Part 2 book “Microbiota in health and disease - From pregnancy to childhood” has contents: Gut microbiota - it’s role in paediatric diseases , from bowel to infant behavior, assessment of microbiota, consequences of dysbiosis outside of the gut, manipulating the gut microbiota.
Part IV Gut microbiota: it’s role in paediatric diseases Chapter The role of intestinal microbiota in infant allergic diseases H Szajewska Department of Paediatrics, The Medical University of Warsaw, Zwirki i Wigury 63A, 02-091 Warsaw, Poland; hania@ipgate.pl Abstract In many countries, particularly in populations with a Western lifestyle, allergic diseases are on the rise As genetic factors have not changed, environmental factors must be playing a role Recently, attention has been focused on the role of the gut microbiota However, despite many years of extensive research, the link between the gut microbiota and allergic diseases still has not been fully clarified The primary objective of this chapter is to provide an overview of the role of the gut microbiota in the development of allergic diseases The role of probiotics and/or prebiotics as microbiota modifiers for the prevention and treatment of allergic diseases is reviewed The focus is on allergic diseases typically found in infants Keywords: children, allergy, atopy, eczema, food allergy, randomised controlled trial, meta-analysis 9.1 Introduction Allergic diseases can occur at almost any age (Boyce et al., 2011; Muraro et al., 2014a) However, some allergic manifestations are most likely to develop for the first time in particular age groups For example, in infants and children younger than years of age, allergy to food (especially milk, eggs, wheat, nuts) is the most common, affecting up to 8% of children (Sicherer, 2011) The pathophysiology is multifactorial Allergy is triggered by environmental factors in individuals with genetic susceptibility The majority of affected infants and children have one or more symptom(s) involving one or more organ system(s), mainly the gastrointestinal tract and/or skin After the age of years, allergy to inhalants becomes the predominant allergy Thus, later in life, asthma, allergic rhinitis, and hay fever become common For diagnosing allergy, obtaining a detailed clinical history is critical The gold standard for the diagnosis of a potential food allergen is the double-blind, placebo-controlled challenge Strict avoidance of the offending allergen is the main therapeutic option The rising number of children and adults with allergic disorders in many countries, particularly in populations with a Western lifestyle, is a major public health concern (Pawankar et al., 2014) The origins of this increase are still not well understood As genetic factors have not changed, environmental factors are thought to be playing a role Recent evidence has demonstrated that, among other factors, disturbances in gut microbiota, defined as dysbiosis, may be relevant (Figure 9.1) This chapter summarises available information on the role of the gut microbiota P.D Browne, E Claassen and M.D Cabana (eds.) Microbiota in health and disease: from pregnancy to childhood Microbiota in health and disease: from pregnancy Academic to childhood DOI 10.3920/978-90-8686-839-1_9, â Wageningen Publishers 2017 165 H Szajewska Duration ofgestation (preterm vs term) • Feeding after delivery (breast vs formula feeding) • Mode of delivery (vaginal vs C-section) • Early-life farm exposure • Early-life antibiotic use Gut microbiota Normobiosis Dysbiosis Provides protection against infections, educates the immune system, ensures tolerance to foods, and contributes to nutrient digestion and energy harvest Immune tolerance Intestinal homeostasis Health metabolism An imbalance of microbial colonies, either in number or type, that have colonised the human body Immune disease (atopy, allergy) Intestinal diseases (IBD, IBS, NEC) Metabolic disease (diabetes, obesity) Figure 9.1 Factors influencing gut microbiota IBD = inflammatory bowel disease; IBS = irritable bowel syndrome; NEC = necrotising enterocolitis in the development of allergic diseases, with focus on allergic diseases typically found in infants and young children Moreover, the role of probiotics and/or prebiotics for the prevention and treatment of allergic diseases is reviewed Finally, this chapter presents suggestions for future clinical research 9.2 Gut microbiota & allergy Results from experimental studies suggest that early exposure to microbial antigens plays an important role in the development of the immune system and the establishment of a balance between T helper (TH) 1/TH2 cell responses Thus, among other processes (Arrieta et al., 2014), contact with microbes appears to be essential for the development of oral tolerance (Sansonetti and Medzhitov, 2009) Originally, the so-called ‘hygiene hypothesis’ suggested that improved hygiene and reduced exposure of the immune