Akihito Endo Mimi L.K. Tang Seppo Salminen
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88 Endo Tang Salminen
results in an altered intestinal microenvironment, which influences the nature of subsequent intes- tinal colonization.
In the newborn, initial colonization with facul- tative anaerobes, enterobacteria, coliforms, pro- teobacteria, lactobacilli and streptococci is rapidly followed by colonization with anaerobic genera such as Bifidobacterium , Bacteroides , Clostridium and lactic acid bacteria. Although recent research indicates that the interhost differences are much less marked than previously thought, molecular analyses demonstrate differences between the mi- crobiota of formula-fed and breastfed infants with respect to bifidobacterial numbers and species composition. In breastfed infants, bifidobacteria constitute 60–90% of the total fecal microbiota, while lactobacilli comprise less than 1% [1, 4] . The most common bifidobacterial species in breastfed infants are B. longum , B. breve and B. infantis [5] . In formula-fed infants, the microbiota is more complex and influenced by the formula composi- tion – for instance, by reported overrepresentation of Clostridium difficile and a higher richness in species. Lactic acid bacteria composition in breast- fed and formula-fed infants is similar (with some geographic differences), with Lactobacillus casei group microorganisms such as L. paracasei and L. rhamnosus being common [unpubl. results].
Differences in microbiota between breastfed and formula-fed infants have lessened with improved infant formulae.
Gut Microbiota in the First Six Months of Life Breastfeeding for 4–6 months will assist in the de- velopment of healthy gut microbiota by provid- ing bifidobacteria and lactic acid bacteria, which reinforce colonization, and by supplying human milk oligosaccharides, which promote a healthy microbiota composition. Breastfeeding also facil- itates the exchange of microbes between mother and infant, since breast milk itself is a rich source of bacteria. Of note, the breast milk microbiota in
mothers having a cesarian section differs from that of mothers having a vaginal delivery [6] . Microbes are also exchanged via skin contact and exposure to the microbiota in the immediate en- vironment. Every individual has a unique, char- acteristic microbiota during later phases of breastfeeding that comprises a dynamic mixture of microbes typical to each individual. Weaning, introduction of solid foods, and antimicrobial drug treatment will break the constant supply of oligosaccharides and microbes from the mother, thus affecting intestinal microbiota development.
Molecular analysis of bacterial communities in healthy babies during the first 10 months of life demonstrates progression from a simple profile in the first days of life to a more complex, diverse profile with members of the genera Bifidobacte- rium , Ruminococcus , Enterococcus , Clostridium and Enterobacter identified by 6 months of age [1–4] . Bifidobacterium and Ruminococcus species dominate the intestinal microbiota with high- level, stable expression over time. A Canadian study on 4-month-old infants reported higher bi- fidobacterial levels and lower clostridial numbers in breastfed infants than in infants receiving for- mula [14] . Ongoing improvements in formulae have lessened these differences [7] .
The healthy intestinal microbiota in infancy is characterized by a large Gram-positive bacterial population which contains significant numbers of bifidobacteria, mainly B. longum , B. breve and B.
infantis . Lactic acid bacteria may play a role in pro- viding the right intestinal environment for bifido- bacteria to dominate. A healthy microbiota during infancy is particularly important as this establish- es the basis for healthy gut microbiota later in life.
Gut Microbiota in Infants from Six Months Onward
After the first 6 months of life, the microbiota be- comes more diverse [1, 6, 9] . Several studies have examined the progression of microbiota from birth
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 87–91 DOI: 10.1159/000360322
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through the first years of life (summarized in fig. 1 ).
Weaning is associated with changes including in- creased levels of Escherichia coli , enterococci, bac- teroides and anaerobic gram-positive cocci and de- creased enterobacteria. Differences between breast- fed and formula-fed infants seem to disappear.
By 1–2 years of age, the microbiota resembles that of adults, although levels of bifidobacteria and enterobacteria in children (16 months to 7 years) remain higher than in adults. Early change of the microbiota to the adult type may be linked with development of eczema [9] . The intestinal microbiota is crucial for normal development of the gut-associated lymphoid tissue and has im- portant effects on intestinal mucosal barrier function and other aspects of intestinal function.
