Bioactive Factors in Human Breastmilk: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by David Ramiro-Cortijo.

Maternal milk, a complex fluid with several bioactive factors, is the best option for the newborn. Its dynamic composition is influenced by diverse factors such as maternal age, lactation period, and health status. 

  • adipokines
  • antioxidants
  • breastfeeding
  • cytokines
  • growth factors

1. Introduction

Preterm infants are those born before 37 weeks of gestation [1]. They are considered extremely preterm at less than 28 weeks, very preterm between 28 and 32 weeks, and moderate to late preterm between 32 and 37 weeks [2].
Prematurity is a serious health problem worldwide, with increasing rates in both low- and high-income countries [2][3]. The World Health Organization (WHO) estimated that the global incidence of preterm delivery was around 11.1% in 2010. The frequency of preterm births (PTBs) in low-income settings is between 12% and 18.1% [2], with Asia and Africa being the areas with the highest rates [4]. The frequency of PTB can vary between 5% and 13% in high-income areas such as the United States of America [5].
PTB is a multifactorial syndrome and has multiple etiologies. The main factors that may increase women’s risk are maternal malnutrition, poor pregnancy weight gain, infections and maternity at extreme ages, short interpregnancy intervals, or/and obstetric complications. Infertility and the subsequent need for assisted reproduction techniques resulting in twin pregnancies are also important factors. Finally, exposure to lifestyle-related toxic substances and environmental pollutants are also considered as potential risk factors [3][4][5][6][7][8].
Preterm infants, in comparison with term infants, have higher morbimortality rates. Throughout the world, prematurity is the second most common cause of death among children under 5, and is the leading cause in high-income countries [4][9]. Late onset sepsis [10], necrotizing enterocolitis (NEC) [11], retinopathy of prematurity (ROP) [12], bronchopulmonary dysplasia (BPD) [13], and neurodevelopmental problems [14] are among the most frequent morbidities. Besides, growing evidence is proving that individuals born preterm are at higher risk of cardiovascular and metabolic diseases in adulthood [15][16][17].
Nutrition during the earliest stage of life is of great importance for the growth and maturation of tissues and organs, especially for those infants with PTB. Breastmilk (BM) is tailored to cover the needs of the newborns, providing the adequate amount of macro and micronutrients for infant growth and development. In addition, it contains several bioactive compounds, which contribute to the maturation of their immune system, among other important aspects. The BM composition is dynamic and varies according to the maternal age, number of pregnancies [18], body mass index (BMI) [19], maternal diet, time of the day, lactation period, and other environmental factors [20]. Therefore, the WHO recommends that infants be exclusively breastfed for the first six month of life, and lactation, together with nutritionally adequate foods, can continue up to two years of age or beyond [21][22]. This recommendation has been endorsed by several Pediatric and Nutrition Associations [23][24][25].
Among the most important bioactive compounds found in BM, the most outstanding are antioxidants, which may help counteracting the negative effects of oxidative stress in newborns [26]. Other bioactive compounds to bear in mind are growth factors and hormones, which regulate the energy intake and maturation of organs. Also, cytokines are present in BM, which may help to protect against infections or reduce inflammatory processes [20]. These bioactive compounds may contribute to the long-term protection of preterm infants against the development of cardiometabolic diseases. Premature infants fed with BM exhibit lower rates of metabolic syndrome, hypertension, or insulin resistance in adolescence, compared with the newborns who are not breastfed [24][27].
BM is the ideal food for neonates during the first days of life and cannot be equaled by artificial substitutes [28]. However, there are mothers who, for several reasons, do not breastfeed their newborns. In 2018, 7.6 million babies were not breastfed [29]. In these cases, commercial formulas and donated BM, generally from mothers with term deliveries [30], are used. The human milk is recognized as a better scavenger of free radicals than the infant formula due to its bioactive compounds, which are lacking in commercial formulas [31][32].

2. Bioactive Compounds in Breastmilk

There is wide evidence that BM prevents many of the perinatal complications associated with preterm labor [33], and BM is recognized as a protective factor against morbidity and mortality. Some of the beneficial factors against preterm complications may be related to the bioactive compounds and interactive elements present in the milk, such as antioxidants, growth factors, adipokines, cytokines, or antimicrobial compounds [34].

