Erika Isolauri

Clinical uses of probiotics for stabilizing the gut mucosal barrier: successful strains and future challenges

Probiotic bacteria are used to treat disturbed intestinal microflora and increased gut permeability which are characteristic to many intestinal disorders. Examples include children with acute rotavirus diarrhoea, subjects with food allergy, subjects with colonic disorders and patients undergoing pelvic radiotherapy and sometimes changes associated with colon cancer development. In all such disease states altered intestinal microflora, impaired gut barrier and different types of intestinal inflammation are present. Successful probiotic bacteria are able to survive gastric conditions and colonize the intestine, at least temporarily, by adhering to the intestinal epithelium. Such probiotic microorganisms appear to be promising candidates for the treatment of clinical conditions with abnormal gut microflora and altered gut mucosal barrier functions. They are also promising ingredients to future functional foods and clinical foods for specific disease states provided that basic requirements for strains and clinical studies are carefully followed.

Improved immunogenicity of oral D x RRV reassortant rotavirus vaccine by Lactobacillus casei GG

In a search for new strategies to improve oral vaccination, the effect of orally administered Lactobacillus casei strain GG (LGG) in conjunction with D x RRV rhesus-human reassortant live oral rotavirus vaccine was tested in 2-5-month-old infants. Infants who received LGG showed an increased response with regard to rotavirus-specific IgM secreting cells, measured using an ELISPOT technique, on day 8 after vaccination. In infants receiving LGG or placebo, respectively, a rotavirus IgM seroconversion was detected in 26/27 (96%), versus 23/27 (85%) cases (p = 0.15) and rotavirus IgA seroconversion was detected in 26/28 (93%) versus 20/27 (74%) cases (p = 0.05). These findings suggest that LGG has an immunostimulating effect on oral rotavirus vaccination. The clinical significance of LGG-enhanced immune responses to oral vaccines should be further evaluated.

A trial in the Karelian Republic of oral rehydration and Lactobacillus GG for treatment of acute diarrhoea.

In a controlled trial in Petrozavodsk, Karelia, the effects of oral rehydration and Lactobacillus strain GG (LGG) on recovery from acute diarrhoea (27% rotavirus, 21% bacterial aetiology) were studied in 123 children aged between 1 and 36 months of age. On admission to hospital, the patients were first randomized to receive either isotonic oral rehydration solution (ORS) with osmolality 311mosmol/l and sodium 90mmol/l (WHO‐ORS), or a hypotonic ORS with osmolality 224mosmol/l and sodium 60mmol/l (Light‐ORS), and thereafter randomized to receive either 5 × 109 colony forming units of LGG or a matching placebo. The two ORS performed equally for acute rehydration, and oral rehydration with either ORS was associated with a shorter duration of diarrhoea than intravenous rehydration (p= 0.036). Patients receiving LGG had a significantly shorter duration of watery diarrhoea [mean (SD) 2.7 (2.2) days] than those receiving the placebo [3.7 (2.8) days, p= 0.03]. LGG significantly shortened the duration of rotavirus diarrhoea but not diarrhoea with confirmed bacterial aetiology.

IMMUNOGENICITY AND SAFETY OF LIVE ORAL ATTENUATED BOVINE ROTAVIRUS VACCINE STRAIN RIT 4237 IN ADULTS AND YOUNG CHILDREN

A candidate oral live rotavirus vaccine, strain RIT 4237, of bovine origin, was tested for immunogenicity and safety in man. In adults the vaccine did not cause clinical symptoms, and a booster response in rotavirus serum antibodies was seen in 2/20 subjects. In seronegative young children one oral dose induced seroconversion to homologous virus in 15/17 (88%) children seronegative by enzyme immunoassay and in 13/19 (68%) children seronegative by a neutralisation assay. The vaccine did not produce gastrointestinal or constitutional symptoms in the children, nor did it cause rotavirus excretion in the stools. The results suggest that the RIT 4237 strain is a promising candidate for a vaccine against human rotavirus, and the vaccine-induced immunity against natural human rotavirus infection should be evaluated in future trials.

Evaluation of the gut mucosal barrier: Evidence for increased antigen transfer in children with atopic eczema

BACKGROUND Intestinal antigen handling determines subsequent immune response to the antigen. Antigens are absorbed across epithelium along two functional pathways. The main pathway is degradative, which reduces the immunogenicity of the antigen. A minor pathway allows the transport of intact proteins, which is crucial for antigen-specific immune responses. The Ussing chamber method allows the quantitative measurement of protein transfer across the intestinal mucosa. OBJECTIVE This study was designed to explore the theory that altered antigen transfer across the intestinal mucosa is a factor in the pathogenesis of atopic eczema, characterized by hyperactivity to environmental antigens. METHODS The absorption and degradation of horseradish peroxidase (molecular weight, 40,000 d) were studied in vitro in Ussing chambers. Eighteen biopsy specimens of upper small intestinal mucosa from 14 patients (aged 0.5 to 8 years) with atopic eczema and 18 specimens from 15 age-matched control subjects were examined. RESULTS The mean (95% confidence interval) absorption of intact horseradish peroxidase was significantly higher in children with atopic eczema than in control subjects: 242 (81-404) pmol . hr(-1) . cm(-2) versus 23 (12-33) pmol . hr(-1) . cm(-2); t = 2.86, p = 0.007. The absorption of degraded horseradish peroxidase was 972 (732-1213) pmol . hr(-1) . cm(-2) in patients with atopic eczema and 672 (532-811) pmol . hr(-1) . cm(-2) in control subjects; t = 2.29, p = 0.03. CONCLUSIONS Our results may reflect a primarily altered antigen transfer in patients who have atopic eczema, which may initiate and perpetuate prompt immune responses to common environmental antigens, including foods.

