Journal of Pediatric Gastroenterology & Nutrition:
Immune Factors in Breast Milk and the Development of Atopic Disease
Iyengar, Shuba R.*; Walker, W.A.†
*Pediatric Allergy/Immunology Division
†Mucosal Immunology Laboratory, Pediatric Gastroenterology, Department of Pediatrics, Massachusetts General Hospital for Children, Department of Nutrition, Harvard Medical School, Boston, MA.
Address correspondence and reprint requests to Shuba R. Iyengar, MD, MPH, Department of Pediatrics, Pediatric Allergy/Immunology and Pulmonary, 175 Cambridge St, 5th Floor, Boston, MA 02141 (e-mail: email@example.com).
Received 26 September, 2011
Accepted 23 May, 2012
W.A.W. is a recipient of a research grant from Mead Johnson Nutrition and receives funding from the National Institutes of Health (Grants RO1-HD12437, R01-HD012437 P01-DK033506 and P30-DK040561; R01-HD059126). W.A.W. has acted as a scientific consultant to infant formula companies. S.R.I. reports no conflicts of interest.
ABSTRACT: Breast-feeding provides protection against infections and contains numerous factors that modulate and promote the development of the infant immune system. These factors include secretory IgA, antimicrobial proteins like CD14, cytokines, and fatty acids. Studies examining the role of breast-feeding in the development of allergic disease in infants demonstrate potentially protective as well as neutral or nonprotective effects, likely due to the heterogeneity in their study design. In this overview, we explore the potential role of immune factors in the breast milk, as well as selected probiotics, in the development of allergy.
The effect of breast-feeding on allergic immune development remains inconclusive. Some elements of breast milk are thought to protect the infant from developing allergic disease, such as eczema and asthma, whereas other factors are implicated in increasing allergic susceptibility. The reasons for this controversy lie in the complexity of the interaction between breast milk and the infant's intestinal environment and immune system.
Human breast milk contains a complex array of immune factors and can be viewed as the interface between the maternal and infant immune systems. It contains functional nutrients that help facilitate the microenvironment necessary for immune system development and gut maturation. Consistent with this idea, microscopic examination of fetal small intestine before birth reveals immature epithelium and sparse lymphoid cells. In contrast, examination of the same section of small intestine after the infant is born and has begun breast-feeding reveals proliferating, mature epithelium with enterocyte differentiation and abundant lymphoid tissue. In addition, breast milk composition evolves over time to help the infant adapt to the dynamic extrauterine environment (Fig. 1). For example, colostrum contains multiple trophic factors that aid in enterocyte proliferation when compared with mature human milk (1). In addition, the colostrum composition of preterm breast milk is different than that of term breast milk, with higher levels of epidermal growth factor (2). Therefore, the complex and dynamic nature of breast milk is thought to be in synchrony with the infant's changing needs and has important implications on immune system development. Alterations in this interaction between breast milk and the infant's immune system are thought to contribute to disease development. Therefore, the composition of immune components in the breast milk of lactating mothers is likely an important factor in whether breast-fed infants are protected against disease. For example, animal studies have demonstrated that the expression of P-glycoprotein, a broad-specificity transmembrane transporter on intestinal enterocytes, is induced by breast milk (and not formula exposure) and is protective against experimental colitis (3). Therefore, lack of specific breast milk components could predispose to intestinal inflammation. Additional human studies are needed to explore how individual differences in maternal breast milk composition could predispose to intestinal inflammatory conditions, such as allergic disease.
Secretory IgA (sIgA), an important component of breast milk, is altered in breast-feeding mothers with allergic disease. sIgA is an immunoglobulin present in both the infant gut and breast milk that is specifically directed against antigens in the mother's environment. Infants are unable to produce their own protective levels until almost 30 days after birth (Fig. 2) (4). Accordingly, sIgA is at its highest levels in breast milk during the colostral phase, when the infant needs this immune protein the most. Low levels of sIgA have been associated with an increased risk of cow's-milk allergy in infants (5). In addition, lower levels of sIgA were found in the colostrum of allergic mothers compared with nonallergic mothers (5). However, another study demonstrated that breast milk sIgA levels did not predict the development of allergic disease in the children up to 18 months of age (6). These differences demonstrate the complexity of the relationship between breast milk factors and the development of allergic disease as well as the heterogeneity in study design. It is likely that the simultaneous interaction of multiple breast milk factors is protective.
