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PubMed1998

Antiinflammatory effects of enterically coated amoxicillin-clavulanic acid in active ulcerative colitis.

The inflammatory activity of colonic mucosal lesions may be stimulated by intraluminal bacteria. Our aim was to investigate whether administration of broad-spectrum antibiotics decreases inflammatory activity in ulcerative colitis. To this end, we performed a randomized, 5-day study with either oral enterically coated amoxicillin-clavulanic acid (1 g + 250 mg, t.i.d.); i.v. methylprednisolone (40 mg/day) and oral placebo (t.i.d.); or both i.v. methylprednisolone and oral amoxicillin-clavulanic acid as above, in 30 patients with clinically active ulcerative colitis. Before and after 5 days of treatment, intestinal inflammation was assessed by the quantification of mucosal release of eicosanoids and interleukin-8 by rectal dialysis in each patient. Breath H2 excretion after oral lactulose was determined as an index of metabolic activity of colonic flora. The total release of (IL-8) interleukin-8 and eicosanoids significantly decreased in patients treated with antibiotic or steroids and antibiotic. Antibiotic treatment, but not steroids, markedly inhibited breath H2 excretion. In conclusion, short-term treatment with enteric-coated amoxicillin-clavulanic acid decreases the intraluminal release of IL-8 and other inflammatory mediators.

Adolescent↗
PubMed2000

Probiotics and inflammatory bowel disease: is there a scientific rationale?

Most conventional forms of drug therapy suppress or modify the host immunoinflammatory response and neglect the other contributor to disease pathogenesis-the environmental microflora. Probiotics are live microbial food ingredients that alter the enteric microflora and have a beneficial effect on health. The rationale for using probiotics in IBD is mainly based on evidence from human studies and experimental animal models implicating intestinal bacteria in the pathogenesis of these disorders. The relationship between bacteria and intestinal inflammation is complex and does not appear to reflect a simple cause and effect. Similarly, the field of probiotics is complex and in need of rigorous research. Until the indigenous flora are better characterized and mechanisms of probiotic action defined, the promise of probiotics in IBD is unlikely to be fulfilled. Because of strain-specific variability and clinical and therapeutic heterogeneity within Crohn's disease and ulcerative colitis, it cannot be assumed that a given probiotic is equally suitable for all individuals. Although preliminary results of probiotic therapy in animal models and humans with ulcerative colitis and pouchitis have been encouraging, their efficacy in treatment or maintenance of remission of Crohn's disease remains to be clarified. However, the circumstantial evidence for some form of biotherapeutic modification of the enteric flora in Crohn's disease seems compelling. In the future, probiotics may offer a simple adjunct to conventional therapy with the emphasis on diet shifting from one of nutritional replenishment alone to a more functional role.

Colitis, Ulcerative↗
PubMed2000

Prediction of treatment refractoriness in ulcerative colitis and Crohn's disease--do we have reliable markers?

Treatment refractoriness is a severe problem in the management of patients with ulcerative colitis and Crohn's disease. Despite some promising new therapeutic approaches, corticosteroids are still the preferential primary treatment for moderate to severe Crohn's disease and of severe ulcerative colitis. However, clinical response to corticosteroids varies, and many patients are resistant to such treatment. Since corticosteroids have frequent and even severe side effects, and toxicity increases with chronic steroid intake, factors predictive of response to such treatment would be very helpful for decisions on further management of these patients. At least in severe attacks of ulcerative colitis, the consensus seems to be that a high frequency of bowel movements as well as a high C-reactive protein and low serum albumin recorded after a few days of intensive medical treatment are important signs for early prediction of treatment failure in the majority of the patients. In Crohn's disease thus far, data on predictive factors are conflicting. No reliable marker with sufficient predictive value for treatment refractoriness could be identified. This might be due to the tremendous heterogeneity of Crohn's disease with many clinical phenotypes, which requires subgroup analysis with sufficient numbers of patients. Corticosteroids as well as other immunomodulating and immunosuppressive medications interfere with the immune system, which plays a central role in the mediation of intestinal inflammation. Treatment refractoriness might have its origin in specific immunological peculiarities eventually reflected in abnormal immunological, biochemical, and clinical parameters. Further exploration of those parameters to predict treatment refractoriness in patients with ulcerative colitis or Crohn's disease is of great clinical importance for safe and efficient management of patients.

Adrenal Cortex Hormones↗
PubMed2002

Antiadhesion molecule therapy in inflammatory bowel disease.

Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. Some of these molecules such as MadCAM-1 are specific for the gastrointestinal endothelium, but in inflammatory bowel diseases most of the adhesion factors are up-regulated. Adhesion molecules also are involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. Recently, therapeutic compounds directed against trafficking of lymphocytes toward the gut mucosa have been designed, and are being developed as a novel class of drugs in the treatment of Crohn's disease (CD) and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Secondly, the changes in adhesion molecules and T-cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered in trials of biological therapies directed against adhesion molecules. Both antiintercellular adhesion molecule-1 (ICAM-1) and anti-alpha4 integrin strategies are being developed. Trials with the anti-ICAM-1 antisense oligonucleotide, ISIS-2302, in steroid-refractory CD have provided conflicting efficacy data. The anti-alpha4 integrin antibodies natalizumab (Antegren) and LDP-02 are in phase III and phase II trials, respectively. In the near future, these novel biological agents may prove valuable therapeutic tools in the management of refractory IBD.

Antibodies↗
PubMed2004

Antibiotics should be used as first-line therapy for Crohn's disease.

The etiology of Crohn's disease remains uncertain, and to date no therapy is curative. Recent experimental evidence suggests that an altered immune response to commensal enteric flora in a genetically susceptible host plays a key role in both the development and perpetuation of the intestinal inflammation of Crohn's disease. Thus, incorporation of antibiotics into the therapeutic armamentarium for Crohn's disease, either as first-line therapy or combined with immunomodulatory drugs, would seem to be a rational strategy. Indeed, most IBD clinicians would attest to the marked benefit of antibiotic therapy in individual patients. Skepticism surrounding this approach arises because evidenced-based analyses' show that the few clinical trials evaluating the efficacy of antibiotics for Crohn's disease have produced equivocal or negative results or have methodological deficiencies, including small number of patients and absence of a placebo group. However, by undertaking an analysis that integrates information from both basic and clinical spheres of study, the dichotomy between experimental and clinical observations tends to merge. This approach underscores certain key factors that determine an optimal response to antibiotics, emphasizes the requirement for assessment in well-defined subsets of patients, and leads to the conclusion that antibiotics do provide benefit for Crohn's disease.

Animals↗
PubMed1999

Nutrition in inflammatory bowel disease.

Clinical and basic research continues to expand our understanding of the complex pathogenesis of inflammatory bowel diseases. The potential roles played by fatty acid intake, serum leptin, and nitric oxide in the promotion of intestinal inflammation in Crohn's disease and ulcerative colitis will be reviewed. In addition, important advances in the areas of bone disease, vitamin deficiency, growth failure, and home parenteral nutrition will be discussed.

Adult↗
PubMed2006

A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn's disease.

BACKGROUND: Intestinal inflammation associated with Crohn's disease is characterized by a type 1 helper T cell response and elevated levels of interleukin (IL)-12. We report our clinical experience with a novel oral IL-12/IL-23 inhibitor (STA 5326) for the treatment of active Crohn's disease. MATERIALS AND METHODS: We conducted an open-label, dose-escalating trial of the orally delivered small molecule immunomodulator STA 5326 in 73 patients with active Crohn's disease (Crohn's disease activity index [CDAI] 220-450, inclusive). Five cohorts of patients were treated for up to 4 weeks with 14 mg twice a day (bid), 35 mg daily (qd), 28 mg bid, 35 mg bid, or 70 mg qd. The endpoints of the study included safety and improvement in clinical activity measured by the CDAI and the Crohn's disease endoscopic index of severity. RESULTS: STA 5326 was well tolerated. Reported adverse events were similar across dose cohorts. The most common (>15%) drug-related adverse events observed were dizziness, nausea, headache, and fatigue. Clinical activity at day 28/29 was observed at qd doses of 28 mg and above for the clinical endpoints of response and remission: 70 points or greater decrease in CDAI (range 42%-82% of patients); 100 points or greater decrease in CDAI (range 38%-64% of patients), and CDAI <150 (range 15%-36%). CONCLUSIONS: Oral qd dosing of STA 5326 for 4 weeks was well tolerated in doses up to 70 mg qd in patients with active moderate to severe Crohn's disease. Clinical activity was observed at qd doses of 28 mg and above.

