Aberrant composition of gut microbiota of allergic infants: a target of bifidobacterial therapy at weaning?

BACKGROUND: Recent data have outlined a relationship between the composition of the intestinal microflora and allergic inflammation, and demonstrated the competence of probiotics in downregulation of such inflammation. AIMS: Our aims were to characterise the relationship between gut microbes and the extent of allergic sensitisation and to assess whether the efficacy of bifidobacterial supplementation in the treatment of allergy could relate to modulation of the intestinal microbiota. METHODS: This randomised study included 21 infants with early onset atopic eczema of whom eight were intolerant (highly sensitised group (HSG)) and 13 tolerant (sensitised group (SG)) to extensively hydrolysed whey formula (EHF). In the SG, six were weaned to EHF without (placebo group (PG)) and seven to EHF with Bifidobacterium lactis Bb-12 supplementation (bifidobacteria treated group (BbG)). The faecal microflora of infants in the HSG was analysed only before weaning whereas in the SG the faecal microflora was analysed both before and after weaning. RESULTS: Infants in the HSG had greater numbers of lactobacilli/enterococci than those in the SG. Serum total IgE concentration correlated directly with Escherichia coli counts in all infants and with bacteroides counts in the HSG, indicating that the presence of these bacteria is associated with the extent of atopic sensitisation. The effect of supplementation was characterised as a decrease in the numbers of Escherichia coli and protection against an increase in bacteroides numbers during weaning. CONCLUSIONS: These data indicate that bifidobacterial supplementation appears to modify the gut microbiota in a manner that may alleviate allergic inflammation. Further studies are needed to confirm this conclusion.

Characterizing the composition of intestinal microflora as a prospective treatment target in infant allergic disease.

We assessed the fecal microflora of 10 healthy infants and 27 infants with atopic eczema during breast-feeding and after weaning. The atopic infants had less frequently Gram-positive species among the most predominant aerobes and smaller total cell counts. Further differences were associated with more extensive manifestations, seen as higher bacteroides and lower bifidobacteria counts. Weaning resulted in decreased bacteroides counts in atopic and total cell counts in healthy infants and diminished predominance by bifidobacteria in both. In conclusion, the most prominent question raised by these data is whether Gram-positive bacteria may have distinctive importance in protection against atopic sensitization. Further studies aiming to answer this question are warranted.

Prospective, controlled, multi-center study on the effect of an amino-acid-based formula in infants with cow's milk allergy/intolerance and atopic dermatitis.

Cow's milk allergy/intolerance is treated by complete avoidance of cow's milk proteins. Because cow's milk is an important food for infants, its avoidance may lead to an increased risk of growth impairment. Whilst there is evidence for the beneficial effects of extensively hydrolyzed cow's milk formulate (eHF) in infants with cow's milk allergy/intolerance, little is known about the effects of amino-acid-based formulae (AA) in such infants. We therefore performed a prospective, controlled, multi-center trial to study the efficacy of AA in comparison with eHF, on the growth and clinical symptoms of 73 infants (median age 5.7 months) with cow's milk allergy/intolerance and atopic dermatitis. Cow's milk allergy/intolerance was proven in all infants by double-blind, placebo-controlled food-challenge. We observed a significant improvement in the SCORAD index in both groups, from a mean of 24.6, at entry, to a mean of 10.7 (p < 0.0001) after 6 months. In the AA group there was a significant increase in the length standard deviation score (p < 0.04), whilst there was no difference in the eHF group. The weight-for-length values were stable in both groups. The energy intake during the study was similar in both groups. Both an AA and eHF resulted in a significant clinical improvement in infants with an early onset of symptoms of cow's milk allergy/intolerance. Feeding an AA resulted in improved growth compared with feeding eHF, despite similar dietary intakes, and may therefore be considered as a beneficial alternative in infants with severe cow's milk allergy intolerance.

Probiotics in the management of atopic eczema.

