This summary is based on ‘Bioactive Compounds in Infant Formula and Their Effects on Infant Nutrition and Health: A Systematic Literature Review’ by Almeida et al. 2021
Malnutrition contributes to approximately 60% of annual deaths worldwide, many of which can be attributed to inappropriate feeding practices during the first year of life1. Breastfeeding is regarded as the ‘gold-standard’ of infant feeding and provides many benefits to the child and infant, however it is not always possible often due to issues with the mother’s or infant’s health. Infant formulas are regarded as the best alternative, as they are usually modified to meet the nutritional requirements of the infant. Cow’s milk is often the main ingredient; however, some formulas use milk from other animals or vegetable products. Human milk contains many bioactive compounds that are desirable to replicate in infant formula. A bioactive compound is a substance which influences processes in the body contributing to function, and ultimately health status. Bioactive compounds in human milk have many functions in addition to nutrition, for example affecting the immune system and hormonal regulation. They are therefore desirable as supplements to infant formula. However, there are many other bioactive compounds which are not fully understood, and therefore cannot yet be added to infant formula. In order to be included in an infant formula, we must be certain that they do not cause harm, and be shown to have a beneficial effect. The aim of the review summarised here was to investigate the scientific evidence of the effects on infant nutrition and health of bioactive compounds commonly found in human breast milk. It was a systematic review, meaning the authors thoroughly investigated all literature related to this topic using a methodological approach.
Casein is present in low concentrations in human milk. It is a protein which acts a source of amino acids and elements such as calcium and zinc, but also provides other bioactive peptides when broken down. These peptides have an immune system and gastrointestinal function2. Breast milk contains mainly – and – caseins. -casein has been found to prevent H. pylori (the bacteria which causes stomach ulcers) infection, among other immuno-modulatory effects3. -casein also forms bioactive peptides when broken down, such as casein phosphopeptides which facilitate the absorption of minerals such as calcium, iron, and zinc4. However, this has not yet been proven to occur with bovine casein, and human and bovine casein do have slightly different structures which may contribute to slightly different functions. In addition, some caseins have been found to have opioid-like action, which can affect a wide range of biological functions such as sleep induction and gastrointestinal function5. In this case, it appears that the activity in infant formulas is similar to that of breast milk, although full effects on health are yet to be determined.
Approximately 70% of human milk is whey proteins of different types which have numerous bioactive functions including regulating the gut microbiome, digestion, and immune function. ⍺-Lactalbumin is the abundant of the whey proteins, and is related to strengthening the immune system and improving infants’ sleep, mood and cognitive development5. There is a much lower concentration of ⍺-Lactalbumin in cow’s milk than in human milk, and therefore infant formula is enriched with isolated ⍺-Lactalbumin. Lactoferrin is another common whey protein in breast milk and is considered an important molecule for the defense against infection due to its ability to bind iron and consequently prevent bacteria from using it for growth6. Again, it also aids in the absorption of iron and other nutrients. Bovine lactoferrin has been found to have similar structure to human lactoferrin, however it does not seem to be as effective functionally when added to infant formula7. Lactoferrin action can also be prevented by the addition of lipopolysaccharides, which are common in infant formula, and therefore must be carefully considered. The use of lactoferrin in infant formulas is also limited by its cost and difficulties in manufacturing, despite potential benefits.
The transfer of maternal antibodies to the infant via breast milk is one of the most widely known advantages of breastfeeding, as this confers immunity to the infant. Although cow’s milk also has antibodies, they do not act in the same way and studies have found that increasing their concentration in infant formula does not yield positive results and this is very difficult to do technically8. The antibodies found in human breast milk also cannot be reproduced, therefore infant formulas must focus on other additives which aid the immune system such as lactoferrin.
Taurine is a non-protein amino acid present in human breast milk. The body cannot synthesise taurine, therefore infants depend on their food source for an adequate supply. Taurine has a wide range of important functions for the infant, such as in the development of the central nervous system and regulation of calcium in cells9. Studies have suggested that taurine deficiency in neonates is associated with long-term developmental problems related to the central nervous system9. Based on this, it is recommended that all infant formulas be enriched with taurine. As there are low amounts in cow’s milk, synthetic taurine should be added. Yet, multiple studies have shown a lack of benefit in supplementing taurine in infant formulas on outcome measures such as growth and developmental effects10. This has led to uncertainty amount the inclusion of taurine, however as there are no adverse events associated, it will likely still be included as a precaution until further studies are conducted.
