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Yogurt and You? Probiotics and Infant Atopic Dermatitis
By David Kiefer, MD. Dr. Kiefer is a Clinical Instructor, Family Medicine, University of Washington, Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson; and Adjunct Faculty at Bastyr University, Seattle; he reports no financial relationship to this field of study.
Probiotics are often thought of as concentrated yogurt capsules, most useful for the prevention or treatment of antibiotic-induced diarrhea. Recent evidence, though, is starting to point to a much greater use for the provision of "good bacteria" to the gastrointestinal tract. This article will review some of the connections between maternal and newborn probiotic intake and the prevention of infant atopic disease; which children might benefit from probiotic supplementation; and the nuances of probiotic dosing.
Probiotics are generally known as live, nonpathogenic microbial food ingredients beneficial to health when provided in adequate amounts.1-3 The term "probiotic" is a general term that may refer to bacteria such as Lactobacilli spp. or Bifidobacteria spp. or yeast such as Saccharomyces boulardii. Probiotics may be found in dietary supplements (most commonly capsules) or fortified foods such as yogurt or milk.
Mechanism of Action
The idea to use beneficial bacteria in the treatment of atopic disease is not necessarily intuitive, but there has been a lot of research to support this line of thinking. Some of the idea behind using probiotics for this condition stemmed from data showing that the composition of the intestinal microflora is different in children with atopic dermatitis; specifically, such children may have decreased levels of normally occurring Bifidobacteria.1 Even the well-documented gastrointestinal effects of probiotic therapy, such as improved IgA immune function, improvements in intestinal barrier function and pathological permeability, and changes in the presence or absence of certain bacteria, may be relevant to atopy.1,2
By improving abnormal intestinal permeability, probiotics may help to modulate the immune system, improving symptoms of atopic disease.1 Also, in early childhood, probiotics may decrease excessive immune responses to foreign antigens, thereby affecting immune tolerance and the extent to which atopy develops.4 This may be particularly important at early ages, when the gastrointestinal tract, immune system, and resulting allergic responses are in development.2 Furthermore, probiotics may also help to balance pro-inflammatory and anti-inflammatory cytokines, contributing to decreased overall inflammation, in addition to helping process macromolecules in the intestinal tract, and decreasing dietary antigen loads.2,4
A "hygiene" hypothesis may explain why probiotic supplementation benefits atopic disease: There may be an increase in atopic diseases due to decreased human exposure to commensal organisms and resulting changes in immune system function.3 Supplementation with probiotics may simulate the exposure to these commensal organisms, leading to increased Th1 and decreased Th2 T-cell responses and resulting in a calming of allergic and autoimmune diseases.3,5 A clinical trial, however, did not find an effect on various immune system parameters in cord blood of newborns delivered to women who had been given 18 billion colony-forming units (cfu) Lactobacillus rhamnosus GG daily from 36 weeks gestation onward.6 One ongoing clinical trial is further examining the potential of probiotic supplementation during infancy to prevent asthma.7
Clinical Trials: Pregnancy and Post-natal
Overall, among all clinical trials, the results have been mixed for the effectiveness of probiotics on childhood eczema. Many variables may account for this, but one expert points out that the clinical effect of probiotic supplementation varies greatly between species of bacteria used, dose administered, and whether there was adequate exclusion of probiotic intake from foods; these three variables in particular are important to consider when assessing probiotic clinical trials.1
A series of research trials has explored the hypothesis that the establishment of beneficial bacteria in the newborn may occur either in utero or during the early postnatal period. For example, one double-blind study randomized 159 women with a family history of atopic disease to take either capsules of Lactobacillus rhamnosus GG (10 billion cfu) or placebo beginning four weeks prior to delivery, and then for six months post-natally during breastfeeding or administered to the child with a spoon if not breastfeeding. The 132 children in the active group who completed the study at year 2 had half the incidence of atopic eczema (relative risk [RR] = 0.51),8 while the 107 at the year 4 follow-up also had significantly less atopic eczema (RR = 0.57).9
A similar approach to pre- and post-delivery probiotic therapy was taken in 1,223 women (either the woman or the father of the baby needed to have diagnosed atopic disease) at 35 weeks of gestation who were prescribed a probiotic mixture (5 billion cfu each of Lactobacillus rhamnosus GG and LC705, Bifidobacterium breve, and Propionibacterium freudenreichii ssp. shermanii) or placebo, and then instructed to administer the same preparation to the newborn every day for six months.10 Of the 1,223 original entrants, 1,018 underwent intention-to-treat analysis, and 925 returned for follow-up at two years. The researchers separately analyzed for allergic diseases and IgE-associated atopic diseases using skin prick and blood tests. Physicians examined each newborn for atopic dermatitis at three, six, and 24 months, finding that eczema occurred less frequently in the probiotic group (odds ratio = 0.74) with a number needed to treat to prevent eczema of 16. The main side effects (abdominal discomfort, vomiting, and excessive crying) occurred in equal amounts among the placebo and treatment groups.
