REVIEW URRENT C OPINION
Gut microbiota and allergic disease: new findings Christina E. West
Purpose of review Disturbed gut colonization patterns are proposed to be associated with the development of allergic disease. Recent findings Studies using new systems biology methods confirm previous findings that early environmental exposures, for example cesarean delivery, are associated with disturbed gut colonization patterns and reduced microbial diversity. Low microbial diversity in infancy is also observed to precede onset of allergic disease. In a large population-based cohort study, probiotic consumption in pregnancy was associated with reduced risk of eczema and rhinoconjunctivitis in the child, but not asthma. The association between probiotics and rhinoconjunctivitis appeared stronger if both mother and child (from 6 months) consumed probiotics. Follow-up data from primary prevention studies with probiotics do not support a role for probiotics in asthma prevention. In meta-analyses, both prebiotics (high-risk infants only) and probiotics modestly reduce the eczema risk, but no other allergic manifestations. Their use is not generally recommended for prevention, or treatment, of allergic disease. Summary Gut microbial patterns are associated with susceptibility to allergic disease, but the incomplete understanding of what constitutes a healthy gut microbiota that promotes tolerance, remains a challenge. Further understanding of gut microbial functions may pave the way for more effective allergy prevention and treatment strategies. Keywords allergy prevention, gut microbiome, intestinal colonization, oral microbiota, probiotics
INTRODUCTION Gut microbiota are vital for human health by maintaining intestinal homeostasis and protection against pathogens, and by exerting metabolic, nutritional, physiological and immunological activities [1,2 ]. There is also growing recognition that microbial exposure is critical for healthy immune [3] and metabolic maturation [4 ]. The pivotal role of the gut microbiota and their corresponding genes (the microbiome) in health and disease has been elucidated by the use of new molecular techniques that enable detection of unculturable bacteria and bacterial communities using the conserved 16S rRNA gene for phylogenetic analyses [1,2 ]. The adult human gut harbors up to 100 trillion bacteria and outnumbers human cells by a factor of 10 [5]. It is also estimated that the microbiome contains 150-fold more genes than the host genome. There is constant interaction between the indigenous bacteria and the host, and under normal circumstances, they thrive in symbiosis. An aberrant composition of the gut microbiota has been associated with the development of intestinal diseases such as &&
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inflammatory bowel disease [6] and necrotizing enterocolitis [7]. Increasingly, disturbed gut colonization patterns and reduced gut microbial diversity are also implicated in other inflammatory disease states, including allergic diseases [8 ]. The hygiene hypothesis was initially proposed to explain the epidemic rise in allergic disease, suggesting that microbial exposures during childhood are needed for proper development of the immune system to prevent allergy development [9]. Increasingly, this hypothesis is being modified by the ‘gut microbial deprivation hypothesis’, with its emphasis on alterations of indigenous gut microbiota during infancy [10]. Over recent years, new systems biology methods have advanced our understanding of gut &
Department of Clinical Sciences, Pediatrics, Umea˚ University, Umea˚, Sweden Correspondence to Dr Christina West, Department of Clinical Sciences, Pediatrics, Umea˚ University, SE 901 85 Umea˚, Sweden. Tel: +46 90 785 2216; fax: +46 90123728; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:261–266 DOI:10.1097/MCO.0000000000000044
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KEY POINTS The current evidence from experimental models, epidemiological and clinical studies indicates that disturbances of gut colonization patterns and a reduced gut microbial diversity are associated with the development of allergic disease. Despite this, we still have not defined ‘the healthy human gut microbiota’ and the optimal patterns of gut colonization to promote tolerance establishment. There is need to develop microbiota markers, including markers of the functional activities of the gut microbiota. Ideally, this may then be used for diagnostic, treatment and prevention strategies.
that meconium harbors a complex, although less diverse, microbiota than that of adults [19]. The meconium samples clustered into two types with different bacterial diversity, richness and composition; one was less diverse, dominated by enteric bacteria and associated with a maternal history of eczema, whereas the other was dominated by lactic acid bacteria and associated with infant respiratory problems. Although small, this study suggests that the meconium microbiota are influenced by maternal health and may have consequences for child health [19]. Collectively, these studies add to the evidence that early gut microbiota are heavily influenced by environmental factors, which may have programming effects and consequences for human health also in a long-term perspective [8 ]. &
microbiota and immune disease. This review summarizes recent findings of the role of gut microbiota in allergic disease.