As with taurine, folates are not made by the human body, and therefore infants must receive them in their food source. Folate is an essential vitamin that is involved in many chemical processes in the body, with deficiency leading to congenital abnormalities, anemia, and neurological diseases in the developing embryo and infant11. Folic acid is the only approved form for infant formulas and infant formula is fortified to reach similar levels to those found in human breast milk.
Polyamines are bioactive substances derived from amino acids. They play an important role in cellular processes and are found in human breast milk as requirements are particularly high during periods of rapid growth12. They are thus important for the development of many organs in the infant after birth. The use of infant formulas enriched with polyamines could have beneficial effects during the first few months of life in particular. They may also improve immunological function, as this has been seen in studies using polyamine supplementation in animal models. More clinical studies are needed to work out the correct safe dose and benefits in infants before they can be added to formulas.
Milk Fat Globule Membrane
Milk fat globule membrane is a substance composed of fats and proteins, and is an important source of bioactive compounds. Human milk fat globule membrane has better digestibility than bovine, meaning the beneficial components are more likely to be absorbed and used by the infant. Regardless, most formulas are devoid of milk fat globule membrane, as the production process replaces the fat from cow’s milk. Therefore, enriching infant formulas with bovine milk fat globule membrane would still be a considerable improvement. Some clinical studies have attempted this and seen positive results such as anti-inflammatory action and improved gastrointestinal health13. There is also evidence that they influence brain development14. The precise mechanism through which these beneficial effects occur, which may limit companies desire to include it.
Docosahexanoic Acid and Arachidonic Acid
Docosahexanoic acid and arachidonic acid are by products of the metabolism of specific kinds of fats, which are not made in the body and therefore must be obtained through feeding. They are supplied to the growing embryo and fetus through the placenta as they are essential for growth and development, again particularly of the central nervous system15. It remains desirable to have a supply of these acids during infancy. Supplementation of infant formula with precursors of these acids has been found to improve eyesight16. As previously mentioned, the fats in cow’s milk-based infant formulas are removed and replaced with vegetable oils as they are thought to have better digestibility and are cheaper. Vegetable oils do not contain high concentrations of these acids, and consequently there have been some studies investigating the impact of formula using a mixture of cow’s milk fat and vegetable oils17. These studies did not find differences in growth and gastrointestinal tolerance, indicating that this is safe. Docosahexanoic acid and arachidonic acid are currently optional ingredients for infant formula, and do have evidence of benefit, although optimal dosing is yet to be fully deciphered.
Prebiotics reach the colon without being broken down, usually fermented by a specific group of bacteria and as a consequence improving host health. The most common are nondigestible carbohydrates, which are present in human breast milk. These carbohydrates encourage the growth of desirable bacteria in the human gut and also have a role in preventing infection. These carbohydrates are very complex, with over 200 distinct types identified in human milk. These types of carbohydrates are absent from cow’s milk, and are thus supplemented with nondigestible carbohydrates which function in a similar way. It is too difficult and expensive to synthesize the exact carbohydrates in human milk. Studies have shown that supplementation of infant formula with these carbohydrates show an improvement in gut microbiome composition and softer stool consistency18, therefore definitely appear to be a worthwhile addition.
Probiotics are living bacteria that when ingested beneficially improve the host’s intestinal microbiome. It is well known that the microbiome differs between formula and breast-fed infants, with breast-fed infants having the likely more beneficial composition. Several bacterial strains have been included in infant formula to investigate their safety and potential beneficial health effects. The results from these studies showed that there were no adverse events associated, but also did not find evidence of benefit19. More research is needed to further characterise potential effects.
Overall, it is evident that there are a huge range of substances in human breast milk which impact infant health and are therefore desirable to include in infant formula. The substances described here are far from an exhaustive list of all the possible bioactive compounds. There is solid evidence that some of these substances are safe and beneficial when added to infant formula, whereas others need further research before they should be considered. Bioactive substances in infant formulas are likely to become more important as we gain further understanding of the role of each substance. This will allow infant formula to be manufactured to be as close to breast-milk as possible and therefore give the infant the best possible outcome.
