Understanding Probiotics and Prebiotics to Prevent Allergic Disease
Understanding Probiotics and Prebiotics to Prevent Allergic Disease
Overall, with regard to the use of probiotics and/or prebiotics for allergy prevention, there are studies that demonstrate a protective effect or no effect. Some, at least for the secondary outcomes, show even a predisposing effect. In addition to genes and environmental factors, a variety of methodological issues are likely to contribute to these inconsistent results that are briefly discussed below.
Similar to other allergy prevention studies, almost all of the trials were carried out in populations at high risk of allergy, typically defined as the presence of at least one parent or sibling affected by an allergic disease. Thus, the results, whether positive or negative, may be applicable only to such a population. Only a few studies that examined the effect of probiotics on allergy were carried out in unselected birth cohorts with regard to allergy risk ( Table 2 & Table 3 ).
All probiotics are not equal. The efficacy and safety of each probiotic microorganism has to be studied separately, as they have different effects. This has been clearly documented in a double-blind RCT (n = 474) by Wickens et al.. The supplementation of both the pregnant mothers and infants with L. rhamnosus HN001, but not with Bifidobacterium animalislactis HN019, reduced the cumulative prevalence of eczema at 2 years by 50%. The protective effect of L. rhamnosus HN001 against eczema, when given for the first 2 years of life only, extended to 4 years of age (90% follow-up). Thus, the clinical effects of any single probiotic or combination of probiotics should not be extrapolated to other probiotics. Likewise, not all prebiotics or synbiotics are equal. The efficacy (and safety) should be established for each product.
Ideally, the diagnosis of allergic diseases should be based on widely agreed-upon criteria. However, in most of the included studies, heterogeneous definitions made direct comparisons between the studies difficult. The single most studied outcome was atopic dermatitis. Only in some trials was the severity of atopic dermatitis assessed. This is despite the fact that it has been recommended that scoring of eczema severity should be reported, as it allows differentiating mild cases from more severe disease.
In a number of studies, in addition to clinically relevant outcomes, skin prick tests or specific IgE blood levels have been assessed. A positive test result is indicative of allergic sensitization, but does not necessarily represent a clinically relevant allergy. Studies by Kalliomäki et al. documented that in offspring at risk for atopic disease, Lactobacillus GG (LGG) given pre- and post-natally reduced the risk of atopic eczema by half a at up to 7 years of age; however, there was no reduction in atopic sensitization. The latter finding suggests that it might be worthwhile to study nonatopic individuals.
Different prevention regimens, particularly with regard to the administration of probiotics, have been studied, including:
The optimal dose and treatment duration of pre-/pro-biotic administration have not been clearly established. The lack of benefit in some of the studies may be due to an insufficient dose and/or duration of the intervention.
Only a very limited number of pre-/pro-biotics have been assessed in more than one study. One such an example is LGG. The results from studies by Kalliomäki et al. and by Kopp et al. that assessed the effect of LGG use for the primary prevention of atopic dermatitis, which were carried out based on almost identical protocols, demonstrate the importance of such repeat studies.
Kalliomäki et al. randomized 159 pregnant women who had atopic disease, who had ≥1 first-degree relative (e.g., mother, father or older sibling) with atopy, or who had a partner with atopy. Mothers were allocated to receive LGG (10 CFU) or placebo for 2–4 weeks before delivery. After delivery, either breastfed infants or the remaining infants received the allocated intervention for 6 months. Compared with the placebo group, in the LGG group there was significant reduction in infant eczema at the ages of 2 years (RR: 0.51; 95% CI: 0.32–0.84), 4 years (RR: 0.57; 95% CI: 0.33–0.97), and 7 years (RR: 0.64; 95% CI: 0.45–0.92). There was no significant difference between groups in the prevalence of asthma in childhood (RR: 3; 95% CI: 0.3–28) or in the prevalence of allergic rhinitis (RR: 2; 95% CI: 0.75–5.6).