INFANT GUT COLONIZATION: NEW FINDINGS Infant gut colonization is a stepwise process that ultimately leads to a predominantly anaerobic community. This has been carefully characterized by the use of traditional culture methods and increasingly by culture-independent methods [1,2 ]. In addition to environmental exposures, genetic, epigenetic and microbiota-associated factors influence gut colonization [1,2 ,11 ]. Recent studies using culture-independent methods have confirmed that exposures such as country of origin [12 ], delivery mode [13 –15 ], antibiotics [16] and breast-feeding [13 ,15 ] influence gut microbiota establishment. Further inquiry has revealed that the initially ‘unstable’ gut microbiome undergoes dynamic changes resulting in an adult-like gut microbiome at about 3 years of age [12 ]. Although there is large interindividual heterogeneity in acquisition and colonization by individual bacterial species, infant microbiomes share characteristics such as lower species richness than adults and a higher proportion of bifidobacteria [12 ]. Increasingly, the previous paradigm of a sterile gut in utero is being challenged by findings that bacterial compounds are found in umbilical cord blood, amniotic fluid, placenta and fetal membranes [11 ,17]. There is also emerging evidence of maternal transmission of microbes across the animal kingdom [18]. This transmission may imprint the offspring microbiota in preparation for the larger microbial exposure transferred during vaginal delivery and breast-feeding [11 ], and may have influenced the microbial composition during evolution. In infants, there is also recent evidence &&
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GUT MICROBIOTA AND ALLERGIC DISEASE Early programming refers to events or stimuli during critical periods of development that may program the long-term structure or function of an organism, thereby influencing the risk of developing later disease [20]. This was first proposed and studied in cardiac and metabolic disease [21], but there is emerging evidence that this is also relevant in the context of other environmentally driven diseases [20]. There is compelling evidence from experimental animal models that gut microbiota are critical for normal development of the immune system [22]. Further inquiry has proposed that early gut colonization plays a critical role in the development of both innate and adaptive immune responses [23 ,24]. Results from earlier human cohort studies suggest that disruptions of gut microbiota in infancy and childhood may influence the risk of developing allergic disease [1], although results have been variable across studies with no clear allergy-promoting or allergy-protective taxa. There are reports of increased risk of asthma and atopy [25] in cesarean-delivered infants. To what extent this is due to delayed gut colonization still needs further clarification, but using 454 pyrosequencing, potentially relevant disturbances in infant gut microbial patterns, such as lower abundance of the genus Bacteroides [13 ,14 ] and lower diversity of Bacteroidetes [14 ] in cesareandelivered infants, have been reported. Recently, birth order was observed to have a strong effect on gut microbial patterns [15 ]. Using quantitative PCR, the colonization rates of lactobacilli and bacteroides increased with increasing number of older siblings, whereas rates of clostridia decreased. Colonization with clostridia at both 5 and 13 weeks of age was also &&
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associated with an increased risk of developing eczema in the subsequent 6 months of life. Mediation analyses demonstrated that there was a statistically significant indirect effect via colonization with Clostridium cluster I (which is proposed to be the true representative for the genus Clostridium) for both birth mode and birth order in association to eczema. These results support a role for gut microbiota in the development of eczema, and suggest that the microbiota may be one of the biological mechanisms underlying the sibling effect [15 ], previously reported to be protective against allergy development [9]. Higher microbial diversity is often regarded as beneficial, although this concept has been challenged [26,27]. Reduced gut microbial diversity in infancy has been reported in children subsequently developing eczema [28,29]. It has been argued that a high diversity of the gut microbiome is more important than the absence or presence of specific genera, but it still remains to be determined whether a high total diversity or diversity within specific taxa [28] is of utmost importance for tolerance development. It is also argued that traditional diversity measures may be too crude [26], and techniques to overcome this by using expanded microbial diversity profiles are being developed [30]. &