BACKGROUND: Over the last two decades the incidence of allergic diseases has increased in industrialized countries, and consequently new approaches have to be explored. OBJECTIVE: The potential of probiotics to control allergic inflammation at an early age was assessed in a randomized double-blind placebo-controlled study. METHODS: A total of 27 infants, mean age 4.6 months, who manifested atopic eczema during exclusive breast-feeding and who have had no exposure to any infant or substitute formula were weaned to probiotic-supplemented, Bifidobacterium lactis Bb-12 or Lactobacillus strain GG (ATCC 53103), extensively hydrolysed whey formulas or to the same formula without probiotics. The extent and severity of atopic eczema, the growth and nutrition of infants, and concentrations of circulating cytokines/chemokines and soluble cell surface adhesion molecules in serum and methyl-histamine and eosinophilic protein X in urine were determined. RESULTS: The SCORAD score reflecting the extent and severity of atopic eczema was 16 (7-25) during breast-feeding, median (interquartile range). After 2 months, a significant improvement in skin condition occurred in patients given probiotic-supplemented formulas, as compared to the unsupplemented group; chi(2) = 12.27, P = 0.002. SCORAD decreased in the Bifidobacterium lactis Bb-12 group to 0 (0-3.8), and in the Lactobacillus GG group to 1 (0.1-8.7), vs unsupplemented 13.4 (4.5-18.2), median (interquartile range), in parallel with a reduction in the concentration of soluble CD4 in serum and eosinophilic protein X in urine. CONCLUSION: The results provide the first clinical demonstration of specific probiotic strains modifying the changes related to allergic inflammation. The data further indicate that probiotics may counteract inflammatory responses beyond the intestinal milieu. The combined effects of these probiotic strains will guide infants through the weaning period, when sensitization to newly encountered antigens is initiated. The probiotic approach may thus offer a new direction in the search for future foods for allergy treatment and prevention strategies.

Concerns and expectations of parents with atopic infants.

The incidence of atopic diseases has rapidly increased in developed countries. The purpose of this study was to describe the problems that parents experience when atopic disease occurs in their children at an early age and what parents expect and get from health care professionals in the management of these problems. The parents of 81 high-risk atopic infants completed a questionnaire during the infant's first attendance at the Tampere University Hospital, Finland. The patients were treated by an intervention team comprising a pediatric nurse and two pediatricians consulting with dietician and a dermatologist to detect the infant's specific food allergies and to introduce and advise on appropriate diets at weaning. After a 9-month intervention period, the parents' perception of the intervention was evaluated by a second questionnaire. The skin prick test was positive to cow's milk in 30%, to egg in 26%, and to cereals in 19%, of infants during breast-feeding. Double-blind placebo-controlled cow's milk challenge was positive in 56% of infants. Upon introduction of a tolerated weaning diet, subjective symptoms and the extent and intensity of atopic eczema diminished as evidenced by lowered SCORAD scores, from 19.3 to 8.2 (F= 57.6, p < 0.0001; SCORAD scoring index combining extent, severity and subjective symptoms of atopic eczema). Ninety per cent of parents found the care of an atopic infant more demanding than that of a healthy child. This was because of the persistence of symptoms, such as atopic eczema and pruritus, and restlessness during sleep. For the management of these problems the parents advocated diagnostic evaluation and elimination of specific foods from the diet of the lactating mother. They expected from the intervention accurate diagnosis of food allergies, practical advice on elimination diets, alleviation of symptoms, and follow-up of growth and nutrition, and they considered the care provided by the intervention team to suffice in these aims. The present data support a comprehensive team approach to the care of atopic infants and their parents.

Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections: a randomized study.

OBJECTIVES: Antimicrobial treatment may disturb the colonization resistance of gastrointestinal microflora, which may induce clinical symptoms, most commonly diarrhea. The severity of antibiotic-associated diarrhea may range from a brief, self-limiting disease to devastating diarrhea with electrolyte disturbances, dehydration, crampy abdominal pain, pseudomembranous colitis, toxic megacolon, or even death. The incidence of diarrhea in children receiving a single antimicrobial treatment is unclear. In addition to more critical use of antimicrobials, adjunctive preventive measures to antibiotic-associated diarrhea are needed. The objective of this study was to evaluate the incidence of diarrhea after antimicrobial treatment in children with no history of antimicrobial use during the previous 3 months. Another aim of this study was to assess the preventive potential of Lactobacillus rhamnosus GG (Lactobacillus GG; American Type Culture Collection 53103), a probiotic strain with a documented safety record and a therapeutic effect in viral gastroenteritis on antibiotic-associated diarrhea. METHODS: Oral antimicrobial agents were prescribed for the treatment of acute respiratory infections at the clinics of the Health Care Center of the City of Tampere or Tampere University Hospital, Finland, to 167 patients who were invited to participate in the study. Of the patients, 48 were lost to follow-up; therefore, the final study population consisted of 119 children from 2 weeks to 12. 8 years of age (mean: 4.5 years). All study subjects met the inclusion criteria: they had not received any antimicrobial medication during the previous 3 months, they did not suffer from gastrointestinal disorders, and they did not need intravenous antimicrobial treatment. The patients were randomized to receive placebo or 2 x 10(10) colony-forming units of Lactobacillus GG in capsules given twice daily during the antimicrobial treatment. Lactobacillus GG and placebo capsules were indistinguishable in appearance and taste. The parents kept a daily symptom diary and recorded stool frequency and consistency at home for 3 months. Diarrhea was defined as at least three watery or loose stools per day for a minimum of 2 consecutive days. In the case of diarrhea, viral (adenovirus, rotavirus, calicivirus and astrovirus) and bacterial (Salmonella, Shigella, Yersinia, Campylobacter, Clostridium difficile, Staphylococcus aureus, and yeasts) analyses were studied in fecal samples. The metabolic activity of the gut microflora was assessed by analysis of fecal urease, beta-glucosidase, and beta-glucuronidase activities. The primary outcome measure was diarrhea during the first 2 weeks after the beginning of the antimicrobial treatment, because this period most likely reflects the effects of antimicrobial use. Secondary outcome measures were the activities of fecal urease, beta-glucuronidase, and beta-glucosidase. RESULTS: On the entire follow-up, 80% of any gastrointestinal symptoms were reported during the first 2 weeks after the beginning of the antimicrobial treatment. The incidence of diarrhea was 5% in the Lactobacillus GG group and 16% in the placebo group within 2 weeks of antimicrobial therapy (chi(2) = 3.82). The treatment effect (95% confidence interval) of Lactobacillus GG was -11% (-21%-0%). In diarrheal episodes, the viral and bacterial analyses were positive for Clostridium difficile in 2 cases and for Norwalk-like calicivirus in 3 cases. The age of the patients with diarrhea was between 3 months and 5 years in 75% of cases in both groups. The severity of diarrhea was comparable in the study groups, as evidenced by similar stool frequency (mean: 5 per day; range: 3-6) and the duration of diarrhea (mean: 4 days; range: 2-8). The activities of fecal urease and beta-glucuronidase, but not beta-glucosidase, changed significantly after the beginning of the antimicrobial treatment in the Lactobacillus GG group and in the placebo group alike. (ABSTRACT TRUNCATED)

