Prebiotics and probiotics in irritable bowel syndrome and inflammatory bowel disease in children.

Underlying pathophysiological mechanisms of irritable bowel syndrome (IBS), a common disorder characterized by abdominal pain associated to a change in stool consistency or frequency, include low-grade inflammation and intestinal microbiota changes. Few and disappointing data are available for prebiotics. A few controlled trials (RCTs) of probiotics are instead available with favourable effects, although most are limited by suboptimal design and small sample size. A recent report from the Rome foundation group included 32 RCTs of probiotics, most of which showed an overall modest improvement in symptoms, with the patients most benefitting from probiotics being those with predominant diarrhoea and those having a post-infectious IBS. A review focusing only on children with functional gastrointestinal disorders concluded that probiotics are more effective than placebo in the treatment of patients with abdominal pain-related functional gastrointestinal disorders, although no effect on constipation was evident. The role for probiotics in inflammatory bowel disease (IBD) appears logical: the endogenous intestinal microbiota plays a central role in their development, and various probiotics have been found effective in animal models of IBD. However, research in humans has been overall quite limited, and it would seem that after a phase of intense research in the first decade of this century, the pace has slowed down, with fewer clinical trials been published in the past 2-3 years. To summarize current evidence: no probiotic has proven successful in Crohn's disease. In ulcerative colitis, on the other hand, data are more promising, and a very recent meta-analysis, that included 23 randomized controlled trials, concluded that there is evidence of efficacy for the probiotic mixture VSL#3 in helping inducing and maintaining remission, as well as in maintaining remission in patients with pouchitis. It is fair to state that for both IBD and IBS, more well-designed, rigorous, randomized clinical trials must be performed.

Celiac disease.

Celiac disease, with a prevalence around 1% of the general population, is the most common genetically-induced food intolerance in the world. Triggered by the ingestion of gluten in genetically predisposed individuals, this enteropathy may appear at any age, and is characterized by a wide variety of clinical signs and symptoms. Among them, gastrointestinal presentations include chronic diarrhea, abdominal pain, weight loss or failure to thrive in children; but extra-intestinal manifestations are also common, and actually appear to be on the rise. They include a large variety of ailments, such as dermatitis Herpetiformis, anemia, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminases, and even female infertility. For the clinician interested in oral diseases, celiac disease can lead to delayed tooth eruption, dental enamel hypoplasia, recurrent oral aphthae. Diagnosing celiac disease requires therefore a high degree of suspicion followed by a very sensitive screening test: serum levels of the autoantibody anti-tissue transglutaminase. A positive subject will then be confirmed by an intestinal biopsy, and will then be put on a strict gluten-free diet, that in most cases will bring a marked improvement of symptoms. Newer forms of treatment which in the future will probably be available to the non-responsive patients are currently being actively pursued.

Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens.

Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.

Use of Lactobacillus-GG in paediatric Crohn's disease.

The potential role of luminal bacteria in initiating the abnormal immune response seen in inflammatory bowel disease is stressed by many observations. A defect in mucosal barrier function could allow luminal bacterial antigens to initiate the chronic relapsing inflammation in Crohn's disease. The potential role of luminal bacteria in initiating the abnormal immune response seen in inflammatory bowel disease is stressed by many observations. A pilot study to investigate the possible effect of Lactobacillus GG in children with active Crohn's disease was conducted. Four male patients were enrolled, median age 14.5 years (range 10-18). In terms of clinical outcome, the patients showed significant improvement. In three patients on Lactobacillus GG, it was possible to taper the dose of steroids. Thus, although our data are obviously very preliminary, Lactobacillus GG appears to be effective in improving the clinical status of children with Crohn's disease. A multicentre study is currently being carried out in 7 US University centres in a randomized, double-blind, placebo-controlled fashion to establish the efficacy of this probiotic in children with Crohn's disease.

Do you still need a biopsy to diagnose celiac disease?

