Which outcome is a risk factor associated with feeding infants formula that is too concentrated

The intestine as the first barrier for nutrients and luminal components and the endocrine pancreas for its major role in glycidic homeostasis have a central role in determining postnatal defence and metabolic programming. At birth the gastrointestinal tract and the pancreas are immature and their development continues during the first years of life. Although mainly genetically programmed, these developmental changes can be modulated by the diet. Breast-feeding is the best protection for infants after birth and as such reduces the risk of diseases during the milk period. It is also associated with long-term health benefits. Compared with formula, human milk is very complex, providing both an optimal nutrition for the newborn and components with biological activities that drive the growth of the intestine and pancreas and contribute to the development of mucosal defences.

The objective of the present review is to compare the effect of breast- v. formula-feeding on the postnatal development of the gastrointestinal tract and the endocrine pancreas and discuss the possible consequences of these differences later in life (Fig. 1). The prevalence of breast-feeding and the associated short- and long-term health benefits, as well as the dynamic changes in human milk composition are considered first. Differences in the pattern of intestinal and pancreatic development during the early postnatal period in breast-fed v. formula-fed neonates are then reviewed. Finally, evidence is given to support the fact that modifying the nutritional content or adding human milk-like components to formula may be favourable for the intestinal and pancreatic developmental patterns. The focus is principally on intestinal and pancreatic development in humans. However, the effect of nutrition on the postnatal gastrointestinal tract and pancreas growth and development is poorly defined in humans, mostly because of ethical difficulties in conducting nutritional intervention studies and obtaining tissue from healthy infants. Therefore, results from in vitro or experimental animal studies have been included.

Short- and long-term child health benefits associated with breast-feeding

Short- and long-term child health benefits associated with breast-feeding have been widely reported(Reference Horta, Bahl and Martines3) and concerns several organs and tissues(Reference Hoddinott, Tappin and Wright2). Benefits are largely dependent on the duration of breast-feeding and on the age of introduction of complementary foods. When focusing on the digestive tract, short-term benefits includes reduced risks of infectious diarrhoea and necrotising enterocolitis(Reference Agostoni, Braegger and Decsi4). Diarrhoea was reported to be reduced by half in breast-fed v. formula-fed infants during the period of breast-feeding(Reference Hoddinott, Tappin and Wright2, Reference Dewey, Heinig and Nommsenrivers5) or even beyond(Reference Howie, Forsyth and Ogston6). Food allergies have also been reported to be less frequent in breast-fed infants(Reference Saarinen and Kajosaari7) although other studies have failed to detect such associations(Reference Savilahti and Saarinen8). Breast-feeding has also been associated with a reduced risk of type 1 diabetes in infancy(Reference Mayer, Hamman and Gay9), while early introduction of cows' milk has been associated with increased risk through stimulation of the autoimmune process(Reference Virtanen and Knip10). However, in a recent extended secondary analysis of a population-based cohort, very early exposure to cows' milk was demonstrated not to be a risk factor for type 1 diabetes and even to diminish its appearance before 8 years of age(Reference Savilahti and Saarinen8). In the same study, no association between breast-feeding duration and the appearance of type 1 diabetes could be found(Reference Savilahti and Saarinen8).

