Key Points
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The rise in food allergy is more rapid than genetic deviation would allow and the current consensus is that environmental factors integrally linked to the ‘modern lifestyle’ are likely to be key drivers of this phenomenon. The concept that these factors might be potentially modifiable is supported by studies demonstrating that food allergy is more common in developed than developing countries, and migrants appear to acquire the incident risk of allergy of their adopted country.
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There is emerging evidence that the early immunomodulatory effects of microbial exposure (including through indoor pet ownership and siblings) and nutritional patterns (including breast or formula feeding, exposure to allergenic solids and specific nutrient optimization such as vitamin D) are both important determinants of the risk of early-onset inflammatory diseases such as allergic disease, including food allergy.
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At present there is no clear evidence that prebiotics, probiotics or synbiotics prevent food allergy and mixed evidence regarding hydrolyzed formula. Although ‘breast is best,’ there are insufficient data currently to support the hypothesis that breastfeeding is protective.
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Food allergy is most commonly acquired during the first year of life, with peak incidence of 5% to 10% occurring at 1 year of age. The prevalence falls until late childhood, where it plateaus at about 3.5% through adulthood.
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Whereas milk and egg allergies are most frequently outgrown in childhood, peanut allergy most commonly remains a lifelong issue. Tree nut, fish and shellfish allergy are also much more likely to continue into adulthood than are egg and cow’s milk allergy.
Introduction
Allergic diseases have become the most common chronic diseases of childhood as part of a shifting profile of disease in modern societies. Even more recently, an epidemic of food allergy has emerged, particularly in the last 10 to 15 years. For good reason, we have described this as the ‘second wave’ of the allergy epidemic. This phenomenon appears to still be evolving in many regions, and it is still unclear why it has occurred decades after the ‘first wave’ of asthma and respiratory allergy reached a peak in industrialized countries.
There is concern that this growing early predisposition for the allergic phenotype may portend a greater burden of later-onset allergic diseases such as asthma and allergic rhinitis, and contribute to an escalating burden of inflammatory disease in this new generation. The parallel increase in many other immune diseases and inflammatory noncommunicable diseases (NCDs) strongly suggests broader immunologic effects of modern risk factors on human health. In this context, allergy may be regarded as the most common and earliest manifestation of the vulnerability of the immune system to modern environmental change. Strategies to improve early ‘immune health’ may therefore not only prevent allergic disease but also ultimately reduce the burden of other inflammatory diseases.
Because the rise in food allergy is more rapid than genetic deviation would allow, the current consensus is that environmental factors integrally linked to the ‘modern lifestyle’ are likely to be key drivers of this phenomenon. The concept that these factors might be potentially modifiable is supported by studies demonstrating that food allergy is more common in developed than developing countries, and migrants appear to acquire the incident risk of allergy of their adopted country.
Factors associated with a ‘modern lifestyle’ include a myriad of changes to our level of public health including improved sanitation, secure water supplies (with associated decreased prevalence of Helicobacter pylori infection), widespread use of antibiotics and increasing rates of immunization, improved nutrition, decreased helminthic infestation, improved food quality (and presumably less microbial load in the food chain) as well as generally improved nutrition and associated obesity. These factors might work individually or in concert to effect a failure in the development of oral immune tolerance in the first year of life when development of IgE-mediated food allergy is most likely to occur. In addition there is likely to be at least some component of gene-environment interaction. That is to say, lifestyle factors may have a differential effect depending on genetic status of the individual.
The Importance and Timing of Early Intervention
This new epidemic of food allergy is most striking in preschool children, particularly in the first year of life. In high-income countries such as Australia, more than 20% of 1-year-old infants now have evidence of food sensitization and more than 10% now have challenge-proven IgE-mediated food allergy. However it is not yet clear whether intervention measures need to be targeted prenatally or will be equally effective if administered postnatally. There is certainly evidence that an atopic predisposition has declared itself by the time of birth in at least some infants although, since food allergy phenotypes cannot be declared until postnatally, it is difficult to tease out whether interventions may still be effective in the postnatal period.