Immune Development
Microbial colonization of the newborn intestine is required for normal immune development, which in turn is important for regulation of gut
inflammatory responses and oral tolerance in- duction. The mucosal immune system of the gas- trointestinal tract is constantly challenged by di- verse antigens, such as microbial and food anti- gens. Such priming of the gut-associated lymphoid tissue is important for two opposing functions:
mounting a response to pathogens and maintain- ing hyporesponsiveness to innocuous antigens.
Mice raised in a germ-free environment fail to de- velop oral tolerance and have a persistent Th2- dependent antibody response [11] . This immune deviation can be corrected by reconstitution of intestinal microbiota, but only if this occurs dur- ing the neonatal period [11] . Prenatal exposure to companion animals is linked with changes in mi- crobiota and infantile pet exposure is negatively associated with wheezy bronchitis at 24 months of age [10] .
An important question is how the microbiota is altered by the significant changes in diet dur- ing the first years of life, and how this affects in- testinal immune development; the host-microbe crosstalk during and after breastfeeding is criti-
Microbial concentration (relative to total)
24 months 6 months
Age
Lactobacilli Unculturables
Bifidobacteria Coliforms Clostridia Bacteroides Others
0 months Adults
Fig. 1. Relative changes in gut microbiota composition suggested by culture-dependent and cul- ture-independent studies. The numbers of bifidobacteria can be influenced by diet, probiotics and prebiotics.
90 Endo Tang Salminen
cal in this regard. The strains of healthy gut mi- crobiota are likely to stimulate local and systemic immune responses via pattern recognition mol- ecules such as Toll-like receptors, providing the host with an anti-inflammatory stimulus and di- recting the host-microbe interaction toward im- mune tolerance. The bifidobacteria-dominated environment in childhood in particular may pro- vide more of an anti-inflammatory stimulus than bacteria from adults, which have been shown to be more proinflammatory. A complex microbial community is required to achieve a healthy mi- crobiota that exhibits powerful antipathogenic and anti-inflammatory capabilities.
Intestinal Function
An absent or inadequate intestinal microbiota has been shown to cause defects in intestinal barrier function. The microbiota may also influence oth- er intestinal functions. Before weaning, formula- fed infants have a greater ability to ferment com- plex carbohydrates than breastfed infants, prob- ably due to the presence of a more complex microbiota. Following weaning, these differences disappear. Breastfed infants have delayed estab- lishment of mucin-degrading microbiota, but this increases in both groups between 6 and 9 months.
Conversion of cholesterol to coprostanol com- mences after 6 months of age, and levels of am- monia, phenol, β-glucosidase and β-glucuronidase activity increase after weaning.
Maintenance and Modulation of the Individually Optimized Healthy Microbiota The healthy gut microbiota created during early life must be maintained throughout life. Devia- tions in microbiota associated with disease can be redirected to a healthy balance by dietary means, for instance by using probiotics or prebiotics.
Probiotics are defined as viable microbes which
through oral administration produce health ben- efits to the host. Probiotics are members of the healthy gut microbiota that mimic the healthy microbiota of a healthy infant, and are generally regarded as safe [12] . Prebiotics are oligosaccha- rides that promote expansion of specific microbes with potential to maintain health. A prerequisite for the efficacy of prebiotics is that such strains are already present in the gut. Carefully designed combinations of probiotics and prebiotics may offer an optimal means of creating and maintain- ing a healthy microbiota as this would mimic the mother-infant relationship of offering both mi- crobes and oligosaccharides to the newborn in- fant.
It is important to recognize that individual probiotic bacterial strains can have distinct and specific effects. Therefore, the effects of one pro- biotic strain cannot be generalized to another, and the individual properties of a probiotic strain must be evaluated prior to clinical application.
Furthermore, in addition to species/strain-spe- cific effects of probiotics, the timing of probiotic administration may also be important. Meta- analysis of randomized controlled trials of probi- otic interventions for allergic disease prevention show beneficial effects when probiotic supple- mentation is commenced during the prenatal pe- riod, and not when probiotics are solely adminis- tered to the infant postnatally [13] . This suggests that prenatal administration may be a requisite for efficacy in the prevention of allergic disease.
These results highlight the different effects of specific probiotics, which are further supported by genomic studies.