Long-term consequences of breast-feeding on health have also gained an increasing attention during recent decades. Breast-feeding may confer protection against diseases such as inflammatory bowel disease and type 2 diabetes, as well as against obesity. The role of breast-feeding in the development of paediatric inflammatory bowel disease was the object of a recent meta-analysis(Reference Barclay, Russell and Wilson11). Breast milk exposure had a significant protective effect on the development of early-onset inflammatory bowel disease, although the authors highlighted the poor quality of existing data and the need to perform well-designed prospective studies. Moreover, it has been specifically demonstrated that in a population with a high prevalence of type 2 diabetes, the Pima Indians, people who had been exclusively breast-fed had significantly lower rates of type 2 diabetes than those who had been exclusively formula-fed(Reference Pettitt, Forman and Hanson12). A recent analysis of published studies acknowledged that breast-feeding in infancy was associated with a reduced risk of type 2 diabetes, with marginally lower insulin concentrations later in life, and lower blood glucose and serum insulin concentrations in infancy(Reference Owen, Martin and Whincup13). A recent report of the WHO underscores the fact that although the beneficial effects of breast-feeding were statistically significant, their magnitude may be relatively modest for some health outcomes(Reference Horta, Bahl and Martines3). The beneficial effect of breast-feeding was smaller for the prevention of type 2 diabetes than those derived from other public health interventions such as dietary advice and physical activity. Breast-feeding was associated with a 22 % reduction in the prevalence of overweight/obesity(Reference Horta, Bahl and Martines3) while the effectiveness of dietary education and physical activity is still debated(Reference Doak, Heitmann and Summerbell14). Therefore the epidemiological data clearly highlight the importance of breast-feeding and its consequences on the susceptibility to later developing diseases.

Human milk composition

There may be several reasons for differences in the health of breast-fed and formula-fed infants. The complex composition of human milk and its dynamic changes over the lactation period are likely to play a major role. In addition to nutrients, human milk also contains hormones, growth factors, immunoglobulins, cytokines, enzymes, etc that support both the growth and the passive defences of the infant. Human milk composition is influenced by gestational age at parturition and postnatal age and it can actively accelerate the development of the infant's own defences(Reference Walker15).

The protein content of human milk decreases rapidly during the first month of lactation (14–16 g/l during early lactation, 8–10 g/l at 3–4 months and 7–8 g/l at 6 months and later). This decrease is mainly due to the diminution in whey protein concentration(Reference Kunz and Lönnerdal16). The ratio of whey:casein changes from 80:20 during the first days of lactation to 60:40 at 2–3 months of lactation. As a consequence, the amino acid content of human milk also varies during the early phase of lactation. The concentration of lipids and lactose is low in the very early milk, which results in a lower energy content of breast milk during early lactation. Thereafter, the fat content of human milk is on average 35 g/l. It is noticeable that although always present, the concentration of PUFA varies widely between women, reflecting the composition of fat in the mother's diet(Reference Innis17). Carbohydrates (about 75 g/l) are mainly provided by lactose (85 %) and complex oligosaccharides.

Human milk also contains a wide variety of proteins that display multiple biological activities: modulation of digestion and utilisation of macro- and micronutrients; immunomodulatory activities; trophic effects on intestinal mucosa; hormonal activities (Table 2). Proteins of human milk are specific and quite different from bovine proteins, and there is a wide variety of unique proteins in human milk with particular biological activities (Table 2). The protein composition of formula reflects more that of mature human milk, without taking into account the gradually changing pattern of human milk protein content along the breast-feeding period, although this goal seems now to be technically and nutritionally conceivable(Reference Lönnerdal18). Considering fat, carbohydrate, mineral and vitamin contents, formula diets are similar to mature human milk, though some components (sphingomyelin, specific oligosaccharides, etc) are still lacking.

Table 2 Overview of the proteins in human and bovine milk and their proposed bioactive functions*

Fig. 4 Basal glycaemia (a) and area under the postprandial time-course curve (AUC) of glucose response above basal values (b) in breast-fed, formula-fed and low-protein formula-fed piglets. Piglets were either breast-fed (BF) or formula-fed from day 7 to day 28 of life with a standard formula (FF) or a low-protein formula providing the same level of protein as sows' milk (LP-FF). Values are means, with standard errors represented by vertical bars. Basal glycaemia was lower in BF piglets than in FF piglets and reducing the protein content of the formula restored the glycaemia to the level of the BF piglets. Postprandial glucose AUC was higher in BF compared with formula-fed piglets, whatever the protein content of the formula (FF and LP-FF). * Mean value was significantly different from that of the FF group (P < 0·05).