development. By studying associations between pacifier cleaning practices and allergy development, they found that children whose parents ‘cleaned’ their pacifier by sucking it were less likely to have asthma, eczema and sensitization at 18 months of age than children whose parents cleaned the pacifier by boiling water or cold water. Protection against eczema remained at age 3 years. Also, the salivary microbiota as assessed by terminal restriction fragment length polymorphism (T-RFLP) differed between children whose parents cleaned their pacifier by sucking it and children whose parents did not. The benefit might be mediated through immune stimulation by microbes transferred to the infant via the parent’s saliva [34 ], an area which should be explored in future studies. &&
PROBIOTICS FOR ALLERGY PREVENTION In a recent report from a large Norwegian population-based cohort study, including 40 614 mother–child pairs, probiotic milk consumption in pregnancy (assessed by a food frequency questionnaire at 22 weeks gestation) was associated with a slightly reduced incidence of eczema and rhinoconjunctivitis, but not asthma, at 3 years of age [35 ]. The association between probiotics and rhinoconjunctivitis appeared to be stronger if both the mother (in pregnancy) and the child (from 6 months of age) had consumed probiotics compared with no consumption, or consumption only by the mother or child, respectively. Although there may be confounding factors, this provides further evidence for the probiotic concept and suggests that probiotics in pregnancy and early life may provide allergy-protective effects in the general population. Probiotics are viable ‘health-promoting’ nonpathogenic bacteria [36] that have been variably shown to exert both immune-stimulating [37,38] and metabolic effects [4 ,39] in human intervention studies. At least 17 published studies have evaluated probiotics for primary prevention of allergic disease (summarized in [40 ]), with variable results. Many questions have been raised regarding optimal strains, dosages, timing and route of administration (to mother, infant or both) [40 ]. Compared with placebo, Rautava and colleagues [41] assessed if maternal supplementation with L. rhamnosus and Bifidobacterium longum (B. longum) strains or L. paracasei and B. longum strains during pregnancy and breast-feeding reduced the risk of developing eczema in high-risk infants (based on maternal atopy). The intervention was initiated 2 months before delivery and was continued for the first 2 months of breastfeeding. The risk of developing eczema in the first 2 years of life was &&
ORAL MICROBIOTA: POSSIBLE LINKS TO ALLERGY DEVELOPMENT There is also emerging interest in the role of oral microbiota in infant health. Recently, infant feeding mode was observed to influence oral microbiota establishment, with the presence of lactobacilli in saliva in breast-fed but not formula-fed infants; the oral microbial profiles of breast-fed infants differing according to delivery mode [31]. In a subsequent study, Lactobacillus gasseri (L. gasseri) isolated in the saliva of breast-fed infants displayed probiotic properties in vitro [32]. Oral tolerance is the default physiologic response to harmless proteins, and normal tolerance development is dependent on exposure to commensal microbiota [3]. So far, studies have focused on the small intestine as the inductive site for oral tolerance although the oral cavity is the first site of encounter between foreign antigens and the lymphoid system. The oropharynx is also surrounded by lymphoid tissue, which, like the gut-associated lymphoid tissues, is covered by M cells, which are specialized in antigen uptake and delivery to antigen-presenting cells and lymphocytes beneath the epithelium [33,34 ]. Hesselmar et al. [34 ] hypothesized that active oral tolerance might be initiated already in the oral cavity, and investigated if oral microbes transferred from parents to infants via pacifiers influenced allergy &&
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reduced in infants of mothers receiving either probiotic combination, but had no effect on sensitization. The lack of effect on sensitization is consistent with most previous studies [40 ], although a recent study reported reduced sensitization and eczema at 6 years of age in high-risk children who had received perinatal L. rhamnosus HN001 supplementation [42 ]. Meta-analyses have concluded that there is a moderate effect of probiotics in the prevention of eczema and IgE-associated eczema in infants [43,44], but not any other allergic outcomes. Specifically, L. rhamnosus GG (LGG), which is the most studied strain, was also effective in the long-term prevention of eczema in one of these meta-analyses [44], although the benefit of LGG is not seen in all studies [40 ]. Long-term follow-up above 5 years of age of already initiated cohorts are scarce [40 ], but have not revealed any preventive effect on asthma development. Three recent follow-up studies objectively assessed lung function by spirometry