 and IL-23 secretion as well as the secretion of downstream effector cytokines, and that this cytokine production is down-regulated following administration of IL-12p40 mAb. [source]


    State of the art: IBD therapy and clinical trials in IBD

    INFLAMMATORY BOWEL DISEASES, Issue S1 2005
    Kim L Isaacs MD
    Abstract Inflammatory bowel diseases (IBD) encompass Crohn's disease and ulcerative colitis, which are diseases characterized by chronic intestinal inflammation. IBD is believed to result from predisposing genetic and environmental factors (specific antigens and pathogen-associated molecular patterns) acting on the immunoregulatory system and causing inflammation of the gastrointestinal mucosa. IBD may be the result of an imbalance of effector (proinflammatory) and regulatory T-cell responses. Three scenarios indicative of the outcome of this balance exist in animal models: balanced effector and regulatory T cells resulting in a normal controlled inflammation; overactive effector T cells resulting in inflammation and disease; and an absence of regulatory T cells resulting in uncontrolled inflammation and severe, aggressive disease. The number of products under study for the treatment of IBD has increased from 3 products and 1 target in 1993 to more than 30 products and more than 10 targets in 2005. The number of products under development and continued investigations into the pathogenesis of IBD emphasize the need to expand clinical research efforts in IBD. [source]


    Ubiquitin protein modification and signal transduction: Implications for inflammatory bowel diseases

    INFLAMMATORY BOWEL DISEASES, Issue 12 2005
    Cormac Taylor PhD
    Abstract A dysregulated immune response to luminal antigen(s) is associated with the development of inflammatory bowel diseases (IBDs). A complex network of inflammatory and immune mediators released by immune and nonimmune cells participate in the physiopathology of IBD. At the molecular level, events leading to the improper use of the signaling grid are likely responsible for the dysregulated activation of various transcription factors and subsequent induction of inflammatory genes. The posttranslational modification of signaling proteins by the ubiquitin system is a critical event in activation or repression of transcription factors. Two important transcriptional pathways in which ubiquitin is central are the nuclear factor-,B and hypoxia inducible factor-1 (HIF-1) pathways, both of which are important components of intestinal homeostasis. In this review, we discuss the role of ubiquitin modification in relation to nuclear factor-,B and HIF-1 signaling and consider its impact on intestinal inflammation. A greater understanding of posttranslational ubiquitin modification may lead to the identification of new therapeutic opportunities for the treatment of IBD. [source]


    Oro-facial granulomatosis: Crohn's disease or a new inflammatory bowel disease?

    INFLAMMATORY BOWEL DISEASES, Issue 9 2005
    FRCP, Jeremy Sanderson MD
    Abstract Background: Oro-facial granulomatosis (OFG) is a rare chronic inflammatory disorder presenting characteristically with lip swelling but also affecting gingivae, buccal mucosa, floor of mouth, and a number of other sites in the oral cavity. Histologically, OFG resembles Crohn's disease (CD), and a number of patients with CD have oral involvement identical to OFG. However, the exact relationship between OFG and CD remains unknown. Methods: Thirty-five patients with OFG and no gut symptoms were identified from a combined oral medicine/gastroenterology clinic. All underwent a standardized assessment of the oral cavity and oral mucosal biopsy to characterize the number of sites affected and the type of inflammation involved. Hematological and biochemical parameters were also recorded. All 35 patients underwent ileocolonoscopy and biopsy to assess the presence of coexistent intestinal inflammation. Results: Ileal or colonic abnormalities were detected in 19/35 (54%) cases. From gut biopsies, granulomas were present in 13/19 cases (64%). An intestinal abnormality was significantly more likely if the age of OFG onset was less than 30 years (P = 0.01). Those with more severe oral inflammation were also more likely to have intestinal inflammation (P = 0.025), and there was also a correlation between the histologic severity of oral inflammation and the histologic severity of gut inflammation (P = 0.047). No relationship was found between any blood parameter and intestinal involvement. Conclusions: Endoscopic and histologic intestinal abnormalities are common in patients with OFG with no gastrointestinal symptoms. Younger patients with OFG are more likely to have concomitant intestinal involvement. In these patients, granulomas are more frequent in endoscopic biopsies than reported in patients with documented CD. OFG with associated intestinal inflammation may represent a separate entity in which granulomatous inflammation occurs throughout the gastrointestinal tract in response to an unknown antigen or antigens. [source]


    Signal transducers and activators of transcription 3 signaling pathway.