Fig. 5 Area under the postprandial time-course curve (AUC) of insulin (a), glucagon-like peptide-1 (GLP-1) (b) and glucose-dependent insulinotropic polypeptide (GIP) (c) responses above basal values in breast-fed, formula-fed and low-protein formula-fed piglets. Piglets were either breast-fed (BF) or formula-fed from day 7 to day 28 of life with a standard formula (FF) or a low-protein formula providing the same level of protein as sows' milk (LP-FF). Values are means, with standard errors represented by vertical bars. The diet did not modify postprandial insulin concentration. FF piglets had higher postprandial GLP-1 and GIP concentrations than BF piglets and lowering the protein content of the formula normalised postprandial GLP-1 and GIP concentrations compared with BF piglets. * Mean value was significantly different from that of the FF group (P < 0·05).

For ethical reasons, no information comparing pancreas development in breast-fed v. formula-fed infants is available, even though differences in insulin secretion have been demonstrated. Similarly there are no data from experimental animal studies. In piglets aged 28 d, we recently found a higher percentage of endocrine tissue due to a higher diameter of the islets in suckled compared with formula-fed piglets (S Blat, A Morise, A Sauret, C Magliola, K Macé, I Le Huërou-Luron and B Sève, unpublished results). This was associated with the higher postprandial glycaemia in suckled v. formula-fed piglets described above.

Towards improved formula to avoid disadvantageous formula-feeding impact on intestinal and pancreatic structure and functions

Protein content

Cows' milk protein is the major source of protein in an infant formula. Present recommendations set a minimum protein quantity of 0·43 g/100 kJ (1·8 g/100 kcal), similar to human breast milk. However, due to differences in protein and amino acid digestibility, bioavailability and efficiency of utilisation between human milk and formula, the amount of protein per energy content is generally higher in formula than in human milk to meet the protein and amino acid requirements of infants (up to 0·60 g/100 kJ (2·5 g/100 kcal) for the formula), i.e. up to 40 % more protein(Reference Jost, Maire and Maynard83, Reference Macé, Steenhout, Klassen, Rigo and Ziegler84). The present tendency is to reduce protein content in formulas towards the minimal level, but its impact on intestinal function has not been investigated.

Using the piglet model, we observed that reducing the protein content of formula towards sows' milk protein level prevented the trophic effect of a standard formula containing 50 % more protein than sows' milk observed in the jejunum (Fig. 2; I Le Huërou-Luron, G Boudry, A Morise and B Sève, unpublished results) but did not modify the effect of formula-feeding on epithelial barrier function (Fig. 3; G Boudry, A Morise, B Sève and I Le Huërou-Luron, unpublished results). It also changed the intestinal lactase and pancreatic trypsin activities towards a maternal milk profile.

In the same piglet model, reducing the protein content of the formula tended to lower the basal glycaemia to a level more similar to that of suckled piglets but did not modify the formula-induced reduction of postprandial glycaemia (Figs. 4 and 5; S Blat, A Morise, A Sauret, C Magliola, K Macé, I Le Huërou-Luron and B Sève, unpublished results). Moreover lower protein content of the formula lowered the postprandial GLP-1 and GIP secretion to levels identical to suckled piglets (Fig. 5). The structure of the endocrine pancreas at the end of the milk period was, however, identical with the two formulas.

PUFA

The long-chain PUFA, arachidonic acid and DHA, are essential structural lipid components of biomembranes and are crucial for normal central nervous system and retina development. Supplementation of formula with these long-chain PUFA has been encouraged to enhance DHA and arachidonic acid status in blood, brain and retina lipids to similar levels of the breast-fed infant. The clinical trials in preterm and healthy full-term infants demonstrated benefits of formula supplementation with DHA and arachidonic acid for the development of visual acuity up to 1 year of age and of complex neural and cognitive functions. At the intestinal level, few trials have evaluated the effect of supplementation of formulas with long-chain PUFA. The only report concluded in no difference in intestinal permeability between long-chain PUFA-supplemented and non-supplemented formula-fed babies(Reference Colome, Sierra and Blasco85).

