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PubMed2001

Increased expression of IL-16 in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is characterised by infiltration of inflamed mucosal regions with CD4(+) T lymphocytes and other mononuclear cells. Interleukin (IL)-16 exerts a strong chemoattractant activity on CD4(+) cells. Moreover, IL-16 activates expression and production of proinflammatory cytokines such as IL-1beta, IL-6, IL-15, and tumour necrosis factor alpha (TNF-alpha) in human monocytes. AIM: To examine if IL-16 expression is increased in IBD patients compared with healthy controls. METHODS: Twenty one patients with IBD (10 with ulcerative colitis (UC), 11 with Crohn's disease (CD)), seven disease specificity controls (DSC), and seven healthy controls were studied. Biopsies were taken during colonoscopies and IL-16 mRNA as well as protein expression were investigated by reverse transcriptase-polymerase chain reaction, ELISA, western blot, and immunohistochemistry. RESULTS: IL-16 mRNA and protein expression in the colonic mucosa of IBD patients were increased twofold compared with healthy controls, DSC, or IBD patients under steroid treatment. Most of the detected IL-16 protein was in its bioactive 17 kDa form and was predominantly expressed in eosinophils. Increased IL-16 expression in UC patients appeared to be mainly restricted to the inflamed regions of the colonic mucosa. Levels of caspase 3, which processes the 68 kDa IL-16 precursor molecule into the biological active 17 kDa form, were not increased. CONCLUSIONS: Our results provide evidence that IL-16 expression is significantly increased in the inflamed colonic mucosa of IBD patients but not in control individuals, DSC, or patients under steroid treatment. Therefore, upregulation of IL-16 expression seems to be specific for chronic intestinal inflammation and could lead to increased secretion of other proinflammatory cytokines in IBD.

Adult↗
PubMed2005

The effects of atorvastatin on gluten-induced intestinal T cell responses in coeliac disease.

Various experimental models suggest that the cholesterol-lowering drugs statins may also modulate immune responses. Cellular level studies on human disorders are needed, however, to provide a rational basis for clinical testing of statins as immune therapy. Coeliac disease, a chronic small intestinal inflammation driven by HLA-DQ2 restricted mucosal T cells that are specific for ingested wheat gluten peptides, is in many ways ideal for this purpose. In addition, there is a need for alternative treatment to the gluten-free diet in this disorder. Here we have assessed the effects of atorvastatin on gluten-reactive T cells, dendritic cells and the coeliac mucosa by in vitro culture of biopsies. Atorvastatin inhibited gluten-induced proliferation and specific cytokine production of human intestinal gluten-reactive T cell clones and lines. Dendritic cells exposed to atorvastatin displayed a reduced expression of the costimulatory molecule CD83 upon maturation with lipopolysaccharide. Incubation of intestinal biopsy specimens with atorvastatin in vitro, however, did not influence gluten-induced cytokine release. In conclusion, atorvastatin has specific effects on isolated gluten-reactive T cells and dendritic cells, but does not shut down the gluten-induced production of proinflammatory cytokines in intestinal biopsies.

Adult↗
PubMed2001

Medium-chain triglyceride-rich enteral nutrition is more effective than low-fat enteral nutrition in rat colitis, but is equal in enteritis.

BACKGROUND: Although enteral nutrition (EN) therapy for Crohn's disease has been confirmed to be as effective as steroid therapy, the precise mechanism responsible for the effects of EN remains unclear, although some of the therapeutic effects of EN are believed to be due to a low dietary fat content. In order to elucidate the influence of fat in EN, it is important to investigate not only the quantity of fat, but also the source of the fat. METHODS: We compared two enteral nutritional formulae: Elental (Ajinomoto) (elemental diet; ED), which contains only 1.5% fat, provided as long-chain triglycerides (LCT), versus Twinline (Snow Brand Milk Products) (TL), which contains a high percentage of fat (20.4%), provided mainly as medium-chain triglycerides (MCT). These formulae were tested on rat enteritis and rat colitis induced by trinitrobenzene sulfonic acid (TNBS). RESULTS: Both ED and TL reduced the manifestations of enteritis. TL had a stronger anti-inflammatory effect than ED for colitis. TL also had nutritional advantages as compared with ED, as shown by the total serum protein in the TL group being significantly higher than that in the ED group. CONCLUSION: The results indicate that intraluminal MCT is suitable as a fat energy source during intestinal inflammation in rats. We suggest that Twinline may be more useful to improve nutritional status and to reduce the mucosal inflammation in rat colitis, but that Twinline is equal in effect to Elental for rat enteritis.

