Early-life benefits of human milk–inspired infant formula
Human milk is a highly complex substance of multifaceted functionality that addresses the newborn’s nutritional and immunological needs. By studying its composition and the dynamic changes that occur throughout lactation, researchers were able to identify and mimic the components that support gut health, suppress inflammation and aid maturation of the developing immune system. This literature review focuses on the science behind human milk–inspired infant formula and the clinical benefits that it confers.
Benefits of colostrum
Colostrum is the small volume of breast milk produced produced by the mother in the first 2–5 days immediately after birth that contains high levels of antibodies, immune cells, proteins, lipids, oligosaccharides and vitamins intended to support the nutritional and developmental needs of a newborn.
Human milk contains approximately 7 percent carbohydrate, of which 80 percent is lactose. The remaining 20 percent consists primarily of human milk oligosaccharides (HMOs), of which there are ≥200 molecules. The concentration of HMOs in colostrum is approximately twice as high as in mature milk (22–24 g/L vs 12–13 g/L). [Adv Nutr 2012;3:473S-482S] Some HMOs in colostrum decline to undetectable levels as lactation proceeds. [J Nutr 2016;146:358-367] (Figure 1)
HMOs are complex glycans, some of which possess anti-inflammatory functions. In the absence of adequate feedback inhibition within the newborn’s gut, stimulation of the hyperinflammatory immune system by newly colonizing bacteria often causes mucosal damage. However, the colostrum components, such as the HMOs, can help attenuate intestinal inflammation and minimize the incidence of immune-based disorders. [J Nutr 2016;146:358-367; Proc Nutr Soc 2000;59:177-185]
Compared with oligosaccharides from mature milk, oligosaccharides from colostrum are more active, and their activities are complementary and synergistic. In quiescent non-inflamed immature human intestine, colostrum HMOs enhance expression of genes involved in immune cell trafficking and proliferation through an extracellular signal-regulated kinase (ERK1/2) pathway. Simultaneously, colostrum HMOs shift the T helper cell 1/T helper cell 2 (Th1/Th2) balance toward that of mature tissues. In inflamed mucosa, colostrum HMOs suppress pathogen-associated molecular pattern (PAMP)–induced release of acute-phase inflammatory factors. Concurrently, colostrum HMOs stimulate expression of tissue repair and tissue homeostasis cytokines. [Mucosal Immunol 2014;7:1326-1339]
Unlike other nutrients in human milk, HMOs are thought to remain largely undigested and unabsorbed by the infant’s small intestine. Some of the HMOs are either not degraded at all or are degraded very slowly by brush border, salivary, and secreted pancreatic enzymes from pigs and adult humans, although infant enzymes have not been tested. [Am J Clin Nutr 2000;71:1589-1596]
Biological activity of HMOs and larger glycans is clinically significant and can be categorized into three types. [Pediatr Res 2014;75:675-679] Firstly, intact HMOs reach the colon, where they act as prebiotics that stimulate the growth of mutualist symbionts of the microbiota, such as bifidobacteria, which are considered beneficial to infant health through suppressing bacterial challenges, thus indirectly reducing gut inflammation. [Glycobiology 2013;23:1281-1292]
Secondly, HMOs are thought to act as receptor analogues that can inhibit the attachment of pathogenic micro-organisms, such as Campylobacter jejuni, the Norwalk virus, and Pseudomonas aeruginosa, to the colonic mucosa receptors, thus protecting the breastfeeding infant. [Adv Nutr 2012;3:473S-482S; Annu Rev Nutr 2005;25:37-58]
Thirdly, a small proportion of HMOs, such as 3’-galactosyllactose (3’-GL), from colostrum and mature milk may be absorbed into the circulation where they can function as immunomodulators, controlling the attachment of neutrophils to endothelial cells and directly quenching inflammation. [Mucosal Immunol 2014;7:1326-1339; Prebiotics and probiotics science and technology. New York: Springer, 2009;207-244]
Studies have demonstrated that HMOs can modulate multiple signalling pathways in immature human gut mucosa ex vivo. The most pertinent example is of 3’-GL isomer inhibiting specific inflammatory signalling elicited by activation of Toll-like receptor-3 in cultured human enterocytes. [Mucosal Immunol 2014;7:1326-1339; J Nutr 2016;146:358-367]
The levels of the three principal (3’-, 4’- and 6’-) GL isomers found in colostrum vary throughout lactation among different mothers. Research from the US suggests that all three isomers decline rapidly and significantly (p<0.05) during early lactation (n=3). [J Nutr 2016;146:358-367] (Figure 1) However, an earlier Japanese study has found that unlike 6’-GL, the levels of 3’-GL and 4’-GL have remained broadly constant between day 4 (n=23) and day 100 (n=18) of lactation, suggesting their continued relevance in infant development. [J Appl Glycosci 2004;51:341-344]Furthermore, commercially available 3’-, 4’- and 6’-GL synthesized through a unique process of fermentation, applied in physiologically relevant concentrations found in pooled mixtures of human milk, were able to attenuate NF-kB inflammatory signalling in human intestinal epithelial cells and in human immature intestine. [J Nutr 2016;146:358-367]