In addition to sIgA, infants in the early postpartum period also lack CD14, an immunoregulatory protein normally present in the mature intestine. Increased levels of CD14 are present in colostrum, but decline in the breast milk with the passage of time. CD14 is the soluble component of Toll-like receptor (TLR) 4 and plays an important role in innate immunity. It binds to lipopolysaccharides (LPSs) from Gram-negative bacteria and intestinal enterocytes, initiating a chain of events that alert the adaptive arm of the immune system. Therefore, its absence reduces the effective response of TLR4 to LPS. CD14 can be linked to allergic disease through the “hygiene hypothesis.” This well-known theory proposed more than 2 decades ago postulates that early exposure to LPS (or endotoxin) decreases the risk of developing allergic disease (7–10). CD14 may increase early exposure of the infant's immune system to LPS on Gram-negative bacteria, which normally reside in the neonatal intestine. Soluble CD14 levels were found to be lower in colostrum of mothers with infants developing atopic symptoms and IgE sensitization than in that of mothers of infants with no atopy at 4 years of age. In addition, it was found to be significantly reduced in human milk at 3 months postpartum in mothers whose infants developed eczema by 6 months of age (11).
Human milk contains an array of cytokines and chemokines, many of which are closely linked to the development of allergic disease. Th2 cytokines, like interleukin (IL) 4, IL-5, and IL-13, are involved in the production of IgE from B cells and are also elevated in the breast milk of allergic mothers (12). Tolerogenic cytokines, like transforming growth factor-beta (TGF-β) and IL-10, are involved in suppressing the inflammatory response and are the predominant breast milk cytokines. Studies from our group have demonstrated that TGF-β can attenuate the inflammatory response in fetal human enterocyte cell lines (13), a platform that recapitulates the infant gut response in vitro. A recent seminal study in a murine model found that aeroallergens can be efficiently transferred from mother to neonate through breast milk (14). Furthermore, these breast-fed progenies were protected from aeroallergen sensitization and reactive airways through TGF-β exposure in the breast milk.
Fatty Acids and Oligosaccharides
Another class of protective substances found in breast milk are polyunsaturated fatty acids and nondigestible oligosaccharides. Both stimulate the proliferation of colonizing bacteria necessary to activate the infant's immune system. Oligosaccharides pass through the small intestine and colon, and are fermented by colonizing bacteria. Short-chain fatty acids and other products are then generated and help create an acidic environment, which selectively stimulates beneficial bifidobacteria and not other bacterial strains. The fatty acid composition of the breast milk may determine whether breast milk promotes or protects against allergic disease. Human studies have demonstrated conflicting results regarding the development of atopy and breast milk fatty acid content (15). However, these studies have been limited by varied dietary and genetic backgrounds, infection, and other environmental influences. In addition, many studies do not take into account the complex interaction of different fatty acid subtypes, such as omega-3 and omega-6 fatty acids, on gut inflammation as well as their effect on the intestinal microbiome. For example, low intake of omega-3 fatty acids in fish oils enhances certain immune functions, whereas high intake inhibits a wide range of functions such as antigen presentation and proinflammatory cytokine production. Similarly, omega-6 fatty acids can exert divergent effects on immune function depending on their levels in the breast milk, which is largely a function of dietary intake (16). Milk oligosaccharides have also been shown to preferentially stimulate bifidobacteria (17). This colonizing bacterial strain, in the presence of specific milk oligosaccharides, produces factors that enhance T regulatory cell activity and promote interestinal tolerance (18).