Antenatal Intervention
During pregnancy, there is close immunologic interaction between the mother and her offspring providing enormous opportunities to influence fetal immune development. The placenta and the fetus are vulnerable to a wide range of exogenous and endogenous maternal influences. Contrary to traditional concepts, human fetal T cells are responsive as early as 22 weeks’ gestation. We have shown emergent differences in immune function at birth in newborns destined to develop allergy indicating that ‘the scene is set’ to some extent by birth. This highlights the importance of considering a broad range of immunomodulatory factors that may begin to have their effects much earlier in pregnancy than previously suspected. Notably, most of the environmental factors implicated in the development of allergic disease (including microbial exposure, dietary factors, cigarette smoke and other pollutants) have been shown to influence fetal immune function and contribute to an increased risk of subsequent allergic disease (reviewed in references 9 and 10). Moreover, there is also preliminary evidence that each of these has been associated with epigenetic effects, including activation or silencing of immune-related genes through epigenetic modifications.
Postnatal Intervention
The early postnatal period also appears to be a critical period in the development of oral tolerance. Events in the gastrointestinal tract are vitally important for normal immune maturation. After birth we encounter a vast array of new antigenic proteins in relatively high ‘doses’. Most of this foreign antigenic load is derived from colonizing commensal bacteria and food components. We have to learn very quickly to distinguish ‘friend’ from ‘foe’ on a large scale. To prevent inflammatory responses to largely harmless antigens, the gastrointestinal associated lymphoid tissue (GALT) has evolved complex mechanisms to promote tolerance as a default response (reviewed in reference 11). The human intestines harbor between 10 and 100 trillion resident microbiota, and this vast and complex ecosystem forms gradually over the first years of life. The collective genetic material of these bacteria (called the ‘microbiome’) is estimated to contain 150 times more genes than our human genome. Through co-evolution and established ‘mutualism’ the microbiota play an essential role in homeostasis of multiple interconnected host metabolic and immune functions.
The success of oral tolerance appears to depend on a number of oral exposures. Although the best known of these is breast milk, ‘optimal’ microbial diversity (still an ill-defined concept) and other dietary immunomodulatory factors including prebiotics (soluble fiber), fat soluble vitamins (including vitamin D) and polyunsaturated fatty acids (PUFAs) may all have important antiinflammatory effects (reviewed in reference 14). There is also some evidence to suggest that both the gastric acid milieu and a possible ‘window of opportunity’ of optimal allergenic solids introduction between 4 and 6 months of age are potential factors for oral tolerance development (see below).
Immunomodulatory Strategies
There is now emerging evidence that the early immunomodulatory effects of microbial exposure (including through indoor pet ownership and siblings ) and nutritional patterns (including breast or formula feeding, exposure to allergenic solids and specific nutrient optimization such as vitamin D) are both important determinants of the risk of early-onset inflammatory diseases such as allergic disease, including food allergy, although the interplay between these two sets of risk factors has not been formally evaluated.
Infant Feeding
Breast Milk
It is universally agreed that human milk should be the first and most important source of nutrition for the infant. It contains a vast array of bioactive factors including hormones, growth factors, neuropeptides and antiinflammatory and immunomodulatory agents that influence many physiologic systems and promote normal gut colonization for both short-term and long-term benefits.