- Fanzo J, Hawkes C, Udomkesmalee E, Afshin A, Allemandi L, Assery O, Baker P, Battersby J, Bhutta Z, Chen K, Corvalan C. 2018 Global Nutrition Report: Shining a light to spur action on nutrition.
- Hebert EM, Saavedra L, Ferranti P. Bioactive peptides derived from casein and whey proteins. Biotechnology of lactic acid bacteria: Novel applications. 2010 Jan 29:233-49.
- Hernandez-Ledesma B, Quiros A, Amigo L, Recio I. Identification of bioactive peptides after digestion of human milk and infant formula with pepsin and pancreatin. International Dairy Journal. 2007 Jan 1;17(1):42-9.
- Enjapoori AK, Kukuljan S, Dwyer KM, Sharp JA. In vivo endogenous proteolysis yielding beta-casein derived bioactive beta-casomorphin peptides in human breast milk for infant nutrition. Nutrition. 2019 Jan 1;57:259-67.
- Wada Y, Loennerdal B. Bioactive peptides derived from human milk proteins—mechanisms of action. The Journal of nutritional biochemistry. 2014 May 1;25(5):503-14.
- Telang S. Lactoferrin: a critical player in neonatal host defense. Nutrients. 2018 Sep 4;10(9):1228.
- Aly E, Ros G, Frontela C. Structure and functions of lactoferrin as ingredient in infant formulas. Journal of Food Research. 2013 Aug 1;2(4):25.
- Nguyen TT, Bhandari B, Cichero J, Prakash S. A comprehensive review on in vitro digestion of infant formula. Food Research International. 2015 Oct 1;76:373-86.
- Kilb W, Fukuda A. Taurine as an essential neuromodulator during perinatal cortical development. Frontiers in cellular neuroscience. 2017 Oct 24;11:328.
- Verner AM, McGuire W, Craig JS. Effect of taurine supplementation on growth and development in preterm or low birth weight infants. Cochrane Database of Systematic Reviews. 2007(4).
- Black MM. Effects of vitamin B12 and folate deficiency on brain development in children. Food and nutrition bulletin. 2008 Jun;29(2_suppl1):S126-31.
- Bjelakovic L, Kocic G, Bjelakovic B, Najman S, Stojanović D, Jonovic M, Pop-Trajkovic Z. Polyamine oxidase and diamine oxidase activities in human milk during the first month of lactation. Iranian Journal of Pediatrics. 2012 Jun;22(2):218.
- Timby N, Domellöf E, Hernell O, Lönnerdal B, Domellöf M. Neurodevelopment, nutrition, and growth until 12 mo of age in infants fed a low-energy, low-protein formula supplemented with bovine milk fat globule membranes: a randomized controlled trial. The American journal of clinical nutrition. 2014 Apr 1;99(4):860-8.
- Gurnida DA, Rowan AM, Idjradinata P, Muchtadi D, Sekarwana N. Association of complex lipids containing gangliosides with cognitive development of 6-month-old infants. Early human development. 2012 Aug 1;88(8):595-601.
- Tinoco SM, Sichieri R, Moura AS, Santos FD, Carmo MD. The importance of essential fatty acids and the effect of trans fatty acids in human milk on fetal and neonatal development. Cadernos de saude publica. 2007;23:525-34.
- Innis SM, Gilley J, Werker J. Are human milk long-chain polyunsaturated fatty acids related to visual and neural development in breast-fed term infants?. The Journal of pediatrics. 2001 Oct 1;139(4):532-8.
- Lien EL, Richard C, Hoffman DR. DHA and ARA addition to infant formula: Current status and future research directions. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2018 Jan 1;128:26-40.
- Closa-Monasterolo R, Gispert-Llaurado M, Luque V, Ferre N, Rubio-Torrents C, Zaragoza-Jordana M, Escribano J. Safety and efficacy of inulin and oligofructose supplementation in infant formula: results from a randomized clinical trial. Clinical Nutrition. 2013 Dec 1;32(6):918-27.
- Braegger C, Chmielewska A, Decsi T, Kolacek S, Mihatsch W, Moreno L, Piescik M, Puntis J, Shamir R, Szajewska H, Turck D. Supplementation of infant formula with probiotics and/or prebiotics: a systematic review and comment by the ESPGHAN committee on nutrition. Journal of pediatric gastroenterology and nutrition. 2011 Feb 1;52(2):238-50.