2.1. Antioxidants in Human Milk

Reactive oxygen species (ROS) are physiologically relevant molecules that participate in cellular signaling processes. However, ROS are highly oxidizing and, in excess, can cause damage to cellular structures. To counteract the oxidative effects of ROS, there are a wide variety of antioxidant systems. There is a delicate balance between ROS and other reactive species and antioxidants. If this balance is lost, the result is oxidative stress. This can be due to an excessive ROS production that exceeds the antioxidant capacity, or insufficient antioxidant systems. Birth represents a significant oxidative challenge because of the switch from the relatively low-oxygen intrauterine environment to the high-oxygen extrauterine atmosphere [35]. Thus, newborns are exposed to an increase in ROS during labor and the transition to neonatal life [36]. PTB disrupts the normal developmental upregulation of antioxidant systems. Increased oxidative stress is observed in preterm neonates compared with full-term infants [37], being a critical factor that exacerbates perinatal morbidities of prematurity [38]. Endogenous antioxidants can be classified as enzymatic (i.e., superoxide dismutase (SOD), catalase, or glutathione peroxidase (GPx)), small non-enzymatic molecules (like glutathione (GSH)), or hormones with antioxidant capacity (such as melatonin) [37][39]. In addition to endogenous antioxidants, several foods, mainly vegetables and fruits, contain antioxidants such as vitamins, carotenoids, and polyphenols, among others.

2.2. Growth Factors in Human Milk

Preterm infants are immature neonates who usually exhibit growth retardation, poor development and physical and neurological deficits. Postnatal growth retardation is likely the result of inadequate nutrition support after delivery, also contributing to poor neonatal health. In this context, in addition to a macronutrient supply, growth factors provided by breastfeeding may be of great importance. Growth factors play a role in the growth, maturation, and integrity of several organs, particularly for the neonatal gastrointestinal tract [40]. They help with the maturation of gut immunity and have anti-inflammatory effects [41][42]. Hirai et al. described the trophic effects of growth factors on fetal and neonatal gastrointestinal tract by promoting the proliferation and differentiation on their immature cells [43]. The highest concentrations of growth factors are provided by colostrum, as the first milk released after birth [44]. The main growth factors present in BM and their trophic effects on neonatal organs and systems are summarized in Figure 1.
Figure 1.
Transference of maternal growth factors through breastmilk and their trophic effects on the growth and maturation of neonatal organs and systems.

2.3. Adipokines in Human Milk

In addition to growth factors, adipokines constitute another group of compounds present in BM which is important for metabolism and infant growth. These cytokines derived from adipocytes have been demonstrated to modify weight gain and fat and lean body mass in infants in the early postpartum period [45] and have long-term effects on metabolic programming. They are also involved in the regulation of food intake and energy balance [46]. Several adipokines, with opposing actions on food intake and energy expenditure, have been found in BM (summarized in Table 1). Thus, it can be hypothesized that the programming of food intake and body composition may be influenced by the relative concentration of these compounds in BM. Likewise, BM adipokines may also modulate the development of metabolic diseases in adulthood such as obesity, type 2 diabetes mellitus, or insulin resistance [47].
Table 1.
Adipokines in human breastmilk.

Adipokines

Tissue Synthesized

Range (ng/mL)

Preterm Infants

Main Neonatal Functions

Leptin

White adipose

Placenta

Mammary

0.2–10.1

↑/?

Anorexigenic

T-lymphocyte responses

Adiponectin

Adipocytes

4.2–87.9

≈/?

Orexigenic

Regulation of lipid/glucose metabolism

Improvement of insulin sensitivity

Anti-inflammatory actions

Resistin

Immune cells

Epithelial cells

0.2–1.8

↑/?

Regulation of glucose homeostasis

Inhibition of adipocyte differentiation

Inflammatory response

Ghrelin

Stomach

Pituitary

Other

0.07–6

?

Orexigenic

Gastric motility and secretion

Adipogenesis

Anti-inflammatory actions

Obestatin

Stomach

Small intestine

0.4–1.3

?

Anorexigenic

Body weight regulation

Nesfatin

Neurons

Pancreas

Other

0.008–0.01

?

Anorexigenic

Production of body fat

Apelin

Heart

Lung

Other

43–81

?

Regulation of cardiovascular system

Fluid homeostasis

Angiogenesis

Regulation of insulin secretion

Adapted from Catli et al. (2014) [47]. Arrows indicate the comparison with term infants (↑, higher; ↓, lower; ≈, similar); ? indicates unavailable or inconclusive data and the need for research [47].