reversibility tests and exhaled nitric oxide levels with no differences between the probiotic and placebo groups [42 ,45 ,46 ]. As the majority of these followup studies have been small [40 ], they may not be powered to evaluate long-term outcomes. Consequently, conservative interpretation of the study findings is needed. Probiotics have shown more promise in the prevention than treatment of eczema, but there are a number of unanswered questions regarding how probiotics mediate their clinical effects [40 ,47 ], and a much clearer message on dosages, optimal timing and duration of administration is needed [48]. Currently, there is not enough evidence to use probiotics for prevention or treatment of allergic disease [40 ,47 ,48], but several ongoing clinical trials will provide further insight. Using nonconventional indigenous gut bacteria might also prove to be more effective [49,50 ,51 ]. &
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NONVIABLE PRODUCTS FOR ALLERGY PREVENTION The viability of probiotics can be an issue during storage and preparation [52], and there has been recent interest in nonviable products. Processed supernatant from LGG improved allergic airway inflammation in an experimental mouse model, thereby suggesting that processed supernatants are an alternative to viable probiotics [53]. Bacterial lysates, lyophilized extracts from bacterial cultures of single strains or from several bacterial species have also been assessed in human intervention studies [54 ,55]. They have already been extensively studied in respiratory diseases and there is preliminary evidence that administration of a bacterial &
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lysate containing heat-killed gram-negative Escherichia coli and gram-positive Enterococcus faecalis to high-risk infants (at least single parental atopy) can reduce the risk of developing eczema [56]. Even though there was no effect of this bacterial lysate on the primary outcome eczema at 3 years, children with one atopic parent had reduced risk of eczema at the end of the intervention. Future studies are anticipated to provide more insight.
DIETARY FIBER, PREBIOTICS AND ALLERGY PREVENTION Dietary fiber and oligosaccharides are important for gut health by promoting ‘favorable’ colonization and production of short-chain fatty acids (SCFAs) [57]. Direct effects on the immune system have also been demonstrated [58]. Preliminary primary prevention studies suggest an allergy-protective effect of neonatal supplementation with prebiotic oligosaccharides; in one study, this was sustained until 5 years of age for eczema and rhinoconjunctivitis [59]. In the most recent Cochrane report, including four studies and 1428 infants (at high risk of attrition), prebiotics added to infant feeds prevented eczema development [60 ]. However, it remains undetermined whether prebiotics should be restricted to high-risk infants, and if there is an effect on other allergic outcomes. To date, their use is not generally recommended for allergy prevention [40 ,60 ]. Direct immunologic effects of oligosaccharides in human studies and animal models [61,62] provide a basis to further explore prebiotics in promoting immune tolerance for allergy prevention. &
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CONCLUSION Evidence from experimental models, epidemiological and clinical studies indicates that disturbances of gut colonization patterns and reduced gut microbial diversity are associated with the development of allergic disease. Despite this, we still have an incomplete understanding of ‘the healthy human gut microbiota’, the optimal patterns of gut colonization to promote tolerance establishment, and the many complex host and microbiota interactions. This may explain some of the inconsistencies in studies using microbiota manipulation strategies for treatment and prevention of allergic diseases. Future studies should aim at identifying microbiota markers [27], including markers of the functional activities of the gut microbiota. Ideally, this may then be used for diagnostic, treatment and prevention purposes. Volume 17 Number 3 May 2014
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Acknowledgements Christina West is sponsored by a Young researcher Award from Umea˚ University and studies by Dr West and colleagues and cited herein received funding from Arla Foods AB, Sweden; through regional agreement between Umea˚ University and Va¨sterbotten county council on cooperation in the field of Medicine; European Union’s Seventh Frame Work Programme under grant agreement n8 222720; Swedish Society for Medical research; Swedish Asthma and Allergy Association; the Ekhaga and Oskar foundations; Insamlingsstiftelsen at Umea˚ University. Conflicts of interest Dr West has received funding and speaker honoraria from Arla Foods; speaker honoraria from Semper AB; speaker honoraria and travel assistance to attend conferences from Nestle´ Nutrition.