In a double-blind RCT involving 105 mother–infant pairs, Kopp et al. randomized 105 pregnant women from families with ≥1 member with atopic dermatitis to receive LGG or placebo both pre- and post-natally. The infants also received LGG or placebo after birth. Kopp et al. found a similar risk of atopic dermatitis in children aged 2 years in the LGG and the placebo groups (RR: 0.96; 95% CI: 0.38–2.33). Notably, children with ≥5 episodes of wheezing bronchitis were more common in the LGG group than in the placebo group.
Thus, whereas Kalliomäki et al. reported that LGG use exerts a preventive effect on the development of atopic eczema, Kopp et al. observed no effect of LGG use on the prevention of atopic dermatitis.
Taken together, these studies underscore the importance of repeat studies. There are various factors that discourage simple repetition (duplication) of trials that could clarify the effect of a given probiotic. These factors include a lack of scientific novelty and/or a lack of interest by potential sponsors in cases involving the administration of a commercially available pre-/pro-biotic product that has been proven effective in a single study. Still, as a rule, repeat studies are needed, as a single study is, rightly, never sufficient to change clinical practice.
In summary, the methodological problems in the available studies (and the lack of a universally accepted mechanism regarding how pre-/pro-biotics work) contribute to the current uncertainty.
Methodological Issues
Overall, with regard to the use of probiotics and/or prebiotics for allergy prevention, there are studies that demonstrate a protective effect or no effect. Some, at least for the secondary outcomes, show even a predisposing effect. In addition to genes and environmental factors, a variety of methodological issues are likely to contribute to these inconsistent results that are briefly discussed below.
Population
Similar to other allergy prevention studies, almost all of the trials were carried out in populations at high risk of allergy, typically defined as the presence of at least one parent or sibling affected by an allergic disease. Thus, the results, whether positive or negative, may be applicable only to such a population. Only a few studies that examined the effect of probiotics on allergy were carried out in unselected birth cohorts with regard to allergy risk ( Table 2 & Table 3 ).
Intervention
All probiotics are not equal. The efficacy and safety of each probiotic microorganism has to be studied separately, as they have different effects. This has been clearly documented in a double-blind RCT (n = 474) by Wickens et al.. The supplementation of both the pregnant mothers and infants with L. rhamnosus HN001, but not with Bifidobacterium animalislactis HN019, reduced the cumulative prevalence of eczema at 2 years by 50%. The protective effect of L. rhamnosus HN001 against eczema, when given for the first 2 years of life only, extended to 4 years of age (90% follow-up). Thus, the clinical effects of any single probiotic or combination of probiotics should not be extrapolated to other probiotics. Likewise, not all prebiotics or synbiotics are equal. The efficacy (and safety) should be established for each product.
Outcomes
Ideally, the diagnosis of allergic diseases should be based on widely agreed-upon criteria. However, in most of the included studies, heterogeneous definitions made direct comparisons between the studies difficult. The single most studied outcome was atopic dermatitis. Only in some trials was the severity of atopic dermatitis assessed. This is despite the fact that it has been recommended that scoring of eczema severity should be reported, as it allows differentiating mild cases from more severe disease.
In a number of studies, in addition to clinically relevant outcomes, skin prick tests or specific IgE blood levels have been assessed. A positive test result is indicative of allergic sensitization, but does not necessarily represent a clinically relevant allergy. Studies by Kalliomäki et al. documented that in offspring at risk for atopic disease, Lactobacillus GG (LGG) given pre- and post-natally reduced the risk of atopic eczema by half a at up to 7 years of age; however, there was no reduction in atopic sensitization. The latter finding suggests that it might be worthwhile to study nonatopic individuals.