Prebiotics

Human milk contains a high amount of complex indigestible oligosaccharides (up to 8 g/l), which are not found in formulas and are thought to be of benefit for the breast-fed infants. In an attempt to provide formula-fed infants with similar benefits, some companies have started supplementing their formulas with oligosaccharides that are, however, structurally different from human oligosaccharides: fructo-oligosaccharides, galacto-oligosaccharides and inulin. The results from several studies clearly demonstrate that these prebiotic mixtures specifically stimulate the growth of bifidobacteria and lactobacilli and reduce the growth of pathogens. The SCFA pattern also tends to be similar to that of breast-fed infants (for a review, see Farano et al. (Reference Farano, Boehm and Garssen86)). While the effect of these prebiotics on intestinal microbiota has been and is still largely explored, few studies have investigated the actual effect of these supplements on intestinal physiology. One study compared intestinal permeability of neonates breast-fed or fed formulas with or without prebiotics. The authors did not observe difference in the lactulose:mannitol ratio between the two groups(Reference Colome, Sierra and Blasco85). The effect of a mixture of galacto-oligosaccharides and inulin on intestinal structure and permeability as well as translocation has been investigated in formula-fed rats. The supplemented group exhibited a higher number of mucosa-associated enterobacteria and an increased incidence of translocation compared with the non-supplemented and the mother-reared group. Epithelial colonic permeability assessed in Ussing chambers was not different amongst groups although ZO1 mRNA expression was reduced by 40 % in the supplemented group compared with the non-supplemented(Reference Barrat, Michel and Poupeau87). A similar galacto-oligosaccharides-induced increase in bacterial translocation has already been observed in adults(Reference Bovee-Oudenhoven, Ten Bruggencate and Lettink-Wissink88, Reference Ten Bruggencate, Bovee-Oudenhoven and Lettink-Wissink89) but whether such a phenomenon in the neonate could be beneficial or not for the maturation of the immune system has not been determined.

Secretory IgA

Breast milk contains high levels of secretory IgA (0·5 to 1·2 g/l), higher than in serum. Secretory IgA prevents attachment and invasion of pathogens by competitively binding and neutralising bacterial antigens. Supplementation of formula with human IgA decreases the incidence of translocation to the liver and spleen in rabbits(Reference Maxson, Johnson and Jackson90). Similarly, supplementation of formula with IgA (but not with IgG) for 7 d decreases the incidence of bacterial translocation to the mesenteric lymph nodes in rabbits to a level similar to that in suckled animals. The passage of labelled Escherichia coli C25 across the ileal epithelium in vitro was reduced in the IgA-supplemented formula-fed animals compared with the non-supplemented or IgG-supplemented animals, suggesting that the action of IgA was at the luminal or epithelial level rather than in the mesenteric lymph nodes themselves(Reference Dickinson, Gorga and Garrett91).

Lactoferrin

Lactoferrin concentration in breast milk varies with lactation stage: from about 10 g/l in colostrum to 3 g/l in mature milk. Lactoferrin antimicrobial activity is due partly to its high affinity for Fe. The combination of Fe and lactoferrin in milk modulates the growth and aggregation of pathogenic bacteria, and inhibits both bacteria and viruses by binding to cell and viral particles. Lactoferrin also possesses anti-inflammatory properties and seems to be involved in phagocytic killing and immune responses. The effect of lactoferrin supplementation of formula to modulate faecal microbiota seems limited, although some ‘bifidogenic’ effect was reported(Reference Balmer, Scott and Wharton92, Reference Roberts, Chierici and Sawatzki93). Similarly, addition of lactoferrin in formula did not affect bacterial translocation in rabbits(Reference Dickinson, Gorga and Garrett91). Nevertheless, a growth factor effect of lactoferrin has been reported in in vitro or ex vivo devices: supplementation of formula with human lactoferrin increases thymidine incorporation into the DNA in a rat crypt cells bioassay(Reference Nichols, McKee and Putman94); lactoferrin also increases proliferation and differentiation in various intestinal epithelial cell lines(Reference Hagiwara, Shinoda and Fukuwatari95, Reference Buccigrossi, de Marco and Bruzzese96). However, no in vivo assay has been performed.