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Gut microbiota and allergic disease: new findings Christina E. West
Purpose of review Disturbed gut colonization patterns are proposed to be associated with the development of allergic disease. Recent findings Studies using new systems biology methods confirm previous findings that early environmental exposures, for example cesarean delivery, are associated with disturbed gut colonization patterns and reduced microbial diversity. Low microbial diversity in infancy is also observed to precede onset of allergic disease. In a large population-based cohort study, probiotic consumption in pregnancy was associated with reduced risk of eczema and rhinoconjunctivitis in the child, but not asthma. The association between probiotics and rhinoconjunctivitis appeared stronger if both mother and child (from 6 months) consumed probiotics. Follow-up data from primary prevention studies with probiotics do not support a role for probiotics in asthma prevention. In meta-analyses, both prebiotics (high-risk infants only) and probiotics modestly reduce the eczema risk, but no other allergic manifestations. Their use is not generally recommended for prevention, or treatment, of allergic disease. Summary Gut microbial patterns are associated with susceptibility to allergic disease, but the incomplete understanding of what constitutes a healthy gut microbiota that promotes tolerance, remains a challenge. Further understanding of gut microbial functions may pave the way for more effective allergy prevention and treatment strategies. Keywords allergy prevention, gut microbiome, intestinal colonization, oral microbiota, probiotics
INTRODUCTION Gut microbiota are vital for human health by maintaining intestinal homeostasis and protection against pathogens, and by exerting metabolic, nutritional, physiological and immunological activities [1,2 ]. There is also growing recognition that microbial exposure is critical for healthy immune [3] and metabolic maturation [4 ]. The pivotal role of the gut microbiota and their corresponding genes (the microbiome) in health and disease has been elucidated by the use of new molecular techniques that enable detection of unculturable bacteria and bacterial communities using the conserved 16S rRNA gene for phylogenetic analyses [1,2 ]. The adult human gut harbors up to 100 trillion bacteria and outnumbers human cells by a factor of 10 [5]. It is also estimated that the microbiome contains 150-fold more genes than the host genome. There is constant interaction between the indigenous bacteria and the host, and under normal circumstances, they thrive in symbiosis. An aberrant composition of the gut microbiota has been associated with the development of intestinal diseases such as &&
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inflammatory bowel disease [6] and necrotizing enterocolitis [7]. Increasingly, disturbed gut colonization patterns and reduced gut microbial diversity are also implicated in other inflammatory disease states, including allergic diseases [8 ]. The hygiene hypothesis was initially proposed to explain the epidemic rise in allergic disease, suggesting that microbial exposures during childhood are needed for proper development of the immune system to prevent allergy development [9]. Increasingly, this hypothesis is being modified by the ‘gut microbial deprivation hypothesis’, with its emphasis on alterations of indigenous gut microbiota during infancy [10]. Over recent years, new systems biology methods have advanced our understanding of gut &
Department of Clinical Sciences, Pediatrics, Umea˚ University, Umea˚, Sweden Correspondence to Dr Christina West, Department of Clinical Sciences, Pediatrics, Umea˚ University, SE 901 85 Umea˚, Sweden. Tel: +46 90 785 2216; fax: +46 90123728; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:261–266 DOI:10.1097/MCO.0000000000000044
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KEY POINTS The current evidence from experimental models, epidemiological and clinical studies indicates that disturbances of gut colonization patterns and a reduced gut microbial diversity are associated with the development of allergic disease. Despite this, we still have not defined ‘the healthy human gut microbiota’ and the optimal patterns of gut colonization to promote tolerance establishment. There is need to develop microbiota markers, including markers of the functional activities of the gut microbiota. Ideally, this may then be used for diagnostic, treatment and prevention strategies.
that meconium harbors a complex, although less diverse, microbiota than that of adults [19]. The meconium samples clustered into two types with different bacterial diversity, richness and composition; one was less diverse, dominated by enteric bacteria and associated with a maternal history of eczema, whereas the other was dominated by lactic acid bacteria and associated with infant respiratory problems. Although small, this study suggests that the meconium microbiota are influenced by maternal health and may have consequences for child health [19]. Collectively, these studies add to the evidence that early gut microbiota are heavily influenced by environmental factors, which may have programming effects and consequences for human health also in a long-term perspective [8 ]. &
microbiota and immune disease. This review summarizes recent findings of the role of gut microbiota in allergic disease.
