Probiotics and Skin
8.3 Eczema
8.3.2 Probiotics for Preventing Eczema
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could still be effective. In contrast to our meta-analysis, a recent meta-analysis by Michail et al. reported a significant difference favoring probiotics in reducing the SCORAD score of children with eczema (mean change from baseline was −3.01 with the 95% CI −5.36 to −0.66, P = 0.01), and children with moderately severe disease were more likely to benefit (Michail et al. 2008). The authors of the latter meta-analysis were able to acquire original data from a greater number of included trials, which may account for the different conclusions of the two studies. However, the clinical significance of a three-point reduction in SCORAD score is unclear and compares poorly with the treatment effect seen with established eczema treatments.
Topical application of probiotics for the treatment of eczema was recently evaluated in a single study that reported a significantly reduced SCORAD score and pruritus following treatment with topical Vitreoscilla filiformis lysate cream versus placebo and decreased loss of sleep compared to the start of treatment (Gueniche et al.
2008). The treatment was also associated with reduced Staphylococcus aureus colo- nization of skin. Future studies evaluating topical probiotics for the management of eczema will be of great interest.
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probiotics (and also prebiotics in one study) have now been reported (Abrahamsson et al. 2007; Dotterud et al. 2010; Huurre et al. 2008; Kalliomaki et al. 2001b; Kim et al. 2009; Kopp et al. 2008; Kukkonen et al. 2007; Niers et al. 2009; Rautava et al.
2006; Soh et al. 2009; Taylor et al. 2007; West et al. 2009; Wickens et al. 2008).
Meta-analysis of these studies shows a significant protective effect of probiotics for preventing eczema and possibly IgE-associated eczema (Fig. 8.2a, b). Nine stud- ies (evaluating 10 interventions) involved a combined prenatal (last 2–6 weeks of pregnancy) and postnatal (6–24 months) treatment: nine probiotic interventions (Abrahamsson et al. 2007; Dotterud et al. 2010; Huurre et al. 2008; Kalliomaki et al.
2001b; Kim et al. 2009; Kopp et al. 2008; Niers et al. 2009; Rautava et al. 2006; Soh et al. 2009; West et al. 2009; Wickens et al. 2008) and one synbiotic intervention (Kukkonen et al. 2007). All but two of these studies recruited infants at increased risk of allergic disease (first-degree relative with allergic disease): The studies by Huurre et al. (2008) and Dotterud et al. (2010) recruited an unselected population of mothers.
Seven of the ten prenatal/postnatal treatments resulted in significantly less eczema during the first 2 years of life. A reduced cumulative incidence of eczema (Dotterud et al. 2010; Kalliomaki et al. 2001b; Kim et al. 2010), IgE-associated eczema (Abrahamsson et al. 2007), or both (Kukkonen et al. 2007; Wickens et al. 2008) at age 2 years was reported with six treatments; and one treatment resulted in a reduced cumulative incidence of parent-reported eczema and doctor-diagnosed eczema at age 3 months but not at 1 or 2 years of age, with no effect on IgE-associated eczema (Niers et al. 2009). Three of the ten prenatal/postnatal treatments showed no statistically significant reduction in rates of eczema or IgE-associated eczema at age 1 or 2 years. We performed a meta-analysis of studies that evaluated combined prenatal and postnatal treatment and found a significant protective effect with probiotic/
prebiotic treatment for both eczema (Fig. 8.2c) and IgE-associated eczema (Fig. 8.2d) without a high level of heterogeneity between the results of individual studies.
In contrast to the findings for probiotics administered prenatally and postnatally, most of the studies (three of four) that evaluated postnatal without prenatal treatment with various probiotic bacteria reported no beneficial effects on the development of eczema or IgE-associated eczema at 12 months (Rautava et al. 2006; Soh et al.
2009; Taylor et al. 2007). Meta-analysis of these four studies revealed no evidence that postnatal treatment without a prenatal component reduces the risk of eczema (Fig. 8.2e). Moreover, in one study, postnatal treatment with L. acidophilus LAVRI-A1 was instead associated with an increased risk of IgE-associated eczema (RR 1.87) at 1 year (Taylor et al. 2007), although there was no significant difference between groups in atopic eczema prevalence at the 2.5-year follow-up (Prescott et al. 2008). One study reported a reduced cumulative incidence of eczema at 13 months following treatment with L. paracasei F19 during weaning (4–13 months of age) (West et al. 2009). Two of these postnatal studies recruited high-risk infants with a family history of allergic disease (Soh et al. 2009; Taylor et al. 2007), and the other two studies included formula-fed infants irrespective of a family history of allergic disease (Rautava et al. 2006; West et al. 2009).