Animals↗
PubMed2003

Targeted disruption of the meprin beta gene in mice leads to underrepresentation of knockout mice and changes in renal gene expression profiles.

Meprins are multidomain zinc metalloproteases that are highly expressed in mammalian kidney and intestinal brush border membranes and in leukocytes and certain cancer cells. Mature meprins are oligomers of evolutionarily related, separately encoded alpha and/or beta subunits. Homooligomers of meprin alpha are secreted; oligomers containing meprin beta are plasma membrane associated. Meprin substrates include bioactive peptides and extracellular matrix proteins. Meprins have been implicated in cancer and intestinal inflammation. Additionally, meprin beta is a candidate gene for diabetic nephropathy. To elucidate in vivo functions of these metalloproteases, meprin beta null mice were generated by targeted disruption of the meprin beta gene on mouse chromosome 18q12. Analyses of meprin beta knockout mice indicated that (i) 50% fewer null mice are born than the Mendelian distribution predicts, (ii) null mice that survive develop normally and are viable and fertile, (iii) meprin beta knockout mice lack membrane-associated meprin alpha in kidney and intestine, and (iv) null mice have changes in renal gene expression profiles compared to wild-type mice as assessed by microarray analyses. Thus, disruption of the meprin beta allele in mice affects embryonic viability, birth weight, renal gene expression profiles, and the distribution of meprin alpha in kidney and intestine.

Animals↗
PubMed2006

Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease.

BACKGROUND & AIMS: It has been variably suggested that nonselective NSAIDs and cyclooxygenase (COX)-2 selective inhibitors aggravate or ameliorate clinical disease activity in patients with inflammatory bowel disease. We assessed the effect of these drugs in patients with inflammatory bowel disease (n = 209) and the possible mechanisms. METHODS: First, patients with quiescent Crohn's disease and ulcerative colitis received the non-NSAID analgesic acetaminophen (n = 26) and the conventional NSAIDs naproxen (n = 32), diclofenac (n = 29), and indomethacin (n = 22) for 4 weeks. The Harvey-Bradshaw index was used to define relapse. Second, to assess the mechanism of relapse, intestinal inflammation was quantitated (fecal calprotectin) before and during treatment (20 patients/group) with acetaminophen, naproxen (topical effect, COX-1 and -2 inhibitor), nabumetone (COX-1 and -2 inhibitor), nimesulide (selective COX-2 inhibitor), and low-dose aspirin (selective COX-1 inhibition). RESULTS: Nonselective NSAIDs were associated with a 17%-28% relapse rate within 9 days of ingestion. No patient had an early relapse on acetaminophen, nimesulide, or aspirin, whereas those on naproxen and nabumetone (20%) experienced relapse. These clinical relapses were associated with escalating intestinal inflammatory activity. CONCLUSIONS: NSAID ingestion is associated with frequent and early clinical relapse of quiescent inflammatory bowel disease, and the mechanism appears to be due to dual inhibition of the COX enzymes. Selective COX-2 inhibition with nimesulide and COX-1 inhibition with low-dose aspirin appear to be well-tolerated in the short-term.

Acetaminophen↗
PubMedDate not supplied

Ileal mucosal mononuclear cells in patients with seronegative spondylarthropathy.