Allergens are normally secreted in breast milk and appear to be an important early source of exposure. This may actually be important in initiating, maintaining and reinforcing normal tolerance to foods and even inhaled allergens. While this has been demonstrated in animals, human evidence is more limited because randomized controlled trials are not possible. Systematic analysis of observational studies on the protective effect of breastfeeding has shown conflicting results, and many of the studies included were conducted decades ago when food allergy was uncommon and methods of assessment were limited. An early review by Muraro et al including 15 observational and 14 interventional studies concluded that breastfeeding for at least 4 months was associated with a reduced cumulative risk of cow’s milk allergy in high-risk infants over 18 months of age. None of these studies was either randomized or prospective, and most systematic reviews since have failed to find a specific beneficial effect on food allergy. Several cohort studies suggested that extended exclusive breastfeeding may increase the likelihood of sensitization or food allergy in infants at high risk (reviewed in reference 28). This may relate to the timing of first complementary foods rather than the effects of breast milk per se (below). In this regard there is some, albeit limited, evidence that continued breastfeeding during the period when complementary foods are initiated may promote tolerance and have protective effects. Even so, many expert bodies recommend that breastfeeding should continue while solids are introduced into the diet although strong scientific evidence that it plays a role in the prevention of allergic disease is both lacking and unlikely to be available due to the unethical aspects of randomization trials that would need to include a ‘no breastfeeding’ arm.
Formula Feeding
There has been significant interest in the use of modified infant formulas – especially partially (PHF) and extensively hydrolyzed cow’s milk formula (EHF) – for prevention of early childhood allergic disease. Intense expectations from families with a history of allergy seeking readily available primary prevention interventions have been responded to by industry with the development of a range of ‘allergy prevention’ formulae. Furthermore expert bodies have felt the need to provide recommendations regarding the use of formula for prevention of allergies. Current infant feeding guidelines in Europe, the USA and Australia all recommend that hydrolyzed formula can be considered as primary prevention therapy for allergic diseases. These guidelines have been informed by the Cochrane review, the last update of which occurred in 2009. This review supports the use of hydrolyzed formula for the prevention of allergy especially in high-risk infants who are unable to be completely breastfed although the authors themselves recommend further larger trials because of the methodological concerns and inconsistency of the findings of the studies included in the review. It should be noted that the findings of this review are heavily influenced by the reported benefits of PHF during the first six years of life demonstrated by the largest study of the review, the German Infant Nutritional Intervention (GINI) study. We have recently demonstrated that the Cochrane review suffers from small-study publication bias (scarcity of small negative studies), and thus is likely to have overestimated the beneficial effect of PHF. Since the last update of this review, new evidence from a large intervention trial of high-risk infants (the Melbourne Atopic Cohort Study; MACS) has emerged challenging the effectiveness of PHF. Additionally, while the GINI study outcomes up until the 6-year follow-up were promising, subsequent results have shown little evidence of an ongoing preventive effect between the ages of 7 and 10 years. These more recent findings have also not yet been incorporated into the Cochrane review. GINI and MACS are the two largest trials conducted to evaluate the effectiveness of PHF and both were industry supported through the provision of formulae. Interestingly, although there is significant debate around the role of PHF for the prevention of allergic disease, both show similar results when the findings of the intention to treat analysis (ITT) are compared. Although both have substantial strengths, each has limitations. As it would be unethical to mandate one type of feeding – breastfeeding exclusively or fully over complementary formula feeding – it is not surprising that both studies are complicated by the impact of parental choice during the feeding intervention. Irrespective of the strengths and limitations of each study, even in the best case scenario, the number of high-risk children who would need to be fed with partially hydrolyzed formula to prevent one child from developing allergic disease in the first year of life is as high as 80 provided infant feeding patterns in GINI were replicated.
It is interesting that most recent recommendations from GINI suggest that casein-predominant EHF might be expected to have a more profound biologic effect because the formula is more extensively modified. However most guidelines’ recommendations are based on the fact that PHF is both cheaper and more palatable than EHF and therefore should be considered in place of EHF. Certainly in some countries EHF can only be medically prescribed, which significantly increases costs to the healthcare system. Added to the fact that a large number of infants would require treatment for a beneficial effect, the data suggest that recommendation of modified formula as a prevention measure for allergic disease may be premature.