Other allergic disease outcomes (recurrent wheeze, asthma, allergic rhinitis, food allergy) were assessed in five studies. Kukkonen et al. found no difference in the
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Fig. 8.2 (a) Meta-analysis of published data from RCTs of probiotics ± prebiotics for the preven- tion of eczema. (b) Meta-analysis of published data from RCTs of probiotics ± prebiotics for the prevention of immunoglobulin E (IgE)-associated eczema. (c) Meta-analysis of published data from RCTs of probiotics ± prebiotics for the prevention of eczema, where treatment was com- menced prenatally. (d) Meta-analysis of published data from RCTs of probiotics ± prebiotics for the prevention of IgE-associated eczema, where treatment was commenced prenatally. (e) Meta- analysis of published data from RCTs of postnatal probiotics for the prevention of eczema, without a prenatal component to treatment
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cumulative incidence of all allergic diseases or IgE-associated allergic diseases (Kukkonen et al. 2007), and Dotterud et al. found no difference in asthma or allergic rhinitis at age 2 years (Dotterud et al. 2010). However, Kopp et al. reported an almost threefold increased risk of recurrent wheezing bronchitis at age 2 years with LGG (Kopp et al. 2008) and trends to increased wheezing or asthma were noted in two other studies (Taylor et al. 2007; Kalliomaki et al. 2007). Additional data on asthma and allergic rhinitis outcomes will become available as further follow-up analyses are performed in the above studies.
Overall, these data suggest that probiotic treatment during late pregnancy and early postnatal life reduces the risk of eczema. It is necessary to examine the studies in a little more detail to define how best to administer probiotics in this context.
First, we should note that most of the combined prenatal/postnatal treatments were effective in reducing eczema and/or IgE-associated eczema during the first 1–2 years of life, whereas most of the treatments involving only a postnatal component of therapy failed to reduce the risk for eczema and/or IgE-associated eczema. This suggests that a prenatal component of treatment is necessary for beneficial effects.
Our own recently published study of prenatal probiotics without a postnatal compo- nent suggests that prenatal treatment is necessary, but not on its own sufficient for preventing eczema (Boyle et al. 2011).
Second, administration of a probiotic mix (LGG, L. acidophilus LA-5, B. lactis Bb-12) solely to women from 36 weeks of pregnancy to 3 months postpartum without direct infant supplementation was sufficient to reduce the cumulative incidence and prevalence of eczema at 2 years (Dotterud et al. 2010), indicating
Fig. 8.2 (continued)
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that direct infant probiotic supplementation during early life may not be an absolute requirement for protective effects. A subgroup analysis of the study by Kalliomaki’s group also found evidence that direct supplementation of infants may not be necessary: the greatest protective effects of LGG treatment in their study were seen in breast-fed infants for whom probiotic was administered to their mothers during pregnancy and breastfeeding, without direct administration to the infant until after 3 months of age (Rautava et al. 2002). The beneficial effects in these breast-fed infants may have been related to increased breast milk transforming growth factor-b2 (TGFb2) levels in breastfeeding mothers treated with LGG (Rautava et al. 2002).
A third important conclusion from reviewing the probiotic prevention studies is that selection of the right strain or strain combination is important. For example, in the study by Wickens et al. (2008), which evaluated two probiotic treatments com- pared with placebo, L. rhamnosus HN001 resulted in beneficial effects on eczema but B. animalis subsp lactis HN019 did not, and the difference in clinical outcome between the two strains was statistically significant. Both strains were associated with immunomodulatory effects in cord blood and breast milk, but only one was clinically effective (Prescott et al. 2008). This emphasizes the specificity of clinical effects of probiotic bacteria and suggests that the immune changes identified in cord blood and breast milk samples in that study may not be sufficient to prevent eczema.
Thus, other mechanistic pathways need to be explored.
A fourth finding that is difficult to explain is the discrepant results of the studies by Kopp et al. and Kalliomaki et al. The two trials used a similar interven- tions of prenatal and postnatal LGG treatment for eczema prevention. The reasons for the discrepancy between the Kalliomaki and Kopp studies are not understood;
however, genetic or dietary differences in the study populations may have contributed to these discrepant outcomes. It has been reported that gene polymorphisms in innate receptors may modify immune responses following signaling through these receptors. For example, CD14/-1721 polymorphisms can modulate the protective effects of farm milk ingestion on the development of eczema (Bieli et al. 2007).
It is therefore possible that the discrepant outcomes of these two studies relate to genetic differences in the study populations. It is likely that the ability of micro- bial exposures (including probiotics and prebiotics) to modulate immune responses and protect against the development of allergic disease is influenced by individual genetic factors.
In summary, current studies suggest a potential role for probiotics or synbiot- ics in the prevention of eczema and/or IgE-associated eczema. Our meta-analy- ses (Fig. 8.2) suggest that probiotics/synbiotics are an effective intervention in this regard, particularly if treatment is administered both prenatally and postna- tally. However, the very different nature of the interventions used in each trial published to date, combined with the inconsistent results of studies using the same intervention, make it difficult to translate these promising studies into a public health recommendation. Further work is needed to understand precisely which probiotic/synbiotic(s) are most effective for preventing eczema, in what way they should be given, and to gain a better understanding of the mechanism of action.
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