Using a protocol similar to the previous studies, 105 German women with a family history of atopic disease were randomized to 5 billion cfu Lactobacillus GG or placebo for 4-6 weeks before expected delivery and for six months afterwards; the main outcome being studied was the incidence of atopic dermatitis in the newborn at 2 years of age.11 No difference was found in the risk or severity of atopic dermatitis in the two groups, making the researchers doubt the effectiveness of probiotic supplementation in primary prevention of atopic dermatitis. Two factors in this study differed from the previously mentioned research and may account for this result: The patients in this study had a more significant family history of atopy, and, a very preliminary hypothesis, were of a different genetic background (other studies examined Finish and Australian women and newborns) possibly with less susceptibility to the effects of probiotics.
Clinical Trials: Newborns
One review of 12 clinical trials involving 781 children with eczema found significant variety in the results of individual trials, which the reviewers mentioned could be due to different strains and doses used.1 Five of the trials used symptom scores and 10 rated eczema severity; none of the trials showed a difference between probiotic and placebo groups (P = 0.33-0.36). Interestingly, subgroup analyses revealed a worsening of eczema (higher SCORAD, an eczema rating system) with Lactobacillus GG vs placebo (P = 0.02), but an improvement symptoms with other Lactobacillus species (P < 0.01).
One example of a double-blind clinical trial randomized 27 breastfed infants (average age, 4.6 months) with atopic dermatitis after weaning to three types of formula: a hydrolyzed whey formula, or the same formula supplemented with either 1 billion cfu/g Bifidobacterium lactis Bb-12, or 0.3 billion cfu/g Lactobacillus GG (ATCC 53103).2 After two months, a skin condition rating system demonstrated a significant improvement in the probiotic groups compared to the placebo group (P = 0.002). Furthermore, statistically significant immune system changes were seen only in the probiotic-supplemented groups; there were decreases in serum CD4 (P = 0.005), changes (decreases with Bifidobacterium and increases with Lactobacillus GG) in serum TGF-beta1 (P = 0.007), and decreases in urine eosinophilic protein X (a reflection of allergic inflammatory activity in atopic disease such as asthma) in both probiotic groups (P = 0.01-0.04). Other immune parameters were unaffected, and the researchers did not mention any adverse effects.
A randomized, double-blind trial in 231 newborns of mothers with atopic disease compared 6 months of Lactobacillus acidophilus (3 billion cfu) to placebo, and found similar rates of atopic dermatitis at age six and 12 months, though only 178 infants completed the trial.5 Allergen skin prick testing and atopic dermatitis was higher in the probiotic group at the 12-month check (P = 0.045), as was sensitization to common allergens when assessed at 12 months (P = 0.030).
A more complicated examination of this topic was undertaken in 230 infants suspected of having cow's milk allergy.12 They were randomized to Lactobacillus rhamnosus GG (5 billion cfu), a mixture of probiotics (5 billion cfu L. rhamnosus GG, 5 billion cfu L. rhamnosus LC705, 200 million cfu Bifidobacterium breve Bbi99, and 2 billion cfu Propionibacterium JS), or placebo, and all placed on an cow's milk elimination diet plus topical skin treatments. At the end of eight weeks, each group was subjected to a double-blind cow's milk rechallenge, and skin symptom scoring was recorded. All groups improved (similarly so) over the course of the study, presumably from the removal of cow's milk from the infants' diet. The only subgroup showing improvement after milk rechallenge was in the Lactobacillus rhamnosus GG group for infants with IgE-associated atopic dermatitis (P = 0.036).
General dosing is mentioned in some sources, such as a minimum of 5-10 billion cfu for children.4 Many experts recommend dosing based on a specific strain or patented product as per clinical trials. Such a recommendation, if based on the clinical trials with a positive effect on atopy, would lead to daily doses of 5-10 billion cfu in the case of Lactobacillus rhamnosus GG. In some cases probiotic mixtures were used in clinical trials, usually with doses of 5 billion cfu of each species, such as Lactobacillus rhamnosus GG, Bifidobacterium breve, and Propionibacterium species.
As a side note, many "therapeutic" yogurts and fermented milks exist and provide some of the same probiotic species seen in clinical trials and basic science research. For example, Activiaâ provides Bifidobacterium animalis, Danactiveä provides 10 billion cfu of Lactobacillus casei per serving, and Yoplaitâ Yo-Plus has 1 billion cfu of Bifidobacterium lactis per serving.