Similarly, prebiotic oligosaccharides have dif- ferent microbiota-modifying properties. Al- though most prebiotic components have been shown to enhance the bifidobacterial microbiota, detailed investigation of specific effects is re- quired. A wide variety of oligosaccharides (hu- man milk oligosaccharides) is found in breast milk and has documented bifidogenic and health- promoting effects on the infant gut. Combina-
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 87–91 DOI: 10.1159/000360322
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tions of galactooligosaccharides and fructooligo- saccharides have been used in infant formulae in specified conditions. Some fructooligosaccha- rides have been reported to enhance levels of un- known microbes in the human gut, thus poten- tially facilitating untoward effects in infants.
Therefore, when evaluating a probiotic or pre- biotic for clinical use, the safety and clinical bene- fit of that specific product must be documented before it can be recommended for clinical appli- cation.
Conclusions
• The healthy human microbiota is metabolically active and provides an important defense mechanism for the host. Deviations in its com- position are related to multiple disease states
promoting the bifidogenic environment via prebiotic galactooligosaccharides and microbes in breast milk and introducing environmental bacteria through contact with the infant • Both the succession of microbial communities
during the first years of life and the sequelae of these events need to be clarified in more detail • The first colonization steps have a crucial role
in the infant microbiota and later health. Bifi- dobacteria play a key role in this process • The mother-infant contact has an important
impact on initial microbiota development, pro- viding the critical first inoculum already prior to birth, followed by another inoculum at deliv- ery, and then progressing with breastfeeding • The potential application of specific probiotics
and/or prebiotics to influence microbiota de- velopment for the treatment and prevention of disease also warrants further evaluation
10 Nermes M, Niinivirta K, Nylund L, Laitinen K, Matomọki J, Salminen S, Isolauri E: Perinatal pet exposure, faecal microbiota, and wheezy bronchitis: is there a connection? ISRN Allergy 2013;
2013: 827934.
11 Sudo N, Sawamura S, Tanaka K, et al:
The requirement of intestinal bacterial flora for the development of an IgE pro- duction system fully susceptible to oral tolerance induction. J Immunol 1995;
159: 1739–1745.
12 van Loveren H, Sanz Y, Salminen S:
Health claims in Europe: probiotics and prebiotics as case examples. Annu Rev Food Sci Technol 2012; 3: 247–261.
13 Tang ML, Lahtinen SJ, Boyle RJ: Probi- otics and prebiotics: clinical effects in allergic disease. Curr Opin Pediatr 2010;
22: 626–634.
14 Azad MB, Konya T, Maughan H, Gutt- man DS, Field CJ, Chari RS, Sears MR, Becker AB, Scott JA, Kozyrskyj AL;
CHILD Study Investigators: Gut micro- biota of healthy Canadian infants: pro- files by mode of delivery and infant diet at 4 months. CMAJ 2013; 185: 385–394.
References
1 Rautava S, Luoto R, Salminen S, Isolauri E: Microbial contact during pregnancy, intestinal colonization and human dis- ease. Nat Rev Gastroenterol Hepatol 2012; 9: 565–576.
2 Jost T, Lacroix C, Braegger CP, Chassard C: New insights in gut microbiota estab- lishment in healthy breast fed neonates.
PLoS One 2012; 7:e44595.
3 Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Bọckhed HK, Gonza- lez A, Werner JJ, Angenent LT, Knight R, Bọckhed F, Isolauri E, Salminen S, Ley RE: Host remodeling of the gut mi- crobiome and metabolic changes during pregnancy. Cell 2012; 150: 470–480.
4 Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J, Knight R, Angenent LT, Ley RE: Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci USA 2011; 108(suppl 1):4578–4585.
5 Favier CF, Vaughan EE, de Vos WM, Akkermans AD: Molecular monitoring of succession of bacterial communities in human neonates. Appl Environ Mi- crobiol 2002; 68: 219–226.
6 Cabrera-Rubio R, Collado MC, Laitinen K, Salminen S, Isolauri E, Mira A: The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. Am J Clin Nutr 2012; 96: 544–551.
7 Rinne MM, Gueimonde M, Kalliomọki M, Hoppu U, Salminen SJ, Isolauri E:
Similar bifidogenic effects of prebiotic- supplemented partially hydrolyzed in- fant formula and breastfeeding on infant gut microbiota. FEMS Immunol Med Microbiol 2005; 43: 59–65.