Timing of First Solids
Infant diet has long been thought to affect the risk of developing food allergies. In the 1960s infants were typically given solid foods in the first 3 months of life, but the 1970s saw the introduction of guidelines recommending delayed introduction of solids until after 4 months of age because of a perceived link between early introduction of gluten and celiac disease. By the late 1990s, expert bodies had begun to recommend delaying solids until after 6 months of age, with further delay in the introduction of allergenic foods such as egg and nuts until at least 2 years of age recommended for infants with a family history of allergy. This did not, however, appear to have the desired effect of reducing the prevalence of food allergy and in 2008 lack of evidence of a protective effect led to the removal of advice to delay the introduction of any foods beyond 4 to 6 months of age with current guidelines outlined below.
A systematic review of the relationship between early introduction of solid foods, defined as introduction before 4 months of age, and allergy, conducted in 2005, identified only one cohort study investigating the relationship between early introduction of solids and food allergy. The one included study, a birth cohort of 135 infants with atopic parents, found that early introduction of solid foods was associated with an increased risk of having reported symptoms of food allergy by 1 year of age. However, no difference was seen in food challenge confirmed allergy and there was also no difference in allergy to milk, egg or wheat, diagnosed by history and skin prick test, at 5 years of age.
In a recent large observational cohort study in Melbourne, Australia, we found no relationship between timing of introduction of solid foods and challenge-confirmed egg allergy at 1 year of age. Solid foods in this cohort were predominantly introduced between 4 and 6 months of age, with only 4% introducing solids before age 4 months and 5% after 6 months, thus an effect of very early or late introduction of solids cannot be ruled out.
Exposure to Allergenic Foods
Early intervention studies primarily investigated the impact of combined maternal and infant allergen avoidance on the prevalence of food sensitization and allergy among ‘high-risk’ infants with a family history of allergy. Not surprisingly, the initial reports from these studies showed lower rates of food sensitization and allergy in infants avoiding allergenic foods, indicating that allergic symptoms did not develop in the absence of exposure to these foods. However, protection did not appear to be maintained after the introduction of allergenic foods into the diet. Later follow-up of the study population in early childhood showed no reduction in the prevalence of food sensitization and allergy among those with early allergen avoidance, suggesting that these strategies were ineffective in promoting the development of tolerance.
More recently, large observational studies have attempted to untangle the impact of timing of introduction of specific foods (such as peanut, egg or cow’s milk) and development of allergy to those foods. The relationship between age at introduction of cow’s milk products and cow’s milk sensitization at age 2 was investigated in the Dutch birth cohort study described previously. Although there was a trend for a decreased risk of sensitization with delayed introduction of cow’s milk, this did not reach statistical significance. This analysis was also limited by the low percentage of the cohort for which sensitization data were available and by the lack of a clinically relevant outcome (symptomatic cow’s milk allergy). A study of 12,234 newborn infants in Israel with 0.5% prevalence of IgE-mediated cow’s milk allergy found that infants exposed to cow’s milk in the first 14 days of life were less likely to be cow’s milk allergic compared to those first exposed to cow’s milk after 14 days, although this was not controlled for family history of cow’s milk allergy.
Two birth cohort studies designed to investigate risk factors for type 1 diabetes investigated the relationship between timing of food introduction and food sensitization or allergy. Both studies contained only infants with a family history or personal genetic risk of diabetes. Poole and colleagues found that introduction of wheat after 6 months of age was associated with an increased risk of parent-reported wheat allergy. This finding was based on 16 children with parent-reported wheat allergy, only four of whom had detectable levels of wheat-specific IgE on blood testing. The authors also failed to control for a history of eczema in the child, which is likely to be associated with both dietary modifications and an increased risk of food sensitization. The second study found that introduction of egg after 10.5 months was associated with an increased risk of sensitization to egg at age 5. The relevance of this finding is questionable as neither history of early allergic symptoms in the child nor family history of food allergy or eczema were considered in the analysis, both of which are likely to be important confounders. A recent Turkish study of 1015 infants found no association between age at introduction of egg and egg sensitization, however the study was relatively underpowered with only 19 egg sensitized infants and, as for the above studies, did not use objectively confirmed food allergy as the outcome.