Probiotics are considered safe in healthy individuals;2 the adverse effects described below (sepsis, bacteremia, fungemia) have not appeared to occur in otherwise healthy people.13 Literature reviews reveal several dozen case reports of bacteremia/fungemia and sepsis in both children and adults who were taking probiotics. In most of the cases there were identifiable risk factors (gastrointestinal pathology, diabetes, recent surgery, cancer); also, not all of the cases had definitively identified the suspect strain nor proven cause and effect.1,3,13 For example, it can be difficult to assess whether Lactobacillus sepsis occurs from normal flora or from ingested probiotics.14
However, as a result of these data, some researchers list contraindications for probiotics, such as anyone with underlying immune system dysfunction, chronic disease, or "debilitation."13 This recommendation is anything but certain, given that some studies show that probiotics are safe for use in people with HIV, and may even prevent necrotizing enterocolitis in preterm neonates despite their often immunocompromised state.14
For children that have a cow's milk allergy, it is important to use only products that are milk-free; if not, there is the possibility of exacerbation of allergic symptoms.15
Of note, there is huge variety in the quality of probiotic supplements. One study of 20 refrigerated (n = 12) and non-refrigerated (n = 8) Lactobacillus products from commercial sites in Seattle found that 30% of the products grew contaminant bacteria species in laboratory culture media, and 20% had no growth at all.16 Some of the contaminants contained gram-negative rods, Bacillus species, and Enterococcus species, potentially harmful with ingestion.
Probiotics are live microbial food supplements that, in adequate amounts, provide a health benefit beyond basic nutrition. Supplementation with certain strains can then populate the intestinal tract, possibly decreasing pathological intestinal permeability and the passage of antigens into the systemic circulation. The hypothesis, and there is some immunological data to support this, is that select bacteria can cause beneficial changes in immune system function and allergic responses to antigens that lead to a benefit in atopic dermatitis.
Clinical trials have been conducted in two main ways: supplementing pregnant women and then newborns, or focusing the probiotic supplementation on newborns at risk of atopic disease. Results have been mixed, with some showing improvements in the incidence of atopic dermatitis, while others have shown no difference. It is possible that the exact strain and dose used determines clinical efficacy; Lactobacillus rhamnosus GG dosed at 10 billion cfu per day was the dose in one positive clinical trial. Adverse effects, the worst being sepsis or bacteremia, seem limited to people with immune system pathology or chronic disease.
The research on probiotic supplementation in childhood atopic dermatitis is in its infancy, no pun intended. Interesting basic science has delineated a compelling mechanism of action, and some clinical trials are showing benefit when pregnant women and/or newborns are supplemented with probiotics, most convincingly at a dose of 5-10 billion cfu daily of Lactobacillus rhamnosus GG, Bifidobacterium breve, and Propionibacterium species, either separately or as a mixture. There is variety in clinical response across populations, perhaps with a genetic basis for why one group responds to probiotic supplementation, while another shows no change or even worsens. Close clinical monitoring is warranted, and only products that have been subject to third-party verification or those used in clinical trials should be incorporated into clinical practice.
1. Boyle RJ, et al. Probiotics for treating eczema. Cochrane Database Syst Rev 2008;(4):CD006135.
2. Isolauri E, et al. Probiotics in the management of atopic eczema. Clin Exp Allergy 2000;30:1604-1610.
3. Hsieh MH, Versalovic J. The human microbiome and probiotics: Implications for pediatrics. Curr Probl Pediatr Adolesc Health Care 2008;38:309-327.
4. Kligler B, Cohrssen A. Probiotics. Am Fam Physician 2008;78:1073-1078.
5. Taylor AL, et al. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: A randomized controlled trial. J Allergy Clin Immunol 2007;119:184-191.
6. Boyle RJ, et al. Effects of Lactobacillus GG treatment during pregnancy on the development of fetal antigen-specific immune responses. Clin Exp Allergy 2008;38: 1882-1890.
7. Cabana MD, et al. Examining the hygiene hypothesis: The Trial of Infant Probiotic Supplementation. Paediatr Perinat Epidemiol 2007;21(Suppl 3):23-28.
8. Kalliomäki M, et al. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet 2001;357:1076-1079.
9. Kalliomäki M, et al. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 2003;361:1869-1871.
10. Kukkonen K, et al. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2007;119:192-198.
11. Kopp MV, et al. Randomized, double-blind placebo-controlled trial of probiotics for primary prevention: No clinical effects of Lactobacillus GG supplementation. Pediatrics 2008;121:e850-e856.
12. Viljanen M, et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: A double-blind placebo-controlled trial. Allergy 2005;60:494-500.
13. Boyle RJ, et al. Probiotic use in clinical practice: What are the risks? Am J Clin Nutr 2006:83:1256-1264.
14. Hammerman C, et al. Safety of probiotics: Comparison of two popular strains. BMJ 2006;333:1006-1008.
15. Bruni FM, et al. Cow's milk allergic children can present sensitisation to probiotics. Acta Paediatr 2008 Oct 6; Epub ahead of print.
16. Berman S, et al. Safety and reliability of Lactobacillus supplements in Seattle, Washington (a pilot study). The Internet Journal of Alternative Medicine 2003;1(2).