2.4. Cytokines in Human Milk

Cytokines are small proteins synthesized by nearly all the nucleated cells [48]. They are signaling molecules involved in the communication between cells [49]. BM is a cytokine-rich food [50]. According to their role in the inflammatory response, cytokines can be divided into those that promote inflammation or protects against infection, and those that decrease inflammation.
A possible role of some cytokines present in BM in preterm infants may be to compensate the delay of the immune system development [51]. It has been hypothesized that immune mediators in human milk may have a powerful role to play in maturating the infant intestine and stimulating the immune system [52]. The stimulation of immune activity by BM cytokines may be related to their capacity to make connections with cells by crossing the intestinal barrier.
There is large variability between cytokine concentrations among breastfeeding women, being pro-inflammatory cytokines generally low [53]. BM cytokine content can be affected by different factors, such as gestational age, maternal diet, infections, smoking, maternal ethnicity, or exercise [53]. In addition, the cytokine profile of BM fluctuates along the different phases of breastfeeding and the clinical significance of cytokine concentrations in neonatal health outcomes is still under debate [54][55].

3. Human Milk Cells

3.1. Stem Cells in Human Milk

Recent data suggest that up to 6% of the cells in human milk are stem cells, and mesenchymal stem cells isolated from BM are potentially reprogrammable to multiple tissue types [56][57]. These cells may be involved in the development of immune cells including the regulatory T cell, which may produce tolerance to non-inherited maternal antigens and suppress anti-maternal immunity. It induces pregnancy microchimerism, leading to intestinal tissue repair and immune development and protection against infectious diseases [57].

3.2. Leukocytes in Human Milk

Leukocytes are highly present in colostrum, which means that breastfed infants are exposed to up to 1010 maternal leukocytes/day [58]; however the contribution of this exposure in infants’ immune development is not yet clear [54]. A study carried out with 61 mothers and neonates showed a significantly smaller proportion of macrophages in BM of mothers with infants that developed an allergy to cow’s milk. In contrast, a higher content of neutrophils, eosinophils, or lymphocytes was associated with lower allergies to cow’s milk [59]. The role of these cells is still far from understood; for example, how these cells pass the stomach and intestinal barriers and access the infant, or their mechanisms of action, remain unclear. Therefore, further research to clarify these aspects of the inflammation and immunity development is required.

4. Human Milk Microbiota

Early microbial colonization is essential for the infant’s metabolic and immunological maturation. Its development begins at birth, and the most important changes occur during the first year of life [60][61]. The microbiome is constantly changing, and it is influenced by hormones, cytokines, and chemokines. After birth, the transference continues along breastfeeding, and it is considered the main cause of variability between exclusively breastfed and formula-fed infants during the first months of life [56][62]. Raw BM is not a sterile food [58] and several reports confirm more than 100 types of viable bacteria/mL in human milk [62], including 65% of the phyla Proteobacteria and 34% of the phyla Firmicutes [49]. Regarding the genera, the most common are Staphylococcus, Streptococcus, Lactobacillus, Enterococcus, Lactococcus, Weissella, Veillonella, and Bifidobacterium [63][64]. It has been described that human milk microbiota at an early age is strongly linked with other perinatal factors such as place of residence, delivery mode, or maternal food intake [65]. With respect to the comparison between preterm and term milk, few studies have reported a difference in the BM microbiome. Some trends include more Bifidobacterium in term milk and more Enterococcus in preterm milk [52][58]. The association between the microbiome and various disorders, such as visceral pain, autism spectrum disorder, cardiovascular risk, obesity, depression, or multiple sclerosis, has been well demonstrated. Besides, the microbiota exerts immune-modulating effects that influence allergic reactions [60]. Thus, the gut microbiome from allergic children differs from non-allergic ones in composition and diversity [66]. It has been hypothesized that early gut colonizers could help in developing and maturing the immune system in infants [67]. Probiotic intake throughout gestation and lactation also leads to specific changes in the neonate [68]. A clinical trial reports the beneficial effect of oral supplementation with Lactobacillus rhamnosus in women during pregnancy and breastfeeding to reduce the allergy risk in infants. Modulatory effects were observed both on milk composition and the infant gut [69]. Variations in microbiota of preterm infants have been associated with a higher predisposition for developing NEC [70]. Taking together the information available, BM could be considered a probiotic food for infants. However, the potential protective effect of the BM microbiome is not fully understood, and additional research in this area is necessary to understand its role in the newborn’s health.

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