Food allergens in cow's milk, such as B lactoglobulin, casein, and whey, can be transferred in the breast milk (19). These and other food allergens implicated in atopic disease, such as egg and peanut, can be detected in human breast milk 4 hours after maternal intake and remain in the milk for several days (20). Breast milk colitis, also called food protein–induced proctocolitis or cow's-milk protein allergy, is a poorly characterized immune reaction to a breast milk food protein (mainly milk proteins) and is the most common food allergy under 2 years of age (21). It causes blood-streaked stools in otherwise healthy infants and usually resolves after the mother is placed on a restricted diet. The pathophysiology of this condition, as well as how other food antigens found in breast milk lead to infant sensitization and allergic disease, has not been determined. However, it is possible that these foreign proteins, in the presence of proinflammatory cytokines and other immune factors, predispose infants to this condition. In contrast, it is likely that these same food proteins, in the presence of other milk factors such as TGF-β and IL-10, lead to mucosal tolerance. Additional studies are needed to elucidate the role of these breast milk factors in the development of either infant sensitization or infant tolerance. Studies investigating these breast milk constituents and the infant intestinal response in both outcomes will facilitate a better understanding of the impact of breast-feeding on infant allergic disease.
IMPACT OF BREAST-FEEDING ON THE DEVELOPMENT OF ATOPY
Multiple studies have attempted to evaluate the impact of breast-feeding on the development of allergic disease in infants and children, with and without an atopic family history. Although most experts maintain that the health benefits of breast-feeding far outweigh any possible negative impacts it may bear, there has been no clear consensus on its effects on allergic disease. Much of the reason for this centers around limitations in several key aspects of study design that have possibly confounded study outcomes. These include variability in the duration of breast-feeding, frequency of breast-feeding, use of supplemental formulas, recall of feeding practices, type of allergic disease being studied, and maternal atopic background. In addition, many studies have focused on sensitization to a particular antigen (ie, positive serum IgE or skin testing) rather than clinical disease. This is particularly problematic because numerous infants are sensitized to particular antigens, but do not develop clinical symptoms.
Therefore, in our review, we focus on studies of high-risk infants (usually a family history of atopy or high cord blood IgE), infants who were mostly or exclusively breast-fed, studies using clinical assessments of eczema or cow's-milk allergy as their outcome variable (and not sensitization), and studies with limited recall bias.
Studies Demonstrating That Breast-feeding Plays a Protective Role
Most experts agree that breast-feeding is the most effective and appropriate feeding method for infants, and that exclusive breast-feeding is effective in minimizing risk for development of allergic disease. The American Academy of Pediatrics stated that there was “evidence that exclusive breast-feeding for at least 4 months compared with feeding intact cow milk protein formula decreases the cumulative incidence of atopic dermatitis and cow milk allergy in the first 2 years of life” (22). This consensus statement is supported by several studies performed by the German Infant Nutritional Intervention (GINI) Program in which 1834 high-risk (for atopy) newborn infants identified were followed prospectively for 3 years (23). Breast-feeding infants were enrolled before 2 weeks of life and were exclusively breast-fed with no history of formula supplementation. Laubereau et al (24) examined 889 infants from the GINI cohort who were exclusively breast-fed for 4 months with an incidence of atopic dermatitis of 9.5% (vs 14.8% in infants supplemented with a cow's-milk–based formula) at the 1-year follow-up (Table 1). Kramer et al (25) followed 101 mother–infant pairs who were exclusively breast-fed for 3 months and found a significant reduction in atopic eczema at 1 year of age. Kerkhof et al (27) also observed a reduction in eczema in this age group as well, although it did not reach statistical significance. Therefore, breast-feeding for 4 months showed a protective effect in infants who were at high risk of developing allergic disease. However, in contrast, the observational arm of this study (in which infants were not at high risk of developing atopic disease) did not demonstrate differences in the incidence of atopic dermatitis.