INFANT GUT COLONIZATION: NEW FINDINGS Infant gut colonization is a stepwise process that ultimately leads to a predominantly anaerobic community. This has been carefully characterized by the use of traditional culture methods and increasingly by culture-independent methods [1,2 ]. In addition to environmental exposures, genetic, epigenetic and microbiota-associated factors influence gut colonization [1,2 ,11 ]. Recent studies using culture-independent methods have confirmed that exposures such as country of origin [12 ], delivery mode [13 –15 ], antibiotics [16] and breast-feeding [13 ,15 ] influence gut microbiota establishment. Further inquiry has revealed that the initially ‘unstable’ gut microbiome undergoes dynamic changes resulting in an adult-like gut microbiome at about 3 years of age [12 ]. Although there is large interindividual heterogeneity in acquisition and colonization by individual bacterial species, infant microbiomes share characteristics such as lower species richness than adults and a higher proportion of bifidobacteria [12 ]. Increasingly, the previous paradigm of a sterile gut in utero is being challenged by findings that bacterial compounds are found in umbilical cord blood, amniotic fluid, placenta and fetal membranes [11 ,17]. There is also emerging evidence of maternal transmission of microbes across the animal kingdom [18]. This transmission may imprint the offspring microbiota in preparation for the larger microbial exposure transferred during vaginal delivery and breast-feeding [11 ], and may have influenced the microbial composition during evolution. In infants, there is also recent evidence &&
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GUT MICROBIOTA AND ALLERGIC DISEASE Early programming refers to events or stimuli during critical periods of development that may program the long-term structure or function of an organism, thereby influencing the risk of developing later disease [20]. This was first proposed and studied in cardiac and metabolic disease [21], but there is emerging evidence that this is also relevant in the context of other environmentally driven diseases [20]. There is compelling evidence from experimental animal models that gut microbiota are critical for normal development of the immune system [22]. Further inquiry has proposed that early gut colonization plays a critical role in the development of both innate and adaptive immune responses [23 ,24]. Results from earlier human cohort studies suggest that disruptions of gut microbiota in infancy and childhood may influence the risk of developing allergic disease [1], although results have been variable across studies with no clear allergy-promoting or allergy-protective taxa. There are reports of increased risk of asthma and atopy [25] in cesarean-delivered infants. To what extent this is due to delayed gut colonization still needs further clarification, but using 454 pyrosequencing, potentially relevant disturbances in infant gut microbial patterns, such as lower abundance of the genus Bacteroides [13 ,14 ] and lower diversity of Bacteroidetes [14 ] in cesareandelivered infants, have been reported. Recently, birth order was observed to have a strong effect on gut microbial patterns [15 ]. Using quantitative PCR, the colonization rates of lactobacilli and bacteroides increased with increasing number of older siblings, whereas rates of clostridia decreased. Colonization with clostridia at both 5 and 13 weeks of age was also &&
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associated with an increased risk of developing eczema in the subsequent 6 months of life. Mediation analyses demonstrated that there was a statistically significant indirect effect via colonization with Clostridium cluster I (which is proposed to be the true representative for the genus Clostridium) for both birth mode and birth order in association to eczema. These results support a role for gut microbiota in the development of eczema, and suggest that the microbiota may be one of the biological mechanisms underlying the sibling effect [15 ], previously reported to be protective against allergy development [9]. Higher microbial diversity is often regarded as beneficial, although this concept has been challenged [26,27]. Reduced gut microbial diversity in infancy has been reported in children subsequently developing eczema [28,29]. It has been argued that a high diversity of the gut microbiome is more important than the absence or presence of specific genera, but it still remains to be determined whether a high total diversity or diversity within specific taxa [28] is of utmost importance for tolerance development. It is also argued that traditional diversity measures may be too crude [26], and techniques to overcome this by using expanded microbial diversity profiles are being developed [30]. &