A landmark study by Du Toit et al compared the prevalence of peanut allergy among Jewish school children in Israel and the UK. Although the study found that Israel had a lower prevalence of peanut allergy in school aged children and that in general peanuts were introduced earlier into the diet of infants in that country compared to the UK, the study design did not allow a direct link between age at first peanut consumption and peanut allergy on the individual level. Furthermore, the study was unable to eliminate other environmental factors as the cause of the differing prevalence of peanut allergy, a possibility that is consistent with the study finding a higher prevalence of other food allergies such as egg, tree nut and cow’s milk allergy in the UK as well as a difference in prevalence of eczema, a co-associated condition. Interestingly, although there was a higher prevalence of egg allergy in the UK, this was not accompanied by a statistically significant difference in age at introduction of egg.
By contrast, the Healthnuts study in Australia found that, compared with introduction at 4 to 6 months, introducing egg into the diet later was associated with higher rates of egg allergy (adjusted odds ratio 3.4 [95% CI 1.8 to 6.5] for introduction after 12 months). Most interestingly, introduction of cooked egg such as scrambled, baked or fried was more protective than simply introducing egg in baked goods, with those who had been introduced to cooked egg at 4 to 6 months being five times less likely to develop egg allergy than those waiting until the normally recommended time of 10 to 12 months of age, even after adjusting for confounding factors. There was no protective effect among infants who were first introduced to baked egg in their diet between 4 and 6 months, presumably because a lower dose exposure does not provide protection. No other factors such as maternal food allergen avoidance or prolonged breastfeeding were associated with altered risk of egg allergy after adjusting for confounders.
Together these studies provide reasonable evidence that delaying the introduction of solids in general or allergenic solids in particular is unlikely to reduce the risk of food allergy and may even paradoxically increase the risk. This is reflected in current guidelines in Australia, Europe and the USA, which no longer provide any recommendations on the best time to introduce these foods, citing a lack of evidence base for the prevention of food allergy.
The most recent American Academy of Pediatrics guidelines ( Table 43-1 ) state that there is insufficient evidence to recommend maternal dietary restrictions during pregnancy or breastfeeding. For infants at high risk of atopic disease, there is some evidence that exclusive breastfeeding for at least 4 months is protective against cow milk allergy in the first 2 years of life. However, there is no evidence that delaying the introduction of solids, including allergenic foods, until after 4 to 6 months is protective.
| Interventions | Summary |
|---|---|
| Pregnancy diet | No evidence of effectiveness |
| Lactation diet | Maternal antigen avoidance does not prevent atopic disease with the possible exception of atopic dermatitis. More data needed |
| Breastfeeding | Evidence exists that exclusive breastfeeding for at least 4 months vs feeding with cow’s milk formula decreases cumulative incidence of atopic dermatitis and cow’s milk allergy in the first 2 years of life Evidence exists that exclusive breastfeeding for at least 3 months protects against wheezing in early life, but there is not convincing evidence that exclusive breastfeeding in high-risk infants protects against allergic asthma beyond 6 years of age |
| Soy formula | No convincing evidence exists for the use of soy formula for allergy prevention |
| Protein hydrolyzate formula | Mixed evidence exists that atopic dermatitis may be delayed or prevented by the use of an extensively or partially hydrolyzed formula as compared to cow’s milk formula in high-risk infants who are not breastfed exclusively for 4 to 6 months although more recent studies suggest a null effect. Not all hydrolyzed formulas have the same protective benefit. Cost must be considered in any decision-making process |
| Delayed introduction of solid foods | No convincing current evidence exists that delaying the introduction of solid food, including fish, egg and peanut, beyond 4 to 6 months protects against the development of allergic disease. There is emerging evidence that introduction of solids between 4 and 6 months may even be protective |
Restoring More Traditional PUFA Status
Declining consumption of antiinflammatory n-3 polyunsaturated fatty acids (PUFA) has been another significant dietary change with increasing urbanization. This has been replaced by increasing intakes of proinflammatory saturated fat and synthetic and n-6 PUFA. In many western diets, the ratio of n-6 to n-3 fatty acids ranges from approximately 20 to 30 : 1 instead of the traditional range of 1 to 2 : 1. Changes in the diets of Australian women are also reflected in the changing content of breast milk, which has similarly shown falling n-3 PUFA content and increasing n-6 PUFA levels. This has led to falling intake of antiinflammatory n-3 PUFA in early life during the critical period of immune maturation.