More recent studies have also demonstrated a protective effect of breast-feeding, but this is again mainly in populations with a high risk of developing atopic disease. A recent meta-analysis by Yang et al (28) examined the association between exclusive breast-feeding for at least 3 months after birth and the development of atopic dermatitis in childhood and revealed that breast-feeding was associated with a decreased risk of atopic dermatitis (odds ratio 0.70; 95% confidence interval [CI] 0.50–0.99) when the analysis was restricted to the studies comparing breast-feeding with conventional formula feeding. In addition, breast-feeding was associated with a slightly lower risk of atopic dermatitis in cohorts with a positive family history of atopy compared with cohorts with a negative family history. Several years prior to this, Gdalevich et al (29) performed a meta-analysis of prospective studies between January 1966 and May 2000 on the association between exclusive breast-feeding in the first 3 months after birth and the onset of atopic dermatitis in childhood and concluded that breast-feeding was protective against incident atopic dermatitis in childhood. This protective effect was more pronounced in children with a family history of atopy. Benn et al (26) observed 15,430 mother–child pairs and found that exclusive breast-feeding for at least 4 months was associated with an increased risk of atopic dermatitis in children with no parents with allergies (incident risk ratio = 1.29, 95% CI 1.06–1.55), but not for children with 2 (incident risk ratio = 0.88, 95% CI 0.69–1.13) parents with allergies, although this trend did not reach significance. These studies were prospective and minimized selection bias (randomized controlled trials on this topic are not practical on ethical grounds). In addition, these studies had a recall period of the feeding history that was 12 months or less to limit recall bias and all (or a subset) of infants were exclusively breast-fed. Importantly, the protective effect of breast-feeding was most pronounced in the high-risk population (Table 1).
Studies Demonstrating That Breast-feeding Plays a Nonprotective or Neutral Role
Several important studies during the past decade have demonstrated that breast-feeding has either no protective effect or predisposes infants to the development of atopy. Sears et al (30) performed a landmark birth cohort study in which 1037 children in New Zealand were followed from age 3 years and assessed every 2–5 years from ages 9 to 26 years. More children who were breast-fed compared with those who were not breast-fed were sensitized at all ages to selected environmental allergens (cats, house dust mites, and grass pollen) and reported current asthma symptoms. These results were not altered when children were stratified by parental history of hayfever or asthma. However, breast-feeding habits were assessed retrospectively at 3 years of age. In addition, a significant number of patients were lost to follow-up (approximately 40%).
Bergmann et al (31) studied 1314 infants prospectively for 7 years and showed that the atopic dermatitis prevalence increased with each year of age and with each additional month of breast-feeding, and that breast-fed infants of atopic parents had a significantly elevated risk of atopic dermatitis in the first 7 years of life. However, the study did not examine patients that were exclusively breast-fed, and approximately 49% of infants received supplemental formula. These factors might have contributed to the weak association found between breast-feeding and atopic dermatitis in the entire study population (Table 2). Ludvigsson et al (32) examined 8300 infants and demonstrated that the duration of exclusive breast-feeding was not associated with a lower risk of atopic dermatitis, even among infants with a family history of atopy. However, this evidence was not strong, likely because the study used self-report questionnaires to assess atopic dermatitis symptoms and severity. Both Mihrshahi et al (33) and Wetzig et al (34) found an exascerbation of eczema in exclusively breast-fed infants. In a recent meta-analysis, Yang et al (28) demonstrated that different methods in atopic dermatitis assessment may significantly influence estimates on the association between breast-feeding and atopic dermatitis. It was found that the protective effect of breast-feeding was observed only when the analysis was restricted to studies that used medical personnel to assess clinical outcomes, such as atopic dermatitis. It is possible that misclassification caused by self-reported questionnaires could bias the results. Therefore, these variations in atopic dermatitis assessment likely contributed to these discrepant results.
In addition to atopic dermatitis assessment measures, heterogeneity in other aspects of study methodology has likely contributed to these varied results as well. As mentioned earlier, these factors include the frequency of breast-feeding (including whether infants were exclusively breast-fed), the recall of feeding practices in retrospective studies, reverse causation (ie, atopic mothers having different breast-feeding practices than nonatopic mothers), and the maternal atopic background.
BREAST-FEEDING WITH SUPPLEMENTATION AND/OR ALLERGEN AVOIDANCE: HELPFUL OR HARMFUL?