Administration, Oral↗
PubMed2006

Prophylactic aspirin therapy does not increase faecal calprotectin concentrations.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAID) can induce enteropathy. Aspirin ingestion is associated with a lower small-intestinal inflammation than other NSAID. Faecal calprotectin concentrations have recently been proposed as a simple non-invasive test to identify NSAID enteropathy. The aim of our pilot study was to evaluate calprotectin concentrations in patients on treatment with low-dose aspirin. METHODS: Twenty-two patients on prophylactic treatment with aspirin were recruited. Twenty-five healthy volunteers were enrolled as a control group. Faecal calprotectin concentrations were determined by enzyme-linked immunosorbent assay. Statistical analysis was performed by t-test for unpaired data. RESULTS: The mean faecal calprotectin concentration in patients (57.95+/-44.28 microg/g) did not show significant differences compared with controls (45.76+/-26.45 microg/g; P=0.251). CONCLUSIONS: We found that low-dose aspirin does not induce an increase in faecal calprotectin increase.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Reduction of colitis by prebiotics in HLA-B27 transgenic rats is associated with microflora changes and immunomodulation.

HLA-B27 transgenic rats develop spontaneous colitis under specific pathogen-free conditions (SPF) but germ-free rats remain disease-free, emphasizing a role for intestinal bacteria in the pathogenesis of chronic intestinal inflammation. Prebiotics are dietary substances that affect the host by stimulating growth and/or activity of potentially health promoting bacteria. The aims of this study were to investigate whether prebiotics can prevent colitis in SPF HLA-B27 rats, and secondly, to explore mechanisms of protection. SPF HLA-B27 transgenic rats received orally the prebiotic combination long-chain inulin and oligofructose (Synergy 1), or not, prior to the development of clinically detectable colitis. After seven weeks, cecal and colonic tissues were collected for gross cecal scores (GCS), histologic inflammatory scores (scale 0-4), and mucosal cytokine measurement. Cecal and colonic contents were collected for analysis of the gut microbiota by PCR-denaturing gradient gel electrophoresis (PCR-DGGE) and fluorescent in-situ hybridization (FISH), and analysis of short-chain fatty acid composition. Prebiotic treatment significantly decreased GCS and inflammatory histologic scores in the cecum and colon. Prebiotic treatment also decreased cecal IL-1beta, but increased cecal TGF-beta concentrations. Inulin/oligofructose altered the cecal and colonic PCR-DGGE profiles, and FISH analysis showed significant increases in cecal Lactobacillus and Bifidobacterium populations after prebiotic treatment compared with water-treated rats. In conclusion, the prebiotic combination Synergy 1 reduced colitis in HLA-B27 transgenic rats, which effect was associated with alterations to the gut microbiota, decreased tissue proinflammatory cytokines and increased immunomodulatory molecules. These results show promise for prebiotics as primary or adjuvant maintenance therapy for chronic inflammatory bowel diseases.

Animals↗
PubMed2005

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

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.

Animals↗
PubMed2005

Ubiquitin protein modification and signal transduction: implications for inflammatory bowel diseases.

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-kappaB 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-kappaB 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.

Animals↗
PubMed2005

T helper 1-inducing property of IL-27/WSX-1 signaling is required for the induction of experimental colitis.

BACKGROUND: WSX-1, a component of the interleukin (IL)-27 receptor, is a novel class I cytokine receptor with homology to the IL-12 receptor beta2 chain. Initially, WSX-1 signaling was reported to play an important role in the promotion of T helper-1 responses, but recent reports have revealed an anti-inflammatory property in WSX-1 signaling. In the present study, we investigated the role of IL-27/WSX-1 signaling in a murine colitis model, dextran sulfate sodium (DSS) colitis, by using WSX-1 knockout (KO) mice. METHODS: First, we observed whether WSX-1 KO mice developed colitis spontaneously. Second, we induced DSS colitis in WSX-1 KO and wild-type (WT) mice. RESULTS: WSX-1 KO mice were observed not to develop colitis spontaneously. The severity of DSS colitis was decreased in WSX-1 KO mice in comparison with WT mice in association with a reduced production of interferon-gamma, IL-6, and tumor necrosis factor-alpha by lamina propria mononuclear cells from WSX-1 KO mice and the absence of T-bet expression in the colon from WSX-1 KO mice. CONCLUSIONS: This study revealed the inflammatory property of IL-27/WSX-1 signaling in intestinal inflammation. As a result, IL-27/WSX-1 signal pathway may thus be a promising candidate for the therapeutic intervention of human inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

Animals↗
PubMed2006

Association of CTLA-4 gene microsatellite polymorphism with ulcerative colitis in Chinese patients.