Based on this, n-3 PUFA rich fish oils have been logical interventions for prevention and treatment of a number of inflammatory conditions. In one of the earliest randomized controlled trial (RCT) intervention studies for allergy prevention, we supplemented allergic women with fish oil from 20 weeks’ gestation and demonstrated a range of immunomodulatory effects in their neonates. We also saw preliminary evidence of reduced food (egg) sensitization and eczema severity at 1 year of age although food allergy itself was not assessed. In a much larger subsequent RCT in 706 pregnant women, we again observed that fish oil supplementation significantly reduced egg sensitization at 12 months of age in high-risk infants. Atopic eczema was also less common in the fish oil group. At the 3-year follow-up, eczema was still less common in the fish oil group although this was no longer statistically significant. These observed reductions may still be important given the cost and burden of allergic disease. In a separate study, we also examined the effects of early postnatal fish oil supplementation in high-risk infants ( N = 420) for the first 6 months of life. We observed that increased infant n-3 PUFA levels were associated with lowered allergen-specific Th2 responses and elevated polyclonal Th1 responses. Although n-3 PUFA levels at 6 months were associated with lower risk of eczema and recurrent wheeze, there was no effect of the intervention per se on the primary study outcomes.
The results from these and other n-3 long-chain PUFA supplementation RCTs suggest that the dose, timing and duration of n-3 long-chain PUFA supplementation may influence sensitization and allergic disease outcomes. It has been proposed that a combination of measures to ensure more traditional PUFA status throughout the pre- and postnatal period, during important periods of immune development and maturation, may be most efficacious. Notably, early interventions using fish oil for allergy prevention in early childhood have also shown benefits for metabolic programming, oxidative stress and reducing cardiovascular risk. Furthermore, in addition to immunomodulation and allergy reduction, we have also seen beneficial effects on aspects of neurodevelopment after both prenatal and early postnatal fish oil supplementation. In summary, restoring the higher n-3 PUFA levels seen in more traditional diets provides a clear example of an early immunomodulatory intervention with potential multisystem benefits.
Vitamin D
The recent hypothesis that low vitamin D may increase the risk of food allergy is supported by two lines of ecologic inquiry. First, there is a strong latitudinal prevalence gradient, with those countries further from the Equator (and thus lower ambient ultraviolet radiation) recording more admissions to hospital for food allergy-related events and more prescriptions for epinephrine autoinjectors for the treatment of anaphylaxis. These findings appear to be independent of longitude, physician density or socioeconomic status. Second, season of birth may play a role: children attending emergency departments in Boston with a food-related acute allergic reaction were more likely to be born in autumn/winter, when vitamin D levels reach their nadir, than in spring/summer and there are similar links to birth seasonality in the southern hemisphere.
We have recently confirmed that Melbourne, the most southern major city in Australia, has the highest reported prevalence of documented infantile food allergy in the world, with more than 10% of a population sample of 1-year-old infants having challenge-proven IgE-mediated food allergy. In a separate study, we have shown that, compared to the northern states, children residing in Australia’s southern states are six times more likely to have peanut allergy at age 6 years and twice as likely to have egg allergy than those in the northern states. We have also shown that the delayed introduction of egg, one of breastfed infants’ richest sources of vitamin D, increases the risk of developing egg allergy by age 12 months by at least 5-fold. Finally, increasing vitamin D insufficiency in Melbourne over the last 20 years, paralleling the rise in food allergy, is supported by our own data showing that 20% of pregnant women are vitamin D insufficient.