Benefits and risks of elimination diets.

Elimination diets have been used for the prevention or treatment of allergic disease with the diet of the pregnant or breastfeeding mother or the child, or both, being modulated as deemed appropriate. Evidence from studies published so far suggests that dietary restrictions are in fact effective only in the treatment of specific food allergies, not in allergy prevention. An elimination diet of a child or a breastfeeding mother entails a risk to normal nutrition and growth of the child. Although studies are lacking, dietary restrictions during lactation may well be harmful also to the mother's health. Substitution of nutritionally important foods and professional guidance are necessary for the successful treatment of food allergies.

Breast-feeding of allergic infants.

OBJECTIVE: Infants may have allergic disease even during exclusive breast-feeding. The aim of this study was to evaluate whether allergic infants should continue breast-feeding. STUDY DESIGN: We studied 100 infants who had atopic eczema during exclusive breast-feeding. The extent and severity of the eczema, allergic sensitization, and the patients' growth and nutrition were assessed during and after cessation of breast-feeding. RESULTS: The mean body length SD score decreased at the onset of allergic disease, and an association was seen between the duration of symptoms and poor growth (r = -.23, P =.04). Some improvement could be achieved by strict elimination diet by the mothers. The atopic eczema improved significantly after breast-feeding was stopped: SCORAD score 20 (range 15 to 27) during and 7 (range 4 to 11) after breast-feeding; t = 5.38, P <.0001, and the relative length of patients increased, in parallel with improved nutritional parameters. CONCLUSIONS: Breast-feeding should be promoted for primary prevention of allergy, but breast-fed infants with allergy should be treated by allergen avoidance, and in some cases breast-feeding should also be stopped. This particularly applies to infants with atopic eczema who also have impaired growth.

Antimicrobial resistance of fecal aerobic gram-negative bacilli in different age groups in a community.

We measured the occurrence of antimicrobial resistance in fecal aerobic gram-negative bacilli by age in community subjects. For none of the eight antimicrobial agents studied were there any statistically significant differences in the carriage rates of resistance in different age groups. Bacterial resistance was common in all age groups, including the children, and occurred for all antimicrobial agents tested.

Lactobacillus casei strain GG reverses increased intestinal permeability induced by cow milk in suckling rats.

BACKGROUND: Lactobacilli constitute a major part of the microflora throughout the gastrointestinal tract. This study aimed to investigate the effect of lactobacilli on the gut mucosal barrier. METHODS: Rat pups were divided into three experimental feeding groups at the age of 14 days. In addition to normal maternal milk, group "milk" received a daily gavage of cow milk, group "milk-GG" received Lactobacillus casei strain GG with cow milk, and controls were gavaged with the same volume of water. At 21 days, the absorption of horseradish peroxidase across patch-free jejunal segments and segments containing Peyer's patches was studied in Ussing chambers. RESULTS: The mean absorption of intact horseradish peroxidase expressed in ng.h-1.cm-2, was significantly different in the study groups in both patch-free segments (controls, 9 [95% confidence interval, 7-12]; milk, 72 [60-87]; and milk-GG, 15 [4-52]) and in segments containing Peyer's patches (controls, 3 [1-17]; milk, 80 [43-151]; and milk-GG, 15 [4-56]). There was a significant increase in the frequency of cells secreting antibodies to beta-lactoglobulin (enzyme-linked immunospot assay) in the milk-GG group. CONCLUSIONS: Prolonged cow milk challenge in suckling rats increases gut permeability to intact proteins, whereas Lactobacillus GG counteracts this permeability disorder. The results suggest a link between the intensity of the antigen-specific immune response and stabilization of the mucosal barrier.