Ulcerative colitis (UC) is characterized by chronic intestinal inflammation as a result of an exaggerated T cell response. Cytotoxic T lymphocyte associated antigen-4 (CTLA-4), expressed mainly in activated T cells, inhibits T cell activation and proliferation by combining B7 through competing CD28 and maintains immune homeostasis. Polymorphisms of the CTLA-4 gene are known to be associated with several autoimmune diseases. The aim of this study was to investigate the association between the CTLA-4 gene microsatellite polymorphism and UC in Chinese patients. Unrelated 100 Chinese patients with UC and 140 healthy controls were studied. The (AT) repeats in the 3' untranslated region of exon 4 of the CTLA-4 gene were amplified by allele-specific polymerase chain reaction (PCR). The amplified products were electrophoresed on a 12% polyacrylamide gel, followed by silver staining. Twenty alleles were found in Chinese patients and healthy controls. The 122-bp allele was increased in UC compared with healthy controls (9.5% vs 0.7%, P = 0.0001/Pc = 0.002, OR = 14.591, 95%CI 3.357-63.420). The frequency of the longer alleles (>or=118 bp) of UC was higher than that in healthy controls (26% vs 4%, P = 0.0001/Pc = 0.0002, OR = 7.644, 95%CI 3.950-14.792), but was not associated with location and severity of the disease. Furthermore, the longer alleles were not associated with haplotypes of C-318T/A+49G of the CTLA-4 gene in Chinese patients with UC. The longer alleles of the CTLA-4 gene microsatellite polymorphism were strongly associated with UC in Chinese patients.

Adolescent↗
PubMed2006

Probiotic treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial with Lactobacillus acidophilus and Bifidobacterium animalis subsp. Lactis.

BACKGROUND: Probiotic treatment may be effective in diseases involving gut microflora and intestinal inflammation. In collagenous colitis (CC), a potential pathogenic role of the gut microflora has been proposed. The effect of probiotic treatment in CC is unknown. Our aim was to investigate the clinical effect of treatment with Lactobacillus acidophilus LA-5 and Bifidobacterium animalis subsp. lactis BB-12 (AB-Cap-10) in patients with CC. MATERIALS AND METHODS: Patients with CC and diarrhea were in a double-blind placebo-controlled study randomized (2:1) to AB-Cap-10 or placebo for 12 weeks. The primary end point was reduction in bowel frequency per week of >or=50%. Secondary end points were changes in bowel frequencies, stool consistency, stool weight, histopathology, and abdominal bloating and pain. RESULTS: Twenty-nine patients were randomized: 21 to probiotics and 8 to placebo. Reduction in bowel frequency per week of >or=50% occurred in 6 of 21 (29%) and in 1 of 8 (13%) patients receiving probiotic and placebo, respectively (P = 0.635). No differences between treatments were observed regarding the secondary end points. Post hoc analysis showed a median reduction in bowel frequency per week from 32 (range 18-84) to 23 (range 11-56; P < 0.005), a reduction in number of days with liquid stools per week from 6 days (range 0-7 days) to 1 day (range 0-7 days; P < 0.005), and an increase in number of days with solid stools per week (P < 0.05) in the AB-Cap-10 group. CONCLUSIONS: AB-Cap-10 had no significant effect on the chosen end points. Post hoc analysis demonstrated amelioration of clinical symptoms in the AB-Cap-10 group, indicating that probiotic treatment may potentially influence the disease course of CC.

Adult↗
PubMed2005

Inflammatory bowel diseases: clinical update of practical guidelines.

Idiopathic inflammatory bowel disease (IBD) includes a collection of disorders of the gastrointestinal tract of unknown aetiology, characterized by intestinal inflammation and a chronic relapsing course associated with local and systemic complications. Traditionally, IBD comprises two prototype entities, ulcerative colitis (UC) and Crohn's disease (CD) and an intermediate variant of these diseases, indeterminate colitis which shows overlapping features of the two major forms. Over the last few years, considerable progress has been made in our knowledge of the pathogenesis of IBD, which is complex and derives from genetic, environmental and immunological interactions. The aetiology remains unclear, but it is well established that the lesions and symptoms are associated with over-production of pro-inflammatory cytokines. In this paper we briefly review the pathophysiology and the new therapeutic approaches to IBD, since from these, new achievement depends the appropriate diagnostic exams to be performed and diagnostic flow charts.