    INFLAMMATORY BOWEL DISEASES, Issue 2 2005
    An Essential Mediator of Inflammatory Bowel Disease, Other Forms of Intestinal Inflammation
    Abstract 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. [source]


    Induction of colonic transmural inflammation by bacteroides fragilis.

    INFLAMMATORY BOWEL DISEASES, Issue 2 2005
    Implication of Matrix Metalloproteinases
    Abstract Background: Commensal bacteria are implicated in the pathophysiology of intestinal inflammation, but the precise pathogenetic mechanisms are not known. We hypothesized that Bacteroides fragilis -produced metalloproteinases (MMPs) are responsible for bacterial migration through the intestinal wall and transmural inflammation. Aim: To investigate the role of bacterial-MMP activity in an experimental model of colitis induced by the intramural injection of bacteria. Methods: Suspensions of viable B. fragilis or Escherichia coli were injected into the colonic wall, and the effect of the MMP inhibitor (phenantroline) on histologic lesion scores was tested. MMP activity in bacterial suspensions was measured by azocoll assay. Results: The inoculation with B. fragilis induced chronic inflammatory lesions that were preferentially located in the subserosa, whereas inoculation with E. coli induced acute-type inflammatory reactions, evenly distributed in both the submucosa and subserosa. Treatment with phenantroline significantly decreased subserosal lesion scores in rats inoculated with B. fragilis, but not in rats inoculated with E. coli. Bacterial suspensions of B. fragilis showed MMP activity, but E. coli suspensions did not. Sonication of B. fragilis reduced MMP activity and virulence to induce serosal lesions. Conclusion: Our data suggest that bacterial MMPs may be implicated in the serosal migration of B. fragilis and in the induction of transmural inflammation. [source]


    Characterization of colonic and mesenteric lymph node dendritic cell subpopulations in a murine adoptive transfer model of inflammatory bowel disease

    INFLAMMATORY BOWEL DISEASES, Issue 6 2004
    John Karlis BScHons
    Abstract Ulcerative colitis and Crohn's disease, collectively termed inflammatory bowel diseases (IBD), are chronic inflammatory diseases of the intestine that afflict more than 4 million people worldwide. Intestinal inflammation is characterized by an abnormal mucosal immune response to normally harmless antigens in the gut flora. In Crohn's disease, the pathogenic mucosal immune response is a typical T helper (TH1) type cell response, whereas ulcerative colitis is predominantly associated with a TH2 response. We are interested in the role of dendritic cells in early immunologic events leading to T cell activation and chronic intestinal inflammation. Using a murine adoptive transfer model of IBD, we found an accumulation of dendritic cells in colon and mesenteric lymph nodes during the early stage of IBD before the appearance of epithelial lesions and tissue degradation. In situ immunostaining and flow-cytometric analysis revealed that approximately 50% of colonic dendritic cells were CD11b+ B220, myeloid dendritic cells and 50% expressed the CD11b, B220+ plasmacytoid phenotype. In corresponding mesenteric lymph nodes, approximately 16% were plasmacytoid dendritic cells. Colonic myeloid dendritic cells were shown to express the co-stimulatory molecule CD40. Both, colonic myeloid and plasmacytoid dendritic cells released interferon-, in situ and stimulated T cell proliferation ex vivo. Our results show that dendritic cells can mature in the intestine without migrating to mesenteric lymph nodes. Mature intestinal dendritic cells may form a nucleation site for a local T cell response and play an important role in the pathogenesis of IBD. [source]