Timing & Duration of Administration
Different prevention regimens, particularly with regard to the administration of probiotics, have been studied, including:
Prenatal (during pregnancy) and postnatal (to lactating mothers or directly to infants; most of the studies). While the results are inconsistent, overall they suggest that combined pre- and post-natal administration may be crucial for the preventive effect of probiotics;
Prenatal administration to pregnant women only (up until delivery). It has been shown that maternal supplementation with probiotics may influence the composition of the infant's gut microbiota and increase anti-inflammatory and immunoregulatory factors in breast milk and cord blood. However, in one RCT conducted in 250 pregnant women carrying infants at high risk of allergic disease, the authors found that administration prenatally of LGG only from 36 weeks of gestation until delivery did not reduce the risk of eczema in children at 1 year of age (RR: 0.88; 95% CI: 0.63–1.22) or IgE-associated eczema (RR: 0.94; 95% CI: 0.53–1.68);
Postnatal administration only (to breastfeeding mother or nonbreastfed infant). While the majority of the studies focused on prenatal and/or early postnatal administration, the results of a trial carried out in Sweden suggest that administration initiated at weaning may be sufficient. This RCT conducted in 171 unselected infants found that compared with placebo, administration of Lactobacillus F19 in complementary food from 4 to 13 months of age reduced the cumulative incidence of eczema from 22 to 11% (p < 0.05). The authors proposed that the mechanism could be mediated by a higher Th1/Th2 ratio in infants receiving Lactobacillus F19.
Optimal Dose
The optimal dose and treatment duration of pre-/pro-biotic administration have not been clearly established. The lack of benefit in some of the studies may be due to an insufficient dose and/or duration of the intervention.
Importance of Repeat Studies
Only a very limited number of pre-/pro-biotics have been assessed in more than one study. One such an example is LGG. The results from studies by Kalliomäki et al. and by Kopp et al. that assessed the effect of LGG use for the primary prevention of atopic dermatitis, which were carried out based on almost identical protocols, demonstrate the importance of such repeat studies.
Kalliomäki et al. randomized 159 pregnant women who had atopic disease, who had ≥1 first-degree relative (e.g., mother, father or older sibling) with atopy, or who had a partner with atopy. Mothers were allocated to receive LGG (10 CFU) or placebo for 2–4 weeks before delivery. After delivery, either breastfed infants or the remaining infants received the allocated intervention for 6 months. Compared with the placebo group, in the LGG group there was significant reduction in infant eczema at the ages of 2 years (RR: 0.51; 95% CI: 0.32–0.84), 4 years (RR: 0.57; 95% CI: 0.33–0.97), and 7 years (RR: 0.64; 95% CI: 0.45–0.92). There was no significant difference between groups in the prevalence of asthma in childhood (RR: 3; 95% CI: 0.3–28) or in the prevalence of allergic rhinitis (RR: 2; 95% CI: 0.75–5.6).
In a double-blind RCT involving 105 mother–infant pairs, Kopp et al. randomized 105 pregnant women from families with ≥1 member with atopic dermatitis to receive LGG or placebo both pre- and post-natally. The infants also received LGG or placebo after birth. Kopp et al. found a similar risk of atopic dermatitis in children aged 2 years in the LGG and the placebo groups (RR: 0.96; 95% CI: 0.38–2.33). Notably, children with ≥5 episodes of wheezing bronchitis were more common in the LGG group than in the placebo group.
Thus, whereas Kalliomäki et al. reported that LGG use exerts a preventive effect on the development of atopic eczema, Kopp et al. observed no effect of LGG use on the prevention of atopic dermatitis.
Taken together, these studies underscore the importance of repeat studies. There are various factors that discourage simple repetition (duplication) of trials that could clarify the effect of a given probiotic. These factors include a lack of scientific novelty and/or a lack of interest by potential sponsors in cases involving the administration of a commercially available pre-/pro-biotic product that has been proven effective in a single study. Still, as a rule, repeat studies are needed, as a single study is, rightly, never sufficient to change clinical practice.
In summary, the methodological problems in the available studies (and the lack of a universally accepted mechanism regarding how pre-/pro-biotics work) contribute to the current uncertainty.