8 Jost T, Lacroix C, Braegger C, Chassard C: Assessment of bacterial diversity in breast milk using culture-dependent and culture-independent approaches. Br J Nutr 2013; 110: 1253–1262.
9 Nylund L, Satokari R, Nikkilọ J, Rajilić- Stojanović M, Kalliomọki M, Isolauri E, Salminen S, de Vos WM: Microarray analysis reveals marked intestinal mi- crobiota aberrancy in infants having eczema compared to healthy children in at-risk for atopic disease. BMC Micro- biol 2013; 13: 12.
2 Nutrition of Healthy Infants, Children and Adolescents
Key Words
Breastfeeding ã Human milk ã Lactation ã Health benefits ã Preterm infants ã HIV, mother-to-child transmission
Key Messages
• Breastfeeding provides optimal nutrition for infants • Breastfeeding has significant positive effects on in- fant health, growth and development and decreas- es the risk of diseases later in life
• Infants should preferably be exclusively breastfed for about 6 months and should continually be breastfed up to the age of 12 months or beyond • In most populations, the duration of breastfeeding
is considerably shorter than recommended. The health profession has therefore an important role in protecting, promoting and supporting breast- feeding © 2015 S. Karger AG, Basel
Introduction
Breastfeeding provides optimal nutrition for the infant and also has many important nonnutri- tional benefits for the child and the mother [1–
5] . Therefore, it has been recommended by the WHO and pediatric societies that one should
aim for exclusive breastfeeding of infants for about 6 months [1, 2] . In industrialized coun- tries, continued partial breastfeeding up to the age of 12 months or beyond is the general rec- ommendation. In populations with high rates of infectious diseases, breastfeeding during the 2nd year of life or longer has been shown to reduce morbidity and mortality, and therefore the rec- ommendation by the WHO has been to continue breastfeeding until the age of 24 months or be- yond. In most populations, the duration of both exclusive breastfeeding and continued breast- feeding is considerably shorter, emphasizing the need to protect, promote and support breast- feeding via broad public health initiatives and support from the health care systems. It has been estimated that, globally, suboptimal breastfeed- ing may result in more than 800,000 deaths an- nually [5] .
Content of Human Milk
Human milk has about the same energy content as cow’s milk, while many nutrients important for growth such as protein, sodium, potassium, mag- nesium and zinc are present in much lower quan-
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 92–96 DOI: 10.1159/000360323
2.1 Breastfeeding
Kim F. Michaelsen
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tities, typically one third to half of the content found in cow’s milk ( table 1 ). This is a reflection of the much slower growth velocity in infants than in calves, and thereby a lower requirement for growth nutrients. The fat content is at the same level as in cow’s milk, while the content of lactose is considerably higher. Human milk also contains many other substances apart from nutri- ents with specific important functions. These in- clude hormones, growth factors, oligosaccha- rides, and immune-related compounds such as antibodies (sIgA), leukocytes (B and T lympho- cytes, neutrophils and macrophages), nucleotides and cytokines. These nonnutritional substances are involved in many of the short- and long-term effects breastfeeding has on the infant.
Positive Effects on the Infant and Mother Breastfeeding has significant positive effects on health and development during infancy, with some effects reaching into childhood and adulthood [1, 2, 6] . Most studies, however, are observational, and confounding can therefore be difficult to rule out;
mothers who choose to breastfeed in industrial- ized countries, for example, are typically better ed- ucated and their children also have a lower risk of developing some diseases. Nevertheless, for many of the effects there is convincing evidence.