Breast-feeding Supplementation With Hypoallergenic Formulas
Several studies have examined the impact of partially hydrolyzed and extensively hydrolyzed (or elemental) formulas on the incidence of allergic disease in infants who are either exclusively formula-fed or partially breast-fed. In a 2006 Cochrane review, 10 randomized and quasirandomized trials with >80% follow-up of participants compared prolonged feeding with hydrolyzed formula (including both partially and extensively hydrolyzed formulas) versus cow's-milk formula in high-risk infants. This meta-analysis found a significant reduction in infant allergy (7 studies, 2514 infants; typical RR 0.79, 95% CI 0.66–0.94) but not infant eczema (8 studies, 2558 infants, typical RR 0.84, 95% CI 0.68–1.04) in patients fed hydrolyzed formula. Two trials compared early, short-term hydrolyzed formula to exclusive human milk feeding with no significant difference in infant allergy or childhood cow's milk allergy reported (35). However, only 1 of these studies involved exclusive bottle feeding and the duration of feeding was only 3 days. No studies have compared exclusive prolonged hydrolyzed (including both partially and extensively hydrolyzed formulas) formula feeding (more than 3 days) with human milk feeding on the incidence of atopic disease.
A revised meta-analysis excluding 4 of the above trials for fraudulent data (36) did not find that the exclusion of the 4 trials demanded a change of the recommendations regarding primary dietary prevention of allergic diseases. A recent meta-analysis of 18 studies that compared partially hydrolyzed formula with intact protein cow's-milk formula found a 44% decrease in atopic manifestations (including atopic dermatitis) among infants receiving partially hydrolyzed formula (summary RR 0.56, 95% CI 0.40–0.77) (37).
Therefore, future birth cohort studies examining the incidence of atopic disease need to directly compare infants fed hydrolyzed (including both partially and extensively hydrolyzed formulas) and nonhydrolyzed formulas to exclusively breast-fed infants for a prolonged period. The incidence of allergic disease, and not simply sensitization, must be assessed over time with clinical assessments, rather than the use of self-reported questionnaires.
Probiotics/Prebiotics and the Development of Atopy
The hygiene hypothesis postulates that early exposure to endotoxin decreases the risk of developing allergic disease by a mechanism that has not been fully elucidated, but may be related to TLR stimulation as previously mentioned. Therefore, this reduced exposure to microbial stimuli associated with a modern lifestyle is suggested to have contributed to the rise in allergic disorders. The intestinal microbiota represents the greatest human microbial exposure, and the acquisition of early intestinal microbiota is the neonate's first major microbial challenge. In addition, the intestinal microbiome has been shown to play an important role in immune regulation. Studies have demonstrated that infants with atopic dermatitis have an altered microbiome compared with nonallergic children (38,39). In addition, selective probiotics, like bifidobacterium, can increase IgA secretion (40) as well as indirectly enhance T regulatory cell activity (18), thereby promoting mucosal tolerance and preventing the allergic response. Therefore, manipulation of the intestinal microbiota during infancy may provide a method of disrupting allergic disease development.
Probiotics are defined as live microorganisms that confer a health benefit to the host when administered in adequate amounts (41). Prebiotics are nondigestible and fermentable ingredients that can selectively stimulate the growth and activity of colonic bacteria and improve the health of the host. For example, prebiotics like breast milk oligosaccharides preferentially stimulate bifidobacterium, which has multiple immune effects as mentioned above. There are several randomized controlled clinical trials (RCTs) evaluating the effect of probiotic bacteria on the prevention and treatment of allergic disease. Recent systematic reviews have concluded that probiotics do not appear to be effective for the treatment of atopic dermatitis, and that there is insufficient evidence to support their use for atopic dermatitis treatment (42,43). However, some studies suggest a potential role for selected probiotics in atopic dermatitis prevention. A recent meta-anaylsis by Tang et al (44) examined 13 RCTs of probiotics and found a significant cumulative protective effect for the prevention of eczema (RR 0.79; 95% CI 0.67–0.92). Most of these studies examined eczema in the first 2 years of life in infants with a family history of allergic disease. In addition, the probiotics studied were used alone or in combination with other probiotics (and in 1 study a prebiotic) and 9 studies involved a combination of prenatal (last 2–6 weeks of pregnancy) and maternal postnatal (6–24 months) treatment. In line with this, other studies (45,46) have demonstrated that the treatment with the probiotic Lactobacillus GG conferred the greatest protective effect against infantile atopic dermatitis when the probiotic was given to their mothers during pregnancy and breast-feeding, and not directly to the infants until after 3 months of age. It is hypothesized that this protective effect is due to Lactobacillus GG administration causing increased breast milk TGF-β 2 levels, which can, as discussed previously, suppress the infant inflammatory intestinal response.