In order to study local immunoregulatory mechanisms in patients with seronegative spondylarthropathy and histological evidence of asymptomatic intestinal inflammation, we determined mononuclear cells in distal ileal mucosa with an indirect immunoperoxidase technique using a panel of monoclonal antibodies. The number of intraepithelial lymphocytes in inflamed mucosa was not significantly increased. They carried mainly the suppressor-cytotoxic CD8 marker (greater than 80%), less frequently the helper T cell marker CD4 and lacked the pan T epitope CD3 in greater than 50%. There were no intraepithelial B cells or natural killer cells. The lamina propria lymphocytes were T and B cells, the former being more numerous. Helper T cells were more frequent than suppressor-cytotoxic T cells. There were no alterations in the proportion of T cells in inflamed mucosa. Natural killer cells were scarce. They occurred in small numbers in a minority of cases with gut inflammation and spondylarthropathy and rarely in inflammatory bowel disease. It is concluded that although there is an increase of lamina propria monocytes, there is no immunoregulatory imbalance in the ileal mucosa of patients with seronegative spondylarthropathy.

Adolescent↗
PubMed1998

Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced enteritis in mice.

BACKGROUND & AIMS: The pathogenesis of Clostridium difficile toxin A-induced intestinal inflammation is not completely understood. The aim of this study was to define the contribution of mast cells to the fluid secretion and neutrophil infiltration associated with toxin A-induced enteritis. METHODS: Fluid secretion and neutrophil infiltration in toxin A- or buffer-challenged ileal loops were assessed in normal, mast cell-deficient, and mast cell-deficient KitW/KitW-v mice that had undergone selective repair of their mast cell deficiency. The effect of a specific substance P-receptor antagonist was also studied. RESULTS: Intestinal fluid secretion and neutrophil recruitment were significantly diminished in mast cell-deficient KitW/KitW-v and mast cell-deficient MgfSl/MgfSl-d mice compared with the respective normal mice. Mast cell-reconstituted KitW/KitW-v mice showed responses similar to the normal congenic mice. Administration of a specific substance P-receptor antagonist (CP-96,345) reduced toxin A-induced intestinal fluid secretion and inhibited neutrophil infiltration in normal, mast cell-deficient KitW/KitW-v, and mast cell-reconstituted KitW/KitW-v mice. CONCLUSIONS: C. difficile toxin A elicits intestinal fluid secretion and neutrophil infiltration by both mast cell-dependent and -independent pathways, and substance P participates in both pathways.

Animals↗
PubMed2026

Metagenomic profiling of gut microbiome in post-cholecystectomy patients with diarrhea: a nested case-control study.

BACKGROUND: Cholecystectomy can cause diarrhea, with an incidence as high as 57.2%, seriously impacting patient prognosis. To investigate the gut dysbiosis following cholecystectomy and identify microbial biomarkers and functional genomics associated with post-cholecystectomy diarrhea (PCD), we conducted a nested case-control study within a prospective cohort. METHODS: We enrolled a cohort of 160 patients. At follow-up completion, 30 patients who developed PCD were matched with 30 non-PCD (NPCD) controls. 16 S rRNA sequencing was used to analyze gut microbiota structure and diversity (mainly at genus level). Representative fecal samples underwent metagenomic sequencing for species level and genetic differential analysis. RESULTS: The potentially pathogenic bacterial species Coprococcus comes and Blautia sp. were significantly enriched in the gut microbiota of PCD patients, with their abundance positively correlated with the degree of intestinal inflammation. In contrast, the potentially beneficial bacterial species Bacteroides intestinalis and Prevotella copri, known to contribute to lipid metabolism and play a role in modulating gut immunity and suppressing inflammatory responses, were found to be significantly depleted in PCD patients. Further metagenomic functional analysis revealed significant enrichment of pathways related to cell motility, membrane transport, and sulfur metabolism in PCD patients. CONCLUSIONS: This work identified potential beneficial and pathogenic bacterial species associated with the onset of PCD, as well as significantly enriched functional pathways within the intestinal microbiota. These findings provide a scientific basis for elucidating the relationship between PCD and gut microbiota, and provide candidate microbial signatures and functional pathways that may inform future microbiota-targeted strategies, pending external and mechanistic validation.