Diet during rotavirus enteritis affects jejunal permeability to macromolecules in suckling rats.

We studied the influence of diet during diarrhea on gut mucosal barrier in a suckling rat model. Rat pups were inoculated with IDIR virus (a group B rotavirus) at 10 d of age. Beginning 2 d postinfection, in addition to maternal milk, group CM received a daily gavage of cow milk and group GG received Lactobacillus casei strain GG, a human strain previously shown to survive the passage through the gastrointestinal tract and temporarily colonize the gut. Group CMGG received a combination of these, and control animals were gavaged with tap water. At 21 d of age, jejunal absorption of intact and degraded horseradish peroxidase (HRP) in Ussing chamber was markedly higher in IDIR virus-infected than in noninfected controls. In the two groups gavaged with cow milk, group CM and group CMGG, the numbers of specific antibody-secreting cells (enumerated by the solid-phase enzyme-linked immunospot assay) against beta-lactoglobulin were significantly higher than in the groups that had not received cow milk. In parallel with immune system activation, a statistically significant increase in the absorption of intact HRP (mean and 95% confidence interval, ng x h-1 x cm-2) was detected: group CM, 302 (155, 586); group CMGG, 174 (56, 545); infected controls, 121 (57, 257); and group GG, 44 (8, 254). A decrease in the uptake of intact HRP (F = 3.64, p = 0.06) and degraded HRP (F = 9.50, p = 0.004) was associated with the introduction of L. casei GG to the diet, irrespective of coexposure to cow milk.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased in vitro intestinal permeability in suckling rats exposed to cow milk during lactation.

Specific mucosal barrier functions of the gut develop in the newborn to combat the constant challenge of foreign antigens. To determine whether exposure to cow milk antigens interferes with this maturational process, jejunal permeability to macromolecules and the activation of immune mechanisms were studied in preweaning rats. At the age of 14 days, rat pups were divided into three feeding groups. Controls (n = 18) remained on normal maternal milk; group CM (n = 27) additionally received a daily gavage feed of cow milk; and in group D (n = 23), cow milk was given to dams. At 21 days, when "gut closure" normally occurs, intestinal in vitro absorption of horseradish peroxidase in its intact form was significantly higher in group CM and in group D than in controls (F = 5.6; p = 0.006): group CM: mean, 37.8 ng/h/cm2; 95% confidence interval (CI), 19.4-73.6; group D: mean, 26.9 ng/h/cm2; 95% CI, 8.2-88.2; controls: mean, 4.0 ng/h/cm2; 95% CI, 1.2-13.9. In association with increased jejunal permeability, there was enhanced jejunal eosinophilic infiltration in group CM. In group D, the number of specific antibody-secreting cells in peripheral blood against beta-lactoglobulin was significantly higher than in group CM and controls. These data indicate that there is a critical period in development when feeding cow milk antigens delays gut closure. They further suggest that mucosal barrier function is impaired due to a local hypersensitivity reaction to cow milk antigens, irrespective of the protection of maternal milk or maternal antigen processing.

Early dietary antigens delay the development of gut mucosal barrier in preweaning rats.

To determine the effects of early antigen exposure on the maturation of the gastrointestinal mucosal barrier, rat pups were divided into three groups at the age of 14 d. In addition to normal maternal milk, group CM (n = 24) received daily a gavage feed of cow's milk and group PH (n = 20) a whey protein hydrolysate during the experimental feeding period (14-20 d). Controls (n = 15) remained on maternal milk only. At 21 d, when "gut closure" normally occurs, intestinal absorption of horseradish peroxidase (HRP), was examined in vitro in Ussing chambers. The absorption of intact HRP [geometric mean (95% confidence interval)] was significantly higher in group CM [35.3 (16.7, 74.7) ng.h-1.cm-2] than in group PH [5.2 (1.4, 19.5) ng.h-1.cm-2] and in controls [3.4 (0.8, 15.1) ng.h-1.cm-2; F = 5.54, p = 0.006]. The absorption of degraded HRP was comparable in all groups. There were no modifications in electrical parameters in association with increased mucosal permeability to HRP. Furthermore, in group CM electron-microscopic studies disclosed accumulation of HRP in the cytoplasm of the epithelial cells and in the intercellular spaces where cell junctions remained unaltered. These results indicate that early administration of antigens delays the process of gut closure. They further suggest that continuously enhanced endocytosis of macro-molecules is induced by an insult to the mucosa as part of the host response to these antigens, irrespective of the protection afforded by maternal milk.