system to the microbial stimulus (‘too clean’ of an environment) during infancy and early childhood predispose to impaired immune regulation in later life, leading to either TH2 diseases (such as allergy) or TH1 diseases (such as type diabetes) (Bach and Chatenoud, 2012; Prescot, 2003; Strachan, 1989) More recently, the hygiene hypothesis has 166 Microbiota in health and disease: from pregnancy to childhood Microbiota in infant allergic diseases been challenged (Haahtela et al., 2015; Hanski et al., 2012; Renz et al., 2011) While exposure to some pathogens protects against atopy, other exposures promote allergic diseases Factors such as the timing of exposure and the properties of the infectious agent, host genetic susceptibility, and other environmental factors also may be important (Fishbein and Fuleihan, 2012; Guarner et al., 2006) Nevertheless, hypotheses suggesting that gut microbiota alterations could lead to the development of allergy are commonly considered Factors that may change gut microbiota (Figure 9.1) and the subsequent effects on allergy risk are discussed below Delivery mode There is consistent evidence that the mode of delivery affects gut microbiota (Adlerberth and Wold, 2009; Azad et al., 2013; Dominguez-Bello et al., 2010; Salminen et al., 2004) Also, recent data using culture-independent methods have confirmed that colonisation patterns differ between infants born by caesarean section compared with infants born vaginally Infants delivered by caesarean section had lower total microbiota diversity, as well as lower abundance and diversity of Bacteroidetes phylum, during the first years of life Moreover, reduced levels of TH1-associated chemokines, with a shift of the TH1/TH2 balance towards a more allergic TH2 response, were documented in infants delivered by caesarean section compared with those born vaginally (Jakobsson et al., 2013) One recent study concluded that mode of delivery was one the key factors (together with cessation of breastfeeding) driving the assembly of an adult-like gut microbiota (Bäckhed et al., 2015) Finally, another recent study showed that differences in gut microbiota composition between infants born naturally and infants delivered by caesarean section were greater than differences due to feeding methods (breast milk versus formula) (Madan et al., 2016) It has been hypothesised that these differences in gut microbiota between infants born via caesarean section versus those born vaginally may contribute to the risk of allergic diseases and asthma However, data are conflicting One systematic review found that caesarean section does appear to moderately increase the risk for allergic rhinitis, asthma, hospitalisation for asthma, and food allergy/food atopy but not the risk of inhalant atopy or atopic dermatitis (AD) (Bager et al., 2008) Also, another meta-analysis found that caesarean section increases the risk of asthma in children by 20% (Thavagnanam et al., 2008) However, the association between the mode of delivery and some allergic manifestations has not been confirmed in some subsequent studies (Pyrhönen et al., 2013) Feeding after delivery Multiple observations have repeatedly shown that the mode of feeding after birth (breastfeeding versus formula) influences the composition of the gut microbiota (Bezirtzoglou et al., 2011; Le Huërou-Luron et al., 2010; Penders et al., 2006) This is mainly due to the fact that human milk contains human milk oligosaccharides that can stimulate the growth and/or activity of beneficial bacteria such as Bifidobacterium (Zivkovic et al., 2011) Term infants who were Microbiota in health and disease: from pregnancy to childhood 167 H Szajewska born vaginally at home and were breastfed exclusively seemed to have the most ‘beneficial’ gut microbiota (highest numbers of bifidobacteria and lowest numbers of Clostridium difficile and Escherichia coli) Compared with breast-fed infants, exclusively formula-fed infants were more often colonised with E coli, C difficile, Bacteroides, and lactobacilli (Penders et al., 2006) The USA infant twin cohort study also detected differences between the breast-fed and formula-fed infants (Yatsunenko et al., 2012) Finally, one recent study showed that mixed feeding (breast milk and formula), which despite recommendations from scientific societies and WHO is a common practice in many settings, resulted in intestinal microbiota communities similar to those found in exclusively formula-fed infants (Madan et al., 2016) While the effect of infant feeding on gut microbiota is clear, conflicting data exist on the relationship between breastfeeding and allergic disease risk Recently, a Lancet review concluded that in children who are breastfed, ‘there is no clear evidence of protection against allergic disorders: no association with eczema or food allergies and some evidence of protection against allergic rhinitis in children younger than years’ (Lodge