Humans↗
PubMed2006

Therapeutic approaches targeting intestinal microflora in inflammatory bowel disease.

Inflammatory bowel diseases, ulcerative colitis, and Crohn's disease, are chronic intestinal disorders of unknown etiology in which in genetically susceptible individuals, the mucosal immune system shows an aberrant response towards commensal bacteria. The gastrointestinal tract has developed ingenious mechanisms to coexist with its autologous microflora, but rapidly responds to invading pathogens and then returns to homeostasis with its commensal bacteria after the pathogenic infection is cleared. In case of disruption of this tightly-regulated homeostasis, chronic intestinal inflammation may be induced. Previous studies showed that some commensal bacteria are detrimental while others have either no influence or have a protective action. In addition, each host has a genetically determined response to detrimental and protective bacterial species. These suggest that therapeutic manipulation of imbalance of microflora can influence health and disease. This review focuses on new insights into the role of commensal bacteria in gut health and disease, and presents recent findings in innate and adaptive immune interactions. Therapeutic approaches to modulate balance of intestinal microflora and their potential mechanisms of action are also discussed.

Animals↗
PubMed2000

Effect of proinflammatory interleukins on jejunal nutrient transport.

AIM: We examined the effect of proinflammatory and anti-inflammatory interleukins on jejunal nutrient transport and expression of the sodium-glucose linked cotransporter (SGLT-1). METHODS: 3-O-methyl glucose and L-proline transport rates were examined in New Zealand White rabbit stripped, short circuited jejunal tissue. The effects of the proinflammatory cytokines interleukin (IL)-1alpha, IL-6, and IL-8, IL-1alpha plus the specific IL-1 antagonist, IL-1ra, and the anti-inflammatory cytokine IL-10 were investigated. In separate experiments, passive tissue permeability was assessed and brush border SGLT-1 expression was measured by western blot in tissues exposed to proinflammatory interleukins. RESULTS: The proinflammatory interleukins IL-6, IL-1alpha, and IL-8 significantly increased glucose absorption compared with control levels. This increase in glucose absorption was due to an increase in mucosal to serosal flux. IL-1alpha and IL-8 also significantly increased L-proline absorption due to an increase in absorptive flux. The anti-inflammatory IL-10 had no effect on glucose transport. The receptor antagonist IL-1ra blocked the ability of IL-1alpha to stimulate glucose transport. IL-8 had no effect on passive tissue permeability. SGLT-1 content did not differ in brush border membrane vesicles (BBMV) from control or interleukin treated tissue. CONCLUSIONS: These findings suggest that intestinal inflammation and release of inflammatory mediators such as interleukins increase nutrient absorption in the gut. The increase in glucose transport does not appear to be due to changes in BBMV SGLT-1 content.

3-O-Methylglucose↗
PubMed2006

Novel strategies to attenuate immune activation in Crohn's disease.

Our understanding of the pathogenic mechanisms that underlie the chronic intestinal inflammation characteristic of Crohn's disease (CD) has advanced greatly in recent years. We now realize that effective treatment will not be achieved through non-specific generalized immunosuppression, but rather with the development of well-designed therapies that target specific immunological pathways. The success of infliximab has driven exploration into the blockade of additional pro-inflammatory cytokines, such as interleukin-12 and interferon-gamma. Novel strategies have also emerged that target other components of the inflammatory cascade, such as the migration of leukocytes to the intestine. The identification of mutations in the nod2/card15 gene that are associated with a predisposition for the development of CD has focused attention on the role of the innate immune system in CD. This has allowed a fundamentally different approach to the development of therapies for CD aimed at intensifying innate immune responses. In parallel with the development of several 'biological' agents, alternative therapeutic options have also shown promising results. The use of probiotic bacteria as both therapeutic agents and delivery vehicles for other molecules is a rapidly developing field. As the role of regulatory T cells in the pathogenesis of CD is revealed, the potential of immunotherapy is being opened up. With so many therapeutic options in sight and the ongoing elucidation of the pathogenesis of CD, it will become steadily more possible to tailor treatment to the clinicopathological and immunogenetic profile of the individual patient.