Using the Healthnuts population based study we found that infants of Australian-born parents, but not of parents born overseas, with vitamin D insufficiency (<50 nM/L) were more likely to be peanut (aOR 11.51, 95% CI 2.01, 65.79, P = .006) and/or egg (aOR 3.79, 95% CI 1.19, 12.08, P = .025) allergic than those with adequate vitamin D levels independent of eczema status. Among those with Australian-born parents, infants with vitamin D insufficiency were more likely to have multiple (≥2) than single food allergies (aOR 10.48, 95% CI 1.60, 68.61 vs aOR 1.82, 95% CI 0.38, 8.77 respectively).These results provide the first direct evidence that vitamin D sufficiency may be an important protective factor for food allergy in the first year of life.
Vitamin D could influence the onset and resolution of food allergy via several plausible mechanisms. The vitamin D receptor is widely expressed in the immune system including T cells, in particular promoting the expression of IL-10 secreting T regulatory cells crucial to maintaining immune tolerance and, potentially, playing a key role in the induction of tolerance in food allergic individuals. Vitamin D metabolites also contribute to innate epithelial defenses by stimulating production of antimicrobial proteins such as cathelicidins and defensins. Randomized controlled trials assessing the potential role of vitamin D in the prevention of food allergy are urgently needed.
Modulation of the Maternal and Infant Microbiome
Changes in the microbiota, induced by a range of modern environmental factors and dietary patterns, are implicated in the rising predisposition to a range of inflammatory and metabolic disorders. This underscores the likely importance of strategies that improve gut homeostasis and the microbiome as part of disease prevention strategies. A low-fiber, high-fat ‘western’ diet is associated with adverse changes in gut microbiome, altered gut barrier function, increased systemic endotoxin and low-grade Toll-like receptor (TLR)-mediated systemic inflammation with increased C-reactive protein (CRP), IL-1β, tumor necrosis factor (TNF) and IL-6. Animal models provide clear evidence that the gut microbiota modulate immune programming, and that manipulation of the microbiome can prevent not only allergic disease and autoimmune phenomena, but also the risk of obesity, cardiovascular and metabolic disease through well-described metabolic effects (reviewed in references 2 and 82).
Early microbial diversity, beginning in utero, is a major driving factor in the normal maturation of both Th1 and T reg function and suppressing the propensity for Th2 allergic responses in early childhood. Epidemiologic studies also indicate that a ‘high microbial environment’ during pregnancy affords greater protection from allergy than postnatal exposure alone. Thus, while continued postnatal microbial exposure is critical for immune maturation and allergy protection, the role of the antenatal period must not be overlooked or underestimated.
Contrary to long-standing assumptions, the womb is not ‘sterile’ after all. In normal healthy pregnancies, microbes can be detected in amniotic fluid, placental and fetal membranes, cord blood and meconium, providing a ‘pioneer’ microbiome. In murine studies, labeled bacteria are transferred from mother to fetus during pregnancy. It is increasingly clear that the maternal microbial environment during pregnancy is also important in early immune programming, providing an initial antenatal source of immunostimulation.
So far, most allergy prevention studies aimed at improving early colonization have focused on improving postnatal colonization in the infant, rather than on influencing immune development during fetal life. The first attempts to increase gut microbial diversity for allergy prevention were with probiotic supplements. Although some of these studies used probiotics in pregnancy, most only used probiotics the last 2 to 4 weeks of gestation with the dominant goal of influencing infant colonization in the postnatal period. The only RCT ( N = 241) to use probiotics earlier than this for allergy prevention (but still for only 8 weeks in late pregnancy) significantly reduced infant eczema.
Collectively there have now been more than 20 studies to examine the effects of probiotics in allergy prevention. Although the findings have been variable, the most consistent finding has been protection from early allergic outcomes such as eczema (reviewed in references 83 and 97). Several meta-analyses have now been performed, each generally concluding that probiotics reduce the risk of eczema but have no consistent effects on food allergy or other allergic outcomes. The most recent meta-analysis included 13 prevention studies and found that probiotic treatment reduced the incidence of eczema by 21% (RR 0.79, 95% CI 0.71–0.88). This effect was still evident when the analysis was restricted to patients with IgE-associated eczema (RR 0.80, 95% CI 0.66–0.96).