et al., 2015; Victora et al., 2016) A variety of methodological problems are likely to have contributed to these inconsistent results (including an inability to randomise and blind; the retrospective design of many studies addressing the association between breastfeeding and allergic disease; parental recall bias; and reverse causality) Early-life antibiotic use Data have consistently shown that antibiotic exposure has an effect on gut microbiota (Fouhy et al., 2012; Hällström et al., 2004; Penders et al., 2006) Some data show that not only antibiotic use by the infant (Penders et al., 2006), but also maternal antibiotic intake during birth, alters the microbiota of new-borns (Arboleya et al., 2015) Interestingly, one recent retrospective study suggests that early-life antibiotic use may diminish breastfeeding benefits in childhood (Korpela et al., 2016) Compared with infants who did not receive antibiotics during breastfeeding, infants who received antibiotics during breastfeeding and up to months after weaning had a higher likelihood of developing excess weight gain and infections during childhood (for more information see Chapter 7: ###Gómez-Gallego and Salminen, 2017) Today, it remains unclear whether there is a similar link for allergic disorders Evidence on the effects of early-life antibiotic use and subsequent development of allergic diseases such as asthma, allergic rhinitis, eczema, and food allergy remains inconsistent (Karpa et al., 2012; Koplin et al., 2012; McBride et al., 2012) Early-life farm exposure It has been hypothesised that early-life farm exposure, reduced cleanliness, and subsequent increased microbial exposure would lead to a more diverse intestinal microbiota Intriguingly, a 2007 study carried out in several European countries found that compared to non-farming children, children from farming backgrounds had less gut microbial diversity (Dicksved et al., 2007) 168 Microbiota in health and disease: from pregnancy to childhood Microbiota in infant allergic diseases Studies on early-life farming exposure and subsequent allergy risk have yielded inconsistent results Earlier, a protective association between early-life farm exposure and respiratory symptoms and allergy in children was reported in developed countries (Von Mutius and Vercelli, 2010) A 2012 study confirmed such an effect in affluent countries, but it found that exposure to farm animals during pregnancy and during the first year of life was associated with increased symptoms of asthma, rhinoconjunctivitis, and eczema in children living in non-affluent countries (Brunekreef et al., 2012) Several studies, including the PARSIFAL (Prevention of Allergy-Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle) study and the GABRIELA (Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community [GABRIEL] Advanced Study), showed a strong association between early-life farm exposure and lower prevalence of asthma and atopic sensitisation (Ege et al., 2011) In contrast, there is no evidence to formulate a conclusion as to whether exposure to a farming environment affects food allergy risk Other factors Other important determinants of the gut microbiota composition in infants include the country of origin (birth in an industrialised country was associated with reduced gut microbiota diversity) (Yatsunenko et al., 2012), infant hospitalisation (hospitalisation and prematurity were associated with a higher prevalence and counts of C difficile) (Penders et al., 2006), and time of weaning (as stated earlier, cessation of breastfeeding rather than introduction of solid food was more likely to contribute to the maturation of the infant’s gut microbiota) (Bäckhed et al., 2015) Differences in the microbiota in allergic and non-allergic individuals In humans, it has been suggested that the composition of the gut microbiota during early life may predict the subsequent development of allergic disorders (Arrieta et al., 2015; Bjorksten et al., 2001) Atopic subjects have more clostridia and tend to have fewer bifidobacteria than non-atopic subjects (Kalliomaki et al., 2001) Reduced diversity of gut microbiota is associated with an increased risk of atopic eczema (Abrahamsson et al., 2014; Forno et al., 2008; Penders et al., 2007; Wang et al., 2008; West et al., 2015) Several studies have also demonstrated a link between infant gut microbiota composition and wheeze and asthma (Abrahamsson et al., 2014; Van Nimwegen et al., 2011) 9.3 Gut microbiota manipulation Key observations that gut microbiota may play a role in the pathogenesis of allergic diseases have provided a strong basis for developing strategies aimed at gut microbiota normalisation Among others, these strategies include the administration of probiotics and/or prebiotics Microbiota in health and disease: from pregnancy to childhood 169 H Szajewska 9.4 Probiotics Probiotics are defined as ‘live microorganisms that, when