Celiac disease is a common and permanent condition caused by an abnormal immune response to ingested gluten in genetically susceptible individuals. Its proper diagnosis is very important even in patients presenting with mild symptoms because severe and debilitating complications may occur in celiac patients not following a strict gluten-free diet. In the past several years, important progress has been made not only in our understanding of the pathogenesis of this condition but also in the availability of tools to screen it. Antigliadin antibodies, once largely used for this purpose, have been basically replaced by the more costly but far more accurate antiendomysium antibodies. More recently, the enzyme-linked immunosorbent assay (ELISA), which measures the antibodies directed against the autoantigen responsible for the disease (tissue transglutaminase), has also been developed and tested as a screening tool. Currently, however, the poor positive predictive value of this test does not allow practitioners to diagnose celiac disease without the duodenal biopsy showing the typical morphologic changes.

Enteropathogenic Escherichia coli strain RDEC-1 produces a novel electrogenic factor active on rabbit ileum in vitro.

BACKGROUND: Attaching and effacing Escherichia coli demonstrate marked species specificity in inducing diarrhea, although its mechanism remains largely unclear. The purpose of this study was to investigate the existence of a soluble, species-specific factor that induces diarrhea in an in vitro model. METHODS: Stripped rabbit ileum was mounted in Ussing chambers, and changes in potential difference and short-circuit current were monitored after the addition of bacterial culture supernatant. RESULTS: The culture supernatant from rabbit-specific strain RDEC-1, but not from human-specific enteropathogenic Escherichia coli strain E2348/69, induced an increase in potential difference and short-circuit current in rabbit ileum mounted in Ussing chambers. This electrical signal was related to chloride ion secretion, was absent in colonic tissue, and was retained in the 30 to 100-KDa fraction of the supernatant. Preliminary experiments failed to show an involvement of calcium or cyclic nucleotides as intracellular messengers. RDEC-1 cured of a 42-MDa plasmid lost the enterotoxicity whereas conjugation of the plasmid into the negative E. coli recipient HB101 resulted in the expression of toxicity. CONCLUSIONS: The authors describe a novel, species-specific factor that helps to explain RDEC-1 diarrhea, which may be relevant to the pathogenesis of enteropathogenic Escherichia coli infection.

Antral nodularity identifies children infected with Helicobacter pylori with higher grades of gastric inflammation.

BACKGROUND: The endoscopic pattern of antral nodularity is a peculiar finding in children with Helicobacter pylori infection. The aim of this study was to determine whether this finding is related to more severe gastritis. METHODS: One hundred seventy-four consecutive children (median age 8.7 years) referred for gastroscopy were studied. Biopsy specimens from the antrum and body of the stomach were taken to assess H pylori status, gastritis score, and lymphoid follicles. Clinical diagnosis, major symptoms and endoscopic findings were recorded. RESULTS: Eighty-four (48%) children (median age 10.5 years) had evidence of H pylori infection. The endoscopic pattern of antral nodularity was found only in children infected with H pylori (34/84, 40.5% vs. 0/90, 0%, p < 0.0001% 100% specificity, 40.5% sensitivity). Among all children infected with H pylori, the gastritis score was higher (p < 0.0001) in those with antral nodularity (n = 34) than in those without (n = 50). Completely normal gastric mucosal histology was never found in children infected with H pylori with antral nodularity. The presence and number of lymphoid follicles was strongly related to the finding of antral nodularity (p < 0.01). CONCLUSIONS: The endoscopic pattern of antral nodularity identifies children with H pylori infection, severe gastritis, and increased lymphoid follicles.

Update on immunologic basis of celiac disease.

During the past few years several seminal studies have greatly expanded our knowledge on celiac disease pathogenesis. This review focuses on aspects that have been most properly addressed and where substantial new information has been gathered include. Topics covered include (a) the identification of T-cell epitopes in gluten and the mechanisms of specific T-cell response in celiac disease small intestine; (b) the mechanisms of induction of mucosal lesion; and (c) the putative role of non-T-cell factors in driving mucosal response to gliadin. After discussing a brief history of the "quest for the cause of celiac disease," we examine the development of the typical celiac lesion (the crypt hyperplastic mucosal atrophy) as it generally unfolds: the increased entry of dietary antigens; the early changes, linked to specific components of the innate immunity rather than to its adaptive branch; the most thoroughly investigated subsequent response, involving a strong T-cell response and cytokines; and the factors responsible for enterocytes' death. The emerging pattern is that of a complex interaction of factors, although far from being completely understood, but fascinating as it opens an incredible window of knowledge on an autoimmune disorder whose environmental factor is known, whose autoantigen is known, whose autoantibodies are known: a truly unique situation in medicine.