Gut Flora in Normal and Disordered States

Infections of the gastrointestinal tract are a major health problem for both adults and children worldwide. Changes in the normal human gut microflora result in the development of intestinal disorders. Pathogenic bacteria alter the intestinal microecology and intestinal colonization resistance. A healthy gastrointestinal microflora forms a barrier against invading organisms. Normal intestinal microbes and some probiotic bacteria can enhance the hosts defence mechanisms against pathogens. They can also improve intestinal immunity by adhering to intestinal mucosa and stimulating local immune responses. Thus the maintenance of a balanced intestinal microecology improves the ability to preserve intestinal integrity.

Intestinal inflammation in children with atopic eczema: faecal eosinophil cationic protein and tumour necrosis factor-alpha as non-invasive indicators of food allergy.

Background Food allergy is contemplated in atopic eczema. Early recognition of food allergies is difficult and the diagnosis is often missed because of the non‐specificity of symptoms. New non‐invasive tests are clearly needed.

Local immune response in patients with cow milk allergy: Follow-up of patients retaining allergy or becoming tolerant

To assist in identifying factors that determine the clinical outcome of cow milk allergy, we subjected to rechallenge 37 patients with a history of cow milk allergy, mean (+/- SD) age 27.6 +/- 7.1 months, after a follow-up of 13.5 +/- 5.1 months with a milk-free diet. A solid-phase enzyme-linked immunoassay was used to assess the total number of immunoglobulin-secreting and specific antibody-secreting cells among peripheral blood lymphocytes primed during provocation by milk antigens, giving indirect evidence of local immune response in the gut. Patients with persistent cow milk allergy (n = 13) had milder reactions at rechallenge than they had shown at the time of diagnosis. Numbers of immunoglobulin-secreting cells in these patients increased significantly from a geometric mean (95% confidence interval) in the IgA class of 1570 (1009, 2445) to 2984 (1941, 4583) IgA-secreting cells/10(6) cells, in the IgG class of 1445 (1067, 1959) to 2740 (1698, 4425) IgG-secreting cells/10(6) cells, and in the IgM class of 842 (534, 1325) to 2235 (1429, 3495) IgM-secreting cells/10(6) cells. By contrast, in patients (n = 24) who had acquired cow milk tolerance, the number of immunoglobulin-secreting cells did not increase during provocation. The total number of IgA-secreting cells before rechallenge was significantly higher than it had been before the initial challenge. The patients who acquired cow milk tolerance also had specific antibody-secreting cells of IgA isotype before the second challenge. These results indicate that in cow milk allergy the ability to mount a local immune response against cow milk antigens, particularly in the IgA class, is related to the suppression of clinical sensitivity.

Age‐dependent variation in the serum concentration of mannan‐binding protein

Mannan‐binding protein (MBP) is an acute phase reactant, and its deficiency is associated with the common opsonic defect and suspectibility to infections and atopic constitution. The aim of this study was to investigate the changes occurring in the serum level of MBP in infancy and during later childhood. We studied the serum concentration of MBP in 611 Finnish children of different ages and 110 adults by using an enzyme immunoassay. In an analysis of successive serum samples from infants at the day of birth and at the ages of 1 and 5 months, and at 1 and 2 years, the serum concentration of MBP increased significantly after birth, and was at its highest (the mean and median were 8.13 and 8.49 mg1−1, respectively) at the age of 1 month. After that, it declined to the initial level until the age of 5 months. The MBP concentration continued to decrease during childhood, and after the age of 12 years the MBP values reached the adult level. In Finnish adults the mean and median concentrations of MBP were 4.48 and 4.02 mg 1−1, respectively, which seem to be higher than those reported previously in other populations. The high concentration of MBP in infants may best be explained by exposure to novel environmental antigens in early childhood, which suggests a protective role for MBP during the period of immaturity of the immunosystem. In older children the high level of MBP can probably be explained by childhood infections and the ensuing need of MBP.

Long-term comparison of antireflux surgery versus conservative therapy for reflux esophagitis.

OBJECTIVE The purpose of the study was to evaluate the long-term symptomatic and endoscopic outcome in gastroesophageal reflux disease with erosive esophagitis, comparing conservative with operative management. METHODS The study comprised 105 of 120 patients consecutively referred for severe reflux symptoms to the gastroenterologic outpatient department of a teaching hospital, where erosive esophagitis was confirmed endoscopically. If conservative management (modified lifestyle and medication) failed to relieve symptoms and heal the esophagitis, antireflux surgery (Nissen fundoplication) was undertaken. Follow-up (median, 10.9 years) evaluation of all patients included comprehensive, standardized interviews; self-scoring of symptoms at the time of referral and currently; and observations at endoscopy. RESULTS Nissen fundoplication was performed on 37 of the 105 patients. At follow-up of these 37 patients, (31) 84% had no or only occasional mild heartburn, (33) 89% were free from erosive esophagitis, and (2) 5% were taking H2 antagonists or omeprazole. The corresponding figures in the 68 patients with only conservative treatment were (36) 53%, (31) 45%, and (14) 21%. The mean change in symptom score between referral time and follow-up was 5.7 in the surgically treated group and 1.7 in the nonsurgically treated group. Fifteen new cases of Barretts metaplasia were found at follow-up. CONCLUSIONS In gastroesophageal reflux disease with erosive esophagitis, surgical treatment gave results subjectively and objectively superior to those from conservative management.