Human milk-inspired infant formula
The maturation of the neonates’ gastrointestinal tract is accompanied by the dynamic enteric process of microbiota development, considered crucial for healthy infant development, in which early nutrition plays an important role. [Pediatr Allergy Immunol 2014;25:428-438] Modelling of infant formula on the components and proportions of human milk aims to mimic the gut environment of breastfed infants in formula-fed infants. As a result, inspired by the molecular size distribution of the nondigestible HMOs, a specific mixture of 90 percent short-chain galacto-oligosaccharides and 10 percent long-chain fructo-oligosaccharides (scGOS/lcFOS; 9:1) was developed. [Anal Biochem 1994;223:218-226; Acta Paediatr Suppl 2003;91:64-67]
ScGOS and lcFOS act as prebiotic substrates that are selectively utilized by the host micro-organisms, which confer a health benefit to the host. [Nat Rev Gastroenterol Hepatol 2017;14:491-502] Infant formulae enriched with this prebiotic mixture promote a gut ecophysiology close to that observed in breastfed infants, which is characterized by high concentrations of lactate and a slightly acidic pH, which promotes a dose-dependent increase in bifidobacterial counts (p<0.01) vs formulae lacking prebiotics. [Am J Clin Nutr 2013;98:561S-571S; J Pediatr Gastroenterol Nutr 2002;34:291-295]
In a prospective, double-blind, parallel-group, multicentre, controlled equivalence trial, 432 infants (age, 0–28 days to 17 weeks) were randomized to receive four formulae: a nonfermented commercially available formula with prebiotics (scGOS/lcFOS), a formula containing 15 percent fermented formula and prebiotics, a formula containing 50 percent fermented formula and prebiotics, and a commercially available formula containing 50 percent fermented formula without prebiotics. [J Pediatr Gastroenterol Nutr 2016;63:e43-e53]
The partly fermented formulae containing the scGOS/lcFOS (9:1) prebiotic mixture supported adequate growth in early life, as demonstrated by both weight gain equivalence between all four formula groups and the similarity in growth development compared with WHO growth standards. (Figure 2) In addition, the formulae were well-tolerated and safe based on growth and adverse event outcomes.
This study also confirmed the established bifidogenic effect of scGOS/lcFOS (9:1) when added to partly fermented formulae, as indicated by the lower percentage of Clostridium difficile, higher occurrence of measurable lactate levels, decreased pH, and increased secretory immunoglobulin A levels observed in the group of infants who were fed with formula containing 50 percent fermented formula and scGOS/lcFOS vs those fed with formula containing 50 percent fermented formula without prebiotics. [J Pediatr Gastroenterol Nutr 2016;63:e43-e53; J Pediatr Gastroenterol Nutr 2005;40:36-42; Early Hum Dev 2008; 84:45-49; J Nutr 2008;138:1141-1147]
Hard stools, which are an exception in breastfed infants, are more frequently observed and are of relevant concern in formula-fed infants. A controlled, double-blind, multicentre, parallel-group, intervention study, randomized healthy, term infants aged 0–28 days to receive either an infant formula with 30 percent of fermented formula combined with a specific mixture of >100 scGOS/lcFOS (9:1, 0.8g/100 mL; n=95), which aims to mimic the complexity and diversity of HMOs, or a non-fermented formula without scGOS/lcFOS (n=105). [JPGN 2016, 62(Suppl 1):422]
Based on 23,352 individual stool consistency observations, the probability to display a specific stool consistency was found to be formula-dependent. For example, over the entire observation period, infants fed with the non-fermented formula without scGOS/lcFOS had a 0.06–0.21 probability of having hard stools, and a 3.6- to 12.5-fold odds ratio (OR) of having hard stools vs fermented formula-fed infants. At the same time, fermented formula-fed infants had a 0.41–0.57 probability of having soft pudding-like stools, and a 2.1- to 2.9-fold OR of having soft pudding-like stools compared with infants fed with the non-fermented formula.
HMOs constitute a major part of the innate immune system that protects the infant immature intestinal mucosa, directs maturation of the immune system, and aid the colonization of the intestine by beneficial bacteria. A fermented infant formula enriched with prebiotics provides a mixture of nutritional and bioactive compounds that mimics the complexity, diversity and functionality of breast milk, and has been shown to support adequate growth and promote a favourable gut environment.