Animals↗
PubMed2001

Activation of beta(1) integrins mediates proliferation and inhibits apoptosis of intestinal CD4-positive lymphocytes.

A characteristic of lamina propria lymphocytes (LPL) is their low proliferative response to stimuli of the CD3 pathway. beta(1) integrins were expressed on LPL; however, their function is unknown. Therefore, we determined whether beta(1) integrins contribute to T cell responses by providing costimulatory signals. Integrins on CD4(+) LPL of controls and patients with inflammatory bowel disease were characterized by flow cytometry. Cells were stimulated by anti-CD3 or anti-CD2 antibodies either alone or in combination with a stimulatory beta(1) integrin antibody (12G10). Proliferation and apoptosis were measured by [(3)H]thymidine pulsing or flow cytometry. Cytokine mRNA and apoptosis-related transcripts were quantified by reverse transcriptase-PCR. We demonstrated that beta(1) integrin costimulation restored CD3-induced proliferation of CD4(+) LPL and reduced activation-induced apoptosis. Activation of beta(1) integrins by addition of 12G10 antibody to CD3-stimulated cells restored their capacity to express proinflammatory cytokine transcripts. Further, expression of the activated form of beta(1) integrins was significantly elevated on LPL from inflamed mucosa. These studies demonstrate that beta(1) integrin costimulation modulates the response of LPL after TCR stimulation. An increased expression of activated beta(1) integrins on LPL in intestinal inflammation may abolish their unresponsiveness to antigens and perpetuate the inflammatory process.

Adult↗
PubMed2005

Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing.

Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor kappaB (NF-kappaB) and antibacterial defenses, but CD clinical specimens display elevated NF-kappaB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-kappaB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1beta (IL-1beta). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-kappaB activation and IL-1beta secretion.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2003

Inflammatory bowel diseases and brain-gut axis.

The influence of stress on inflammation in inflammatory bowel disease (IBD) is reviewed. In experimental forms of colitis in rats, stress reactivated the disease. A study of stable IBD patients who were followed for over five years explored the influence of stress on exacerbating the disease. Those patients with high prolonged stressful life events were found to have a 90% recurrence rate of their colitis as compared to only 40% recurrence in low stress patients. Some of the mediators of stress include VIP, TNFalpha, heat shock proteins, glucocorticoid and catecholamines. Stress was shown to increase intestinal permeability to markers such as Cr-EDTA, HRP and dextran 10,000 in rats. In addition, stress increases the permeability of intestinal M-cells. Finally, stress increased the permeability of Paneth cells to HRP. Since Paneth cells synthesize NOD2 mRNA and protein, stress may play a role in the genesis or reactivation of Crohn's disease involving the terminal ileum. Brain-gut interactions via neural, hormonal and cytokine signals can diminish the mucosal protective factors and increase the permeability of luminal antigens into the intestinal epithelial and immune cells. Stress appears to play a key role in exacerbating and accentuating the intestinal inflammation in IBD through brain-gut interactions.

Animals↗
PubMed2004

Ursodeoxycholic acid ameliorates experimental ileitis counteracting intestinal barrier dysfunction and oxidative stress.

The aim of this study was to evaluate the effect of ursodeoxycholic acid (UDCA) on intestinal permeability (IP) and reactive oxygen species (ROS) generation in indomethacin-induced enteropathy, a well-known experimental model of Crohn's disease. Seventy-eight male Wistar rats were randomly assigned to receive indomethacin, indomethacin + UDCA, or vehicles. Indomethacin induced a significant increase in the fraction of urinary excretion of 51Cr-EDTA following oral administration (7.9 +/- 1.3 vs 2.3 +/- 0.2%; P < 0.05) and lucigenin-amplified chemiluminescence in intestinal fragments ex vivo (10.1 +/- 1.9 vs 2.6 +/- 0.4 cpm x 10(3)/mg; P < 0.05) compared to controls. UDCA significantly reversed these effects (P < 0.05), without being incorporated in biliary bile acid composition (HPLC analysis). These findings support a local protective effect of UDCA in experimental ileitis by the modulation of intestinal barrier dysfunction and oxidative stress. In short, they provide insights into mechanisms of action of UDCA in intestinal inflammation and a new perspective on the treatment of Crohn's disease.