development. By studying associations between pacifier cleaning practices and allergy development, they found that children whose parents ‘cleaned’ their pacifier by sucking it were less likely to have asthma, eczema and sensitization at 18 months of age than children whose parents cleaned the pacifier by boiling water or cold water. Protection against eczema remained at age 3 years. Also, the salivary microbiota as assessed by terminal restriction fragment length polymorphism (T-RFLP) differed between children whose parents cleaned their pacifier by sucking it and children whose parents did not. The benefit might be mediated through immune stimulation by microbes transferred to the infant via the parent’s saliva [34 ], an area which should be explored in future studies. &&
PROBIOTICS FOR ALLERGY PREVENTION In a recent report from a large Norwegian population-based cohort study, including 40 614 mother–child pairs, probiotic milk consumption in pregnancy (assessed by a food frequency questionnaire at 22 weeks gestation) was associated with a slightly reduced incidence of eczema and rhinoconjunctivitis, but not asthma, at 3 years of age [35 ]. The association between probiotics and rhinoconjunctivitis appeared to be stronger if both the mother (in pregnancy) and the child (from 6 months of age) had consumed probiotics compared with no consumption, or consumption only by the mother or child, respectively. Although there may be confounding factors, this provides further evidence for the probiotic concept and suggests that probiotics in pregnancy and early life may provide allergy-protective effects in the general population. Probiotics are viable ‘health-promoting’ nonpathogenic bacteria [36] that have been variably shown to exert both immune-stimulating [37,38] and metabolic effects [4 ,39] in human intervention studies. At least 17 published studies have evaluated probiotics for primary prevention of allergic disease (summarized in [40 ]), with variable results. Many questions have been raised regarding optimal strains, dosages, timing and route of administration (to mother, infant or both) [40 ]. Compared with placebo, Rautava and colleagues [41] assessed if maternal supplementation with L. rhamnosus and Bifidobacterium longum (B. longum) strains or L. paracasei and B. longum strains during pregnancy and breast-feeding reduced the risk of developing eczema in high-risk infants (based on maternal atopy). The intervention was initiated 2 months before delivery and was continued for the first 2 months of breastfeeding. The risk of developing eczema in the first 2 years of life was &&
ORAL MICROBIOTA: POSSIBLE LINKS TO ALLERGY DEVELOPMENT There is also emerging interest in the role of oral microbiota in infant health. Recently, infant feeding mode was observed to influence oral microbiota establishment, with the presence of lactobacilli in saliva in breast-fed but not formula-fed infants; the oral microbial profiles of breast-fed infants differing according to delivery mode [31]. In a subsequent study, Lactobacillus gasseri (L. gasseri) isolated in the saliva of breast-fed infants displayed probiotic properties in vitro [32]. Oral tolerance is the default physiologic response to harmless proteins, and normal tolerance development is dependent on exposure to commensal microbiota [3]. So far, studies have focused on the small intestine as the inductive site for oral tolerance although the oral cavity is the first site of encounter between foreign antigens and the lymphoid system. The oropharynx is also surrounded by lymphoid tissue, which, like the gut-associated lymphoid tissues, is covered by M cells, which are specialized in antigen uptake and delivery to antigen-presenting cells and lymphocytes beneath the epithelium [33,34 ]. Hesselmar et al. [34 ] hypothesized that active oral tolerance might be initiated already in the oral cavity, and investigated if oral microbes transferred from parents to infants via pacifiers influenced allergy &&
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reduced in infants of mothers receiving either probiotic combination, but had no effect on sensitization. The lack of effect on sensitization is consistent with most previous studies [40 ], although a recent study reported reduced sensitization and eczema at 6 years of age in high-risk children who had received perinatal L. rhamnosus HN001 supplementation [42 ]. Meta-analyses have concluded that there is a moderate effect of probiotics in the prevention of eczema and IgE-associated eczema in infants [43,44], but not any other allergic outcomes. Specifically, L. rhamnosus GG (LGG), which is the most studied strain, was also effective in the long-term prevention of eczema in one of these meta-analyses [44], although the benefit of LGG is not seen in all studies [40 ]. Long-term follow-up above 5 years of age of already initiated cohorts are scarce [40 ], but have not revealed any preventive effect on asthma development. Three recent follow-up studies objectively assessed lung function by spirometry reversibility tests and exhaled nitric