Growth factors

Human breast milk contains various factors such as epidermal growth factor (EGF; range 30–100 μg/l), insulin-like growth factor-I (IGF-I; range 6–8 μg/l) or transforming growth factor-β (range 1–2 μg/l) that are suspected of modulating intestinal growth and maturation. Rat pups fed a formula supplemented with pharmacological or physiological doses of EGF for 3–4 d showed an increased intestinal cell proliferation compared with rats fed the non-supplemented formula(Reference Berseth97, Reference Pollack, Goda and Colony98). Other studies have investigated the effect of EGF with parenteral administration, which makes it difficult to conclude on the beneficial effect of supplementing formulas with this growth factor. It is, however, interesting to notice that subcutaneous treatment of formula-fed rabbits with EGF significantly reduced bacteria translocation to levels similar to those in suckled rabbits(Reference Okuyama, Urao and Lee99). IGF-I might also have a trophic effect, since feeding piglets with formula supplemented with pharmacological doses of recombinant human IGF-I increases enzymes (lactase and maltase) and villous height of the small intestine(Reference Houle, Schroeder and Odle100) compared with non-supplemented animals. Results are not so clear-cut when physiological doses of IGF-I are provided to young piglets(Reference Marion, Bebin, Thomas and ITP and INRA101).

Nucleotides

Human breast milk naturally contains free nucleotides (50–150 μmol/l) which can be added in formulas. Various studies have examined the effect of dietary nucleotides on intestinal structure and function in adults(Reference Yu102), concluding with a trophic effect of nucleotides. However, few studies have examined the effect of supplementing formula with those compounds on intestinal structure of the neonate. The effects of nucleotide-supplemented formulas on infant microbiota are contradictory: some clinical trials observed a bifidogenic effect of nucleotides on faecal microbiota(Reference Gil, Corral and Martinez-Valverde103) while others did not(Reference Balmer, Hanvey and Wharton104). Intestinal permeability and pancreatic enzyme secretion were also not modified by the addition of nucleotides in the formula of neonates(Reference Cosgrove, Losty and Jenkins66, Reference Colome, Sierra and Blasco85).

Concluding remarks

Clinicians have long noticed that infants fed breast milk display better resistance to illness during the first year of life. The more recent awareness of the long-term health benefits of breast-feeding has re-stimulated research on formula composition which must provide both nutrition and support for functional development of organs. Changes in lifestyle during recent decades, including nutritional habits of nursing mothers that may influence breast-milk composition, duration of breast-feeding and the physiological properties of some molecules present in the breast-milk as well as formula composition are also taken into account. Surprisingly incomplete attention has been paid to the role of breast-feeding v. formula-feeding on the functional development of the digestive tract, in spite of its main role in processing dietary molecules into available nutrients for the organism, allowing their utilisation by peripheral tissues, and in regulating the flux of antigenic materials that participate in the maturation of gut-associated lymphoid tissue. One major issue in human studies on the effect of breast- v. formula-feeding on the digestive tract function is the great number of confounding factors which are difficult to circumvent, such as quantification of food intake in breast-fed infants, the very variable length of exclusive breast-feeding and the great variability of the composition of formulas. Animal models are of great help to control some of these confounding factors even if controlling food intake in suckled animals is difficult too. Artificial rearing on formula is also not always possible due to immaturity at birth of some species, and is time consuming. Another challenge of animal studies is to be able to provide the pups with artificial milks as similar as possible to maternal milks. However, the need for such studies is crucial to better understand the mechanisms involved in the short- and longer-term benefits of breast-feeding v. formula-feeding.

Acknowledgements

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

All authors contributed equally to the preparation of this paper.

There are no conflicts of interest.

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