administered in adequate amounts, confer a health benefit on the host’ (Hill et al., 2014) In humans, by far, the most commonly used probiotics are bacteria from the genus Lactobacillus or Bifidobacterium and a non-pathogenic yeast, Saccharomyces boulardii The exact mechanisms by which probiotics mediate protection against allergic diseases are not known However, strengthening of gut mucosal barrier function, activation of TH2 counter-regulatory immune responses, and maintenance of the gut microbial balance may play a role Prevention A 2015 systematic review (Cuello-Garcia et al., 2015) reviewed the role of probiotics for the prevention of allergies The reviewers concluded that there are significant benefits of probiotic supplements in reducing the risk of eczema when administered to women during the last trimester of pregnancy (14 randomised controlled trials (RCTs), n=3,109, relative risk (RR) = 0.71, 95% confidence interval (CI) = 0.60-0.84) or during breastfeeding (10 RCTs, n=1,595, RR=0.61, 95%CI=0.50-0.74); however, no such effect was observed when probiotics were used exclusively during breastfeeding (1 RCT, n=88, RR=0.57, 95%CI=0.29-1.11) Probiotics given to infants also reduced the risk of eczema (15 RCTs, n=3,447, RR=0.81, 95%CI=0.7-0.94) In contrast to the effect on eczema, probiotics compared with no probiotics had no effect on the risk of other allergies such as asthma/wheezing, food allergy, and allergic rhinitis as well as no effect on the nutritional status or incidence of adverse effects Overall, the quality of evidence was low or very low due to the risk of bias, inconsistency and imprecision of the results, and the indirectness of available research In 2015, the World Allergy Organization (WAO) developed recommendations about the use of probiotics in the prevention of allergy based on the findings from the systematic review discussed above (Table 9.1) (Fiocchi et al., 2015) One important limitation of the WAO guidelines is the lack of answers to the most important practical questions Which probiotic(s) should be used to reduce the risk of eczema? When should one start the administration of probiotics with proven efficacy? When should one stop? What is the dose of an effective probiotic? Of note, 2014 recommendations developed by the European Academy of Allergy and Clinical Immunology (EAACI), based on the results of a systematic review of RCTs (De Silva et al 2014), concluded that there is no evidence to support the use of probiotics (also prebiotics) for food allergy prevention (Muraro et al., 2014b) In summary, at the present time, there is insufficient evidence that any specific probiotic plays a significant role in the prevention of atopic disease in the infant Treatment The role of probiotics in the treatment of AD/eczema remains questionable The most recent systematic review with a meta-analysis identified 25 RCTs involving 1599 participants (Kim et 170 Microbiota in health and disease: from pregnancy to childhood Microbiota in infant allergic diseases Table 9.1 Current recommendations for the use of probiotics and prebiotics for allergy prevention World Allergy Organization (WAO) 2015 (probiotics) and 2016 (prebiotics) Probiotics Prebiotics European Academy of Allergy and Clinical Immunology 2014 Prevention of allergy There is no evidence • Evidence does not indicate that probiotic supplementation reduces the risk to support the use of of developing allergy in children prebiotics or probiotics for Prevention of eczema food allergy prevention • There is a likely net benefit from using probiotics The WAO guideline panel suggests using probiotics in: − pregnant women at high risk1 for having an allergic child; − women who breastfeed infants at high risk1 of developing allergy; − infants at high risk1 of developing allergy (conditional recommendations; very low quality evidence) The WAO guideline panel suggests: • using prebiotic supplementation in not-exclusively breastfed infants, both at high1 and at low risk for developing allergy • not using prebiotic supplementation in exclusively breastfed infants (conditional recommendations; very low quality evidence) No recommendation about prebiotic supplementation during pregnancy or in breastfeeding mothers High risk was defined as the presence of a biologic parent or sibling with asthma, allergic rhinitis, eczema, or food allergy al., 2014) Compared with placebo, the use of probiotics (in some trials together with prebiotics) significantly reduced Scoring of Atopic Dermatitis (SCORAD) values overall (weighted mean difference (WMD) -4.51, 95%CI = -6.78 to -2.24), in adults (WMD -8.26, 95%CI = -13.28 to -3.25), and in children to 18 years of age (WMD -5.74, 95%CI = -7.27 to -4.20), but not in infants younger than year (WMD 0.52, 95%CI = -1.59 to 2.63) (Kim et al., 2014) Data regarding whether probiotics may be effective in the management of cow’s milk allergy (CMA) are mixed, with encouraging