Breast milk contains multiple factors that modulate and promote the development of the infant immune system, including its potential protective role against allergic disease. These factors include immunoglobulins such as secretory IgA, antimicrobial proteins such as CD14, cytokines, and fatty acids. In addition to providing protection against infections that may promote atopic disease, breast-feeding also promotes the establishment of an intestinal microbiota that may protect against atopic disease, possibly by stimulating tolerogenic cytokines, such as TGF-β, or stimulating a Th1 response (47). Exclusive breast-feeding, in addition to having other well-recognized benefits, can protect against the onset of atopic dermatitis by decreasing exposure to external allergens, or possibly, presenting them to the infant in a way that promotes allergen tolerance. This promotion of tolerance is likely through the presence of co-stimulatory immune factors. In situations in which exclusive breast-feeding is not possible, atopic dermatitis may be delayed or prevented by the use of extensively or partially hydrolyzed formulas, compared with cow's-milk formula. However, additional studies are needed that directly compare prolonged use of these formulas with exclusive breast-feeding. Studies also suggest a potential role for selected probiotics in atopic dermatitis prevention, and future studies will need to standardize the probiotic strain as well as amount used in a larger cohort of pregnant women in order to better assess these effects.
Studies examining the role of breast-feeding in the development of allergic disease in infants have failed to demonstrate the protective effect of breast milk because of the heterogeneity in study methods (including breast-feeding frequency, recall of feeding practices, and maternal atopic background).
Future studies examining both prenatal as well as perinatal factors are warranted to address many of these issues in order to better evaluate the association between breast-feeding and allergy prevention. Because an RCT is not possible for ethical reasons, this would be best accomplished through a birth cohort study recruiting pregnant mothers from atopic and nonatopic backgrounds with term gestations in their last 2 weeks of pregnancy and following them and their infants until 6 months postpartum. Detailed diet histories from both mother and infant would be obtained prospectively before and after birth, including information of breast-feeding duration, use of supplemental formulas and probiotics, and solid food introduction. Cord blood lymphocyte functional studies would examine tolerance to specific allergens. Stool samples obtained at regular intervals would examine infant microbiota and its possible influence on future allergic disease. Infants would be examined by medical providers at regular intervals for the presence of atopic dermatitis (using standardized scoring methods) as well as food allergic symptoms and other allergic disease (confirmed by IgE testing), and not just the presence of allergic sensitization. Each different allergic disease entity would be examined separately, rather than being grouped into the same category. In addition, serial breast milk samples could be analyzed for the presence of several important immune factors, including secretory IgA, antimicrobial proteins, Th1/Th2 cytokines, food allergens, oligosaccharides, and fatty acids. The breast milk cytokine composition would then be compared in patients with and without specific allergic diseases, such as atopic dermatitis, to determine whether tolergenic cytokines, such as TGF-β and IL-10, are more likely to be present in the breast milk fed to infants who did not develop atopic dermatitis.
In summary, although the overall effect of breast-feeding on allergic disease remains unknown, most practitioners agree that exclusive breast-feeding is the preferred method of nutrition for all infants based on other potential benefits of breast-feeding. We believe that breast milk is protective against allergic disease, and that studies thus far have demonstrated mixed results due to the heterogeneity in study methods. Some of the predominant immunomodulatory effects of breast milk, such as that of TGF-β and IL-10 which are involved in suppressing the inflammatory response, support this hypothesis.
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allergy; breast milk; breast-feeding; hypoallergenic formulas; probiotics
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