We speculate that, given the likely role of the maternal microbiome in pregnancy for both immune and metabolic homeostasis, it is logical to investigate the effects of the combination of pre- and probiotics (synbiotics) much earlier in pregnancy, at a time when fetal responses are first initiated. Providing some support for this, a recent large-scale observational study of 40,614 Norwegian mother-child pairs found that probiotic milk consumption in pregnancy (assessed at 22 weeks’ gestation) was associated with a reduced incidence of atopic eczema and allergic rhinoconjunctivitis at 3 years of age. To our knowledge the only RCT ( N = 256) to use probiotics from the first trimester did not assess immune effects or allergic outcomes but reported a number of metabolic benefits for both the mother and the fetus. Even in the final weeks of pregnancy, probiotics have been shown to significantly alter expression of innate TLR-related genes in the placenta and in the fetal gut. We have also shown changes in cord blood serum cytokines.
There is now growing interest in using ‘prebiotic’ fiber to promote favorable colonization and reduce inflammation. In humans, prebiotic fiber selectively stimulates growth of beneficial gut microbiota, particularly bifidobacteria but also lactobacilli, in a dose dependent manner. Prebiotic fermentation products, short-chain fatty acids (SCFA), have direct antiinflammatory effects. This promotes intestinal integrity and reduces systemic endotoxin and antigenic load in experimental models. Acetate, butyrate and propionate are among the most abundant SCFA and play a critical role in local and systemic metabolic function and stimulating regulatory immune responses. Accordingly, human randomized controlled trials using prebiotics have shown some beneficial effects on the microbiome and immune function with reduced systemic inflammation, and metabolic dysregulation.
There are now several studies in the postnatal period showing beneficial effects on early colonization and a reduction of eczema with prebiotic supplementation although effects on the prevention of food allergy have been disappointing, which is somewhat surprising since eczema and food allergy so frequently co-associate in the first year of life. The first major study to investigate the effect of prebiotics on allergy prevention used a mixture of galactooligosaccharide/fructoologosaccharide prebiotics during the first 6 months of life in formula-fed infants at high risk of atopy. At 6 months of age the rate of eczema was significantly lower in the treatment group (9.8%; 95% CI 5.4–17.1%) compared with the placebo group (23.1%; 95% CI 16.0–32.1%). By 2 years of age, the cumulative incidence of eczema, recurrent wheeze and allergic urticaria were all significantly lower in the treatment group compared with the control group, although the follow-up was limited to approximately half of the original population. In a similar study of formula-fed infants at low risk of allergy, there was also a significant reduction in eczema in those randomized to a formula containing prebiotics (neutral oligosaccharides and pectin-derived acidic oligosaccharides) compared with regular formula. The results of other studies are awaited before recommendations can be considered.
Studies of prebiotic oligosaccharides in pregnancy are also still limited. In animal models, prebiotics in pregnancy alter colonization and metabolic homeostasis and reduce eczema-like inflammation in offspring. Observational studies in human pregnancy show that high-fiber diets are associated with a reduced risk of pre-eclampsia and dyslipidemia. To our knowledge, the only RCT to use prebiotics in pregnancy was too small ( N = 48) to reliably assess immune effects on the fetus or clinical effects, but did achieve favorable changes in maternal gut microbiota. This highlights the need for human studies of prebiotics in pregnancy.
While the use of a prebiotic alone may be effective, the combination with bifidobacteria and lactobacilli probiotics is a logical strategy to assist in favorable diversity, already showing some benefit in the postnatal period. Prebiotics promote microbial diversity by stimulating the growth of commensals. Prebiotics also provide the substrate for antiinflammatory short-chain fatty acid production by bacteria. This is likely to have more global effects on gut homeostasis than only adding one or two probiotic strains into the vast and complex ecosystem of the gut.
In summary, at present there is no clear evidence that prebiotics, probiotics or synbiotics prevent food allergy.
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