Is lactobacillus GG helpful in children with Crohn's disease? Results of a preliminary, open-label study.

BACKGROUND: Lactobacillus GG is a safe probiotic bacterium known to transiently colonize the human intestine. It has been found to be useful in treatment of several gastrointestinal conditions characterized by increased gut permeability. In the current study, the efficacy of Lactobacillus GG was investigated in children with Crohn's disease. METHODS: In this open-label pilot evaluation viewed as a necessary preliminary step for a possible subsequent randomized placebo-controlled trial, four children with mildly to moderately active Crohn's disease were given Lactobacillus GG (10(10) colony-forming units [CFU]) in enterocoated tablets twice a day for 6 months. Changes in intestinal permeability were measured by a double sugar permeability test. Clinical activity was determined by measuring the pediatric Crohn's disease activity index. RESULTS: There was a significant improvement in clinical activity 1 week after starting Lactobacillus GG, which was sustained throughout the study period. Median pediatric Crohn's disease activity index scores at 4 weeks were 73% lower than baseline. Intestinal permeability improved in an almost parallel fashion. CONCLUSIONS: Findings in this pilot study show that Lactobacillus GG may improve gut barrier function and clinical status in children with mildly to moderately active, stable Crohn's disease. Randomized, double-blind, placebo-controlled trials are warranted for a final assessment of the efficacy of Lactobacillus GG in Crohn's disease.

Evidence favouring the gastro-oral route in the transmission of Helicobacter pylori infection in children.

OBJECTIVE: Several studies support the view that Helicobacter pylori is acquired in early life and within families. However, the exact route of transmission remains unknown. Given that H. pylori colonizes only the human gastric mucosa, the hypothesis that history of vomiting in siblings may be a relevant risk factor was tested in a paediatric setting. METHODS: One hundred urban children (age range 0.8-16.6 years, median 9), 44% with evidence of active H. pylori infection, were recruited. A structured questionnaire dealing with socio-economic issues was completed. Vomiting siblings and siblings of vomiting index children were screened for H. pylori by means of (13)C-urea breath test. Serum samples from index children were assayed for immunoglobulin G to hepatitis A (HAV) and Epstein-Barr virus (EBV) in order to check for faecal-oral and oral-oral exposure, respectively. RESULTS: Vomiting siblings of H. pylori-infected index children and siblings of H. pylori-infected vomiting index children had a high rate of active H. pylori infection (60 and 67%, respectively). History of vomiting in siblings was positively associated with active H. pylori infection in the index children (multivariate odds ratio 2.4, 95% confidence interval 1.3-4.3). Seropositivity for HAV and EBV was found in 1 and 68 index children, respectively. The agreement between active H. pylori infection and EBV seropositivity was not significant (kappa = 0.26). CONCLUSIONS: History of vomiting in siblings is an independent risk factor for H. pylori. Nowadays, transmission of H. pylori in urban children may involve the gastro-oral route more than the faecal-oral or oral-oral pathways.

Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: a multicenter European trial.

BACKGROUND: The probiotic Lactobacillus GG is effective in promoting a more rapid recovery of acute, watery diarrhea in children with rotavirus enteritis. Very limited information is available, however, on the potential role of such agents in non-rotaviral diarrheal episodes. Furthermore, no evidence is available concerning the efficacy of Lactobacillus GG administered in the oral rehydration solution during oral rehydration therapy. A multicenter trial was conducted to evaluate the efficacy of Lactobacillus GG administered in the oral rehydration solution to patients with acute-onset diarrhea of all causes. METHODS: Children 1 month to 3 years of age with acute-onset diarrhea were enrolled in a double-blind, placebo-controlled investigation. Patients were randomly allocated to group A, receiving oral rehydration solution plus placebo, or group B, receiving the same preparation but with a live preparation of Lactobacillus GG (at least 10(10) CFU/250 ml). After rehydration in the first 4 to 6 hours, patients were offered their usual feedings plus free access to the same solution until diarrhea stopped. RESULTS: One hundred forty children were enrolled in group A, and 147 in group B. There were no differences at admission between the groups in age, sex, previous types of feeding, previous duration of diarrhea, use of antibiotics, weight, height, weight-height percentile, prevalence of fever, overall status, degree of dehydration, and percentage of in- versus outpatients. Duration of diarrhea after enrollment was 71.9 +/- 35.8 hours in group A versus 58.3 +/- 27.6 hours in group B (mean +/- SD; P = 0.03). In rotavirus-positive children, diarrhea lasted 76.6 +/- 41.6 hours in group A versus 56.2 +/- 16.9 hours in groups B (P < 0.008). Diarrhea lasted longer than 7 days in 10.7% of group A versus 2.7% of group B patients (P < 0.01). Hospital stays were significantly shorter in group B than in group A. CONCLUSIONS: Administering oral rehydration solution containing Lactobacillus GG to children with acute diarrhea is safe and results in shorter duration of diarrhea, less chance of a protracted course, and faster discharge from the hospital.