Anti-Inflammatory Agents↗
PubMed2006

Long-term clinical outcome in patients with congenital chloride diarrhea.

OBJECTIVES: Congenital chloride diarrhea (CLD) is a rare, autosomal recessive disorder of intestinal Cl/HCO3 exchange caused by mutations in the SLC26A3 gene and characterized by persistent Cl rich diarrhea from birth. Treatment is symptomatic and replacement therapy with NaCl and KCl has been shown to be effective in children, but the long-term prognosis remains unclear. We studied the largest known cohort of patients to evaluate the long-term outcome of CLD and to search for extraintestinal manifestations. METHODS: This is a cross-sectional clinical evaluation and retrospective analysis of medical history of 36 Finnish patients with CLD, born in the 1960s (n = 8), 1970s (n = 7) and 1980s (n = 21). RESULTS: Early diagnosis and aggressive salt replacement therapy were associated with normal growth and development, in addition to significantly reduced mortality rates among the groups of patients born in the different decades, respectively (P = 0.001). No deaths due to CLD were observed after 1972. Enuresis, slight soiling and hospitalizations for gastroenteritis were common, especially in childhood, but 92% of the patients found their health excellent or good. Complications documented were end-stage renal disease (n = 1) and hyperuricemia (n = 4), novel findings possibly associated with CLD being male subfertility (n = 3), spermatoceles (n = 3), intestinal inflammation (n = 2), inguinal hernias (n = 4) and increased concentrations of sweat Cl in 12% of the patients. CONCLUSIONS: When early diagnosed and adequately treated, the long-term prognosis of CLD is favorable. A putative role of a primary anion exchange defect of SLC26A3 in male subfertility and the decline of renal function due to chronic dehydration deserve further characterization.

Adolescent↗
PubMed2007

Toll-like receptor signaling in intestinal epithelial cells contributes to colonic homoeostasis.

PURPOSE OF REVIEW: Since intestinal epithelium expresses Toll-like receptors, it was suggested that the intestinal epithelium is actively involved in the maintenance of colonic homeostasis. Here we describe our recent findings, which support an active contribution of colonic epithelium to intestinal homeostasis via a unique activation of epithelial TLR9. RECENT FINDINGS: Recent data indicate that stimulation of Toll-like receptors by intestinal microbiota supports colonic homeostasis. Several Toll-like receptors are expressed in intestinal epithelium. TLR9, an intracellular protein in immune cells, is expressed on the cell surfaces of intestinal epithelium, both on the apical and the basolateral membrane. TLR9 signaling varies in a domain-specific manner; whereas JNK is activated by TLR9 ligand both apically or basolaterally, NF-kappaB is activated only via basolateral stimulation. In apical TLR9 stimulation, IkappaB is phosphorylated and ubiquitinated but is not degraded, and NF-kappaB-dependent inflammatory signals are not transduced. Stimulation of apical TLR9 compromises the inflammatory cascade induced basolaterally by several other Toll-like receptor ligands, suggesting that apical exposure to luminal microbial DNA restrains intestinal inflammation. SUMMARY: These data indicate that certain luminal bacterial products support colonic homeostasis via activation of epithelial Toll-like receptors. The role of epithelial Toll-like receptor expression and activation in the pathogenesis of human inflammatory bowel disease is yet to be explored.

Animals↗
PubMed1993

Effect of methylprednisolone on small bowel, spleen and liver changes in a murine model of inflammatory bowel disease.

The aim of this study was to evaluate the influence of methylprednisolone (1 mg/kg, i.p.) on inflammatory lesions in the small bowel, liver (pericholangitis) and spleen (lymphofollicular proliferation), in a model of inflammatory bowel disease induced by 2.4-dinitrofluorobenzene in previously sensitized BALB-c mice. As a parameter of corticosteroid anti-inflammatory and immunosuppressive action, we simultaneously investigated its effects on mononuclear cell accumulation within the ileal lamina propria and submucosa during the observed time period (1-30 days). We noted a significant decrease in accumulation of mononuclear cells within the lamina propria (P < 0.001). An effect on mononuclear cell infiltration within the ileal submucosa was also noted but was not statistically significant. In addition, pericholangitis in the liver and lymphofollicular proliferation in the spleen were not observed in the experimental group during treatment with methylprednisolone. The results of this study indicate that the previously described model of intestinal inflammation could be used in further research of present and new therapeutic modalities for inflammatory bowel disease.

Animals↗