oxide levels with no differences between the probiotic and placebo groups [42 ,45 ,46 ]. As the majority of these followup studies have been small [40 ], they may not be powered to evaluate long-term outcomes. Consequently, conservative interpretation of the study findings is needed. Probiotics have shown more promise in the prevention than treatment of eczema, but there are a number of unanswered questions regarding how probiotics mediate their clinical effects [40 ,47 ], and a much clearer message on dosages, optimal timing and duration of administration is needed [48]. Currently, there is not enough evidence to use probiotics for prevention or treatment of allergic disease [40 ,47 ,48], but several ongoing clinical trials will provide further insight. Using nonconventional indigenous gut bacteria might also prove to be more effective [49,50 ,51 ]. &
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NONVIABLE PRODUCTS FOR ALLERGY PREVENTION The viability of probiotics can be an issue during storage and preparation [52], and there has been recent interest in nonviable products. Processed supernatant from LGG improved allergic airway inflammation in an experimental mouse model, thereby suggesting that processed supernatants are an alternative to viable probiotics [53]. Bacterial lysates, lyophilized extracts from bacterial cultures of single strains or from several bacterial species have also been assessed in human intervention studies [54 ,55]. They have already been extensively studied in respiratory diseases and there is preliminary evidence that administration of a bacterial &
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lysate containing heat-killed gram-negative Escherichia coli and gram-positive Enterococcus faecalis to high-risk infants (at least single parental atopy) can reduce the risk of developing eczema [56]. Even though there was no effect of this bacterial lysate on the primary outcome eczema at 3 years, children with one atopic parent had reduced risk of eczema at the end of the intervention. Future studies are anticipated to provide more insight.
DIETARY FIBER, PREBIOTICS AND ALLERGY PREVENTION Dietary fiber and oligosaccharides are important for gut health by promoting ‘favorable’ colonization and production of short-chain fatty acids (SCFAs) [57]. Direct effects on the immune system have also been demonstrated [58]. Preliminary primary prevention studies suggest an allergy-protective effect of neonatal supplementation with prebiotic oligosaccharides; in one study, this was sustained until 5 years of age for eczema and rhinoconjunctivitis [59]. In the most recent Cochrane report, including four studies and 1428 infants (at high risk of attrition), prebiotics added to infant feeds prevented eczema development [60 ]. However, it remains undetermined whether prebiotics should be restricted to high-risk infants, and if there is an effect on other allergic outcomes. To date, their use is not generally recommended for allergy prevention [40 ,60 ]. Direct immunologic effects of oligosaccharides in human studies and animal models [61,62] provide a basis to further explore prebiotics in promoting immune tolerance for allergy prevention. &
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CONCLUSION Evidence from experimental models, epidemiological and clinical studies indicates that disturbances of gut colonization patterns and reduced gut microbial diversity are associated with the development of allergic disease. Despite this, we still have an incomplete understanding of ‘the healthy human gut microbiota’, the optimal patterns of gut colonization to promote tolerance establishment, and the many complex host and microbiota interactions. This may explain some of the inconsistencies in studies using microbiota manipulation strategies for treatment and prevention of allergic diseases. Future studies should aim at identifying microbiota markers [27], including markers of the functional activities of the gut microbiota. Ideally, this may then be used for diagnostic, treatment and prevention purposes. Volume 17 Number 3 May 2014
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Acknowledgements Christina West is sponsored by a Young researcher Award from Umea˚ University and studies by Dr West and colleagues and cited herein received funding from Arla Foods AB, Sweden; through regional agreement between Umea˚ University and Va¨sterbotten county council on cooperation in the field of Medicine; European Union’s Seventh Frame Work Programme under grant agreement n8 222720; Swedish Society for Medical research; Swedish Asthma and Allergy Association; the Ekhaga and Oskar foundations; Insamlingsstiftelsen at Umea˚ University. Conflicts of interest Dr West has received funding and speaker honoraria from Arla Foods; speaker honoraria from Semper AB; speaker honoraria and travel assistance to attend conferences from Nestle´ Nutrition.
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