Testing for serum IgG antibodies to Helicobacter pylori cytotoxin-associated protein detects children with higher grades of gastric inflammation.

BACKGROUND: Little information is available about the relationships between Helicobacter pylori cytotoxin-associated protein (CagA) and clinicopathologic features in children. The purpose of this study was to test whether determining serum IgG antibodies to CagA is a useful tool for detecting more severe disease. METHODS: One hundred twenty-seven consecutive children (age range, 0.75-17.8 years; median, 9.4 years) referred for gastroscopy were included in the study. Antral and corpus biopsies were taken for gastric histology and H. pylori detection. Major symptoms and endoscopic findings were recorded. A serum sample was drawn from each child and assayed for IgG antibodies CagA by a commercial enzyme-linked immunosorbent assay. RESULTS: Sixty-three (50%) children had no evidence of H. pylori infection, 28 (22%) were H. pylori positive/CagA positive, and 36 (28%) were H. pylori positive/CagA negative. There were no differences in clinical diagnosis and occurrence of any predominant symptom according to H. pylori and CagA status. Findings of antral nodularity were more frequent (p = 0.003) in H. pylori-positive/CagA-positive children than in H. pylori-positive/CagA-negative children. The gastritis score was significantly higher in H. pylori-positive/CagA-positive children than in H. pylori-positive/CagA-negative children (5.7 +/- 1.9 vs. 3.8 +/- 1.6, respectively; p = 0.0003), either in the antral (p = 0.0002) or in the corpus (p = 0.001) mucosa. Inflammation (p = 0.0001) and activity (p = 0.0001) scores were both higher in H. pylori-positive/CagA-positive children than in H. pylori-positive/CagA-negative children, but the H. pylori density score was not significantly different (p = NS). In no case was normal gastric mucosa found in H. pylori-positive/ CagA-positive children. Lymphocytic gastritis (p = 0.0008) and lymphoid follicles (p = 0.000003) were a more frequent finding in H. pylori-positive children than in H. pylori negative children, irrespective of CagA status. CONCLUSION: Testing for serum IgG to CagA detects higher grades of gastric inflammation among children with H. pylori infection. It may be useful in targeting H. pylori-positive/ CagA-positive children for antimicrobial therapy while reducing the need for endoscopy and gastric biopsy.

Perturbed bioelectrical properties of the mouse cecum following hepatectomy and starvation: the role of bacterial adherence.

Previous work in our laboratory has demonstrated that bacterial adherence alone to the intestinal epithelium, as occurs following catabolic stress, significantly perturbs the normal electrophysiology of the cecal mucosa. The aim of this study was to further characterize these effects in the mouse cecum following hepatectomy and short-term starvation, and to define the role of bacterial adherence in this process. Groups of mice underwent a surgical hepatectomy and were either fed or starved during the postoperative period. Groups of controls underwent sham operations and were either fed or starved postoperatively. Electrophysiologic studies in Ussing chambers at 48 hours were performed. Bacterial adherence to the mucosa was assessed by culture and histologic staining. To determine the role of bacteria in the altered electrophysiologic response, ciprofloxacin decontamination studies were performed. Only mice subjected to both hepatectomy and starvation developed bacterial adherence of sufficient magnitude (>10(5) cfu/gm) to alter mucosal electrophysiology (short-circuit current and basal potential difference). Ciprofloxacin decontamination completely abrogated this effect. Ion replacement studies suggested that active sodium transport was primarily responsible for the observed changes in mucosal electrophysiology. Bacterial-epithelial cell interactions may be responsible for altered mucosal ion transport observed following operative catabolic stress and short-term starvation.