The most evident effect of breastfeeding is pro- tection against infectious diseases, especially di- arrhea and respiratory tract infections [1] . This is the main reason that mortality in low-income countries is several times higher among those not being breastfed. In high-income countries, the risk of diarrhea in breastfed infants is only about one third of the risk in infants not breastfed [2] . These differences could be explained by passive protection of mucous membranes provided by the antibodies and other immune components in hu- man milk, but there is also evidence that the child’s own immune system is positively influ- enced by breastfeeding. There is also convincing evidence that breastfeeding has positive effects on long-term health and development [1, 2, 6] . The influence of breastfeeding on the development of the immune system could be the reason for the fact that some immune-related diseases, e.g. asth- ma, type 1 diabetes, inflammatory bowel diseases and some childhood cancers, are less common among children who have been breastfed than among children who are predominantly formula fed. A consistent finding throughout many stud- ies from both industrial and low-income coun- tries is a small but significant advantage of breast- feeding to later cognitive function [6] . This effect is likely to be related to an optimal ratio between n–3 and n–6 fatty acids and the content of the long-chain polyunsaturated fatty acid docosa-
Table 1. Mean macronutrient and energy contents in mature human milk and in cow’s milk
Component Mature human
milk (≥14 days)
% of energy
Cow’s milk % of
energy
Protein 1.0 g/100 g 6 3.4 g/100g 21
Of which caseins 0.4 g/100 g (40% of protein)
2.4 2.8 g/100 g (80% of protein)
17
Fat 3.8 g/100 g 52 3.7 g/100 g 51
Lactose 7.0 g/100 g 42 4.6 g/100 g 28
Minerals 0.2 g/100 g – 0.8 g/100 g –
Energy 66 kcal/100 g 100 65 kcal/100 g 100
Adapted from Koletzko [13].
94 Michaelsen
hexaenoic acid in human milk. Breastfeeding has also an effect on growth. Breastfed infants gain weight faster during the first months of life and are leaner and slightly shorter than formula-fed infants at the age of 12 months [ 7 ; Chapter 1.1].
This was the main reason why the WHO devel- oped a new global growth standard based on breastfed infants [ 8 , 9 ; Chapter 4.1]. It has been suggested that the difference in growth pattern could be one of the reasons why breastfed infants have a lower risk of some noncommunicable dis- eases, including obesity, later in life.
Breastfeeding also affects maternal physiolo- gy and health. From a global perspective, the most important byproduct is the inhibitory effect on ovulation, i.e. lactational amenorrhea, which in populations with low use of contraceptives en- hances child spacing, and thereby has a positive effect on infant and young child health. Breast- feeding also has a positive effect on maternal health. Breastfeeding induces utilization of ma- ternal body fat stores and thus can help to de- crease excessive body fat depots. Cumulative du- ration of breastfeeding for more than 12 months is in some studies associated with substantial re- ductions in the risk of breast and ovarian cancer, type 2 diabetes and rheumatoid arthritis [2] .
Potential Untoward Effects of Breastfeeding
Transmission of HIV
Breastfeeding can cause mother-to-child trans- mission of HIV. Therefore, breastfeeding by HIV-positive mothers is not recommended in high-income countries. In low-income countries with a high prevalence of infectious diseases and high infant mortality, mothers are recommended to breastfeed until 12 months of age if they receive antiretroviral drugs. In these settings, replace- ment feeding should only be used if it is accept- able, feasible, affordable, sustainable and safe.
The UN agency guidelines on HIV and infant feeding were updated 2010 [10] .
Hypernatremic Dehydration
If there are problems with initiation of milk pro- duction during the first 1–2 weeks after delivery and no other fluids are given, there is a risk that the infant develops hypernatremic dehydration.
In severe cases this can cause convulsions and brain damage, and in rare cases death [11] . This can be prevented by supervision and support dur- ing initiation of breastfeeding, monitoring weight loss and urine production, and provision of other fluids if there are signs of dehydration.
Environmental Contaminants
The content of environmental contaminants is higher in breast milk than in cow’s milk or infant formulae because of the accumulation particular- ly of lipid-soluble contaminants in maternal tis- sues [1] . Some studies have shown an association between high levels of contaminants in the moth- er’s blood and negative effects on health and de- velopment of the infant. However, it is difficult to disentangle intrauterine exposure from exposure through breast milk. There is general agreement that the positive effects of breastfeeding are far more important than the potential negative ef- fects, but also that it is important to reduce the level of contaminants in the environment and in the diet of pregnant and lactating mothers.
Maternal Medication
Most drugs given to a breastfeeding mother are excreted in her milk. However, there are only a few drugs with an absolute contraindication. A mother should not breastfeed if she receives che- motherapy, ergotamines, amphetamines or statins [2] . Information on the safety of maternal medication is given on the LactMed website [12] .
Support of Breastfeeding
Many factors influence the initiation and dura- tion of breastfeeding: cultural patterns, the moth- er’s perception, and the attitudes of friends and
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 92–96 DOI: 10.1159/000360323