results in more recent studies A 2008, double-blind, placebo-controlled RCT performed in 119 children infants with CMA found that Lactobacillus casei CRL431 and Bifidobacterium lactis Bb12 added to extensively hydrolysed formula did not significantly affect clinical tolerance to cow’s milk after and 12 months of treatment At 12 months, the cumulative tolerance to cow’s milk was 81% in the placebo group and 77% in the probiotics group (odds ratio (OR) = 1.1, 95%CI = 0.6 to 1.9) (Hol et al., 2008) Results from a more recent study suggest that the choice of probiotics and infant formula selection influence the rate of acquisition of tolerance in children with CMA One RCT randomly allocated infants Microbiota in health and disease: from pregnancy to childhood 171 H Szajewska with CMA (while still receiving intact protein formula) to either a group that received extensively hydrolysed casein formula or a group that received the same extensively hydrolysed formula containing Lactobacillus rhamnosus GG After months of an exclusion diet, a double-blind, placebo-controlled, milk challenge was performed in 55 patients, and evidence of tolerance was seen in 21.4 and 59.3% of infants, respectively However, the difference in acquisition of immunotolerance was significant only for those children with non-IgE-mediated CMA (P=0.017) (Berni-Canani et al., 2012) Another open-label, non-RCT evaluated the acquisition of tolerance in a total of 260 infants aged to 12 months with confirmed CMA fed different formulas The rate of oral tolerance after year of treatment, as determined by a food challenge, was significantly higher in the groups that received extensively hydrolysed casein formula, particularly with Lactobacillus GG (78.9%), but also without (43.6%), compared with the other groups that received hydrolysed rice formula (32.6%), soy formula (23.6%), and amino acidbased formula (18.2%) (Berni-Canani et al., 2013) Together, while these data are promising, larger RCTs are needed to confirm these findings, to define the mechanisms of action, and to evaluate the potential factors influencing the response in subjects with CMA 9.5 Prebiotics A 2015 expert definition defines a prebiotic as ‘a non-digestible compound that, through its metabolisation by microorganisms in the gut, modulates composition and/or activity of the gut microbiota, thus conferring a beneficial physiological effect on the host’ (Bindels et al., 2015) In humans, non-digestible carbohydrates, such as inulin, oligofructose, fructooligosaccharides (FOS), and galactooligosaccharides (GOS), are the most intensively studied and commonly used prebiotics Many studies have shown that they increase the faecal counts of bacteria thought to be beneficial such as bifidobacteria or certain butyrate producers Prevention See Table 9.1 for a summary of the 2014 EAACI (Muraro et al., 2014a,b) and 2016 WAO (CuelloGarcia et al., 2016) guidelines for the use of prebiotics in the prevention of allergy The latter recommendations are based on findings from 18 RCTs All studies were carried out in nonbreastfed infants Supplementation with prebiotics compared with no supplementation resulted in a reduced risk of developing asthma or recurrent wheezing (RR=0.37, 95%CI = 0.17 to 0.8), a reduced risk of developing food allergy (RR=0.28, 95%CI = 0.08 to 1.00), and a similar risk of developing eczema (RR=0.57, 95%CI = 0.3 to 1.08) As with probiotics, the effects of different prebiotics are not equivalent It remains unclear which prebiotic(s) to use; 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and Claassen, E., 2015 Safety of probiotics and synbiotics in children under 18 years of age Beneficial Microbes 6: 615-630 Wickens, K., Black, P.N., Stanley, T.V., Mitchell, E., Fitzharris, P., Tannock, G.W., Purdie, G., Crane, J and Probiotic Study Group, 2008 A differential effect of probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial Journal of Allergy and Clinical Immunology 122: 788-794 Yamasaki, C., Totsu, S., Uchiyama, A., Nakanishi, H., Masumoto, K., Washio, Y., Shuri, K., Ishida, S., Imai, K and Kusuda, S., 2012 Effect of Bifidobacterium administration on very-low-birthweight infants Pediatrics International 54: 651-656 340 Microbiota in health and disease: from pregnancy to childhood ... (WMD -8 .26 , 95%CI = -1 3 .28 to -3 .25 ), and in children to 18 years of age (WMD -5 .74, 95%CI = -7 .27 to -4 .20 ), but not in infants younger than year (WMD 0. 52, 95%CI = -1 .59 to 2. 63) (Kim et al., 20 14)... Claassen and M.D Cabana (eds.) Microbiota in health and disease: from pregnancy to childhood Microbiota in health and disease: from pregnancy Academic to childhood DOI 10.3 920 /97 8-9 0-8 68 6-8 3 9-1 _9,... Microbiota in health and disease: from pregnancy to childhood Microbiota in health and disease: from pregnancy to childhood DOI 10.3 920 /97 8-9 0-8 68 6-8 3 9-1 _10, © Wageningen Academic Publishers 20 17 179