Animals↗
PubMed1991

Reactive oxygen metabolites and colitis: a disturbed balance between damage and protection. A selective review.

Enhanced local production of reactive oxygen metabolites has been found in association with colitis, both experimentally and in humans. Cellular and biochemical systems involved have been identified, and 5-aminosalicylic acid-containing drugs but, more effectively, specific scavengers have been found to reduce the intestinal inflammatory process. The multitude of reactions in which oxygen metabolites participate provides a new area of research in intestinal inflammation. These basic studies might bring related clinical studies in an era of new anti-inflammatory drugs for inflammatory bowel disease specifically designed to scavenge toxic oxygen metabolites.

Animals↗
PubMed2006

Induction of differential immune reactivity to members of the flora of gnotobiotic mice following colonization with Helicobacter bilis or Brachyspira hyodysenteriae.

Aberrant host immune responses to bacterial components of the resident microflora may initiate and perpetuate gastrointestinal inflammation. To investigate how microbial perturbation promotes host immunological responsiveness to commensal bacteria and contributes to the development of typhlocolitis, we selectively colonized defined (altered Schaedler) flora C3H mice with either Helicobacter bilis or Brachyspira hyodysenteriae. Following selective colonization, tissues were analyzed for gross/histopathologic lesions and bacterial antigen-specific B- and T-cell responses. Gnotobiotic mice colonized with H. bilis or B. hyodysenteriae developed typhlocolitis of varying severity, with the most severe gross and histopathogical lesions observed in B. hyodysenteriae-colonized mice. Antigen-specific IgG1 and IgG2a responses to the resident microflora were increased in both H. bilis-and B. hyodysenteriae-colonized mice. The greater antibody responses were associated with less severe cecal inflammation in H. bilis-colonized mice. Altered Schaedler flora (ASF)-stimulated mesenteric lymphocytes from B. hyodysenteriae-colonized mice produced higher levels of interferon-gamma and interleukin (IL)-4 than did lymphocytes from H. bilis-colonized mice. However, ASF-stimulated mesenteric and splenic lymphocytes from both H. bilis and B. hyodysenteriae-colonized mice secreted higher amounts of IL-10 compared to similarly stimulated lymphocytes recovered from control mice. These results indicate that microbial perturbation may induce differential immune responses to nonpathogenic resident bacteria that can lead to intestinal inflammation.

Animals↗
PubMed2003

Interleukin-1 beta selectively increases substance P release and augments the ascending phase of the peristaltic reflex.

Exposure of muscle strips to interleukin (IL)-1beta stimulates substance P (SP) expression, suggesting a link between IL-1beta and the increase in SP expression during intestinal inflammation. The present study examined whether the SP expression induced by IL-1beta is reflected by enhanced SP release and SP-mediated reflex activity. Exposure of innervated longitudinal colonic muscle strips to IL-1beta for 8 h increased SP synthesis in, and greater SP release from excitatory motor neurones in response to KCl or electrical field stimulation (EFS), and enhanced longitudinal muscle contraction in response to EFS. IL-1 Ra and IL-1beta antibody blocked IL-1beta-induced increase in SP release and muscle contraction. Neither vasoactive intestinal peptide (VIP) nor somatostatin release was increased. The increase in SP release was reflected in enhanced circular muscle contraction in response to stretch. VIP-mediated descending relaxation of circular muscle was not affected. The selective increase in ascending contraction induced by exposure to IL-1beta was blocked by IL-1 Ra or IL-1beta antibody. We conclude that the selective increase in SP expression induced by IL-1beta in excitatory motor neurones is reflected by enhanced SP release and longitudinal muscle contraction in response to EFS, and enhanced SP release and circular muscle contraction during the ascending phase of the peristaltic reflex.

Animals↗