Breast Milk and Metabolic Programming: Short-Term and Long-Term Health Benefits

Abstract

Nutrition plays a major role in the development of health and disease later in adulthood. Breastfeeding is considered a cornerstone of healthy infant nutrition. It provides energy and nutrients that will help preventing both undernutrition, overweight and obesity. The Developmental Origins of Health and Disease (DOHaD) theory suggests that breast milk may play a role in modulating epigenetic factors such as DNA methylation from early stages of the life cycle. Exclusively breastfeeding infants presented lower blood pressure and serum cholesterol in adult life and lower risk of obesity and metabolic disorders, such as diabetes, hypertension or cardiovascular disease. It is believed that these effects are associated with the nutritional differences between breast milk and infant formula, such as lower protein content and the presence of bioactive components in breast milk. Epigenetic mechanisms may be the cause for the so claimed protective effect of breast milk in relation to the development of many diseases.

1. Introduction

Breastfeeding is considered one of the keys elements in the promotion and protection of the health of infants worldwide. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition described breastfeeding as the natural and advisable way of supporting the healthy growth and development of young children [1].

The World Health Organization (WHO) promotes the adoption of counseling guidelines to extend breastfeeding periods, suggesting that breastfeeding should begin within the first hour after birth, be exclusive for the first 6 months without any other liquids or solids, including water. After 6 months, breast milk alone is not sufficient and should be combined with appropriate complementary foods that are safe and adequate [2, 3, 4, 5, 6].

Breastfeeding is an essential aspect of healthy infant nutrition and growth, as it continues to supply energy and nutrients that help prevent undernutrition, overweight, and obesity [7, 8, 9, 10].

The prevalence of breastfeeding has undergone changes over time, reaching its lowest point after World War II due to social and technological shifts affecting women’s roles, income, education, and the widespread use and aggressive marketing of breast milk substitutes [8, 9]. However, starting in the 1970s, there was a resurgence of breastfeeding, particularly among employed women [8].

In response to the Innocenti Declaration, the World Health Organization (WHO) and UNICEF launched the Baby Friendly Hospital Initiative in 1992 [10, 11]. The program’s objective is to protect, support, and promote breastfeeding in health facilities such as obstetrics, neonatology, and pediatrics services [11]. The aim is to provide new mothers and their infants with the information and confidence needed to initiate and continue breastfeeding. A baby-friendly facility complies with the International Code of Marketing of Breastmilk Substitutes by endorsing, supporting, and promoting breastfeeding while ensuring appropriate use of breast milk substitutes when necessary [11].

The European Region has the lowest breastfeeding rates, with only 14% of women breastfeeding their babies for up to 6 months according to data published in 2015. This highlights the importance of initiating breastfeeding within the first hour after birth to improve breastfeeding rates. Campaigns like the Baby Friendly Hospital Initiative should be encouraged [12]. Returning to the workplace can be a barrier to exclusive and continued breastfeeding. Maternity leave has been linked to better maternal and child health outcomes, with 40 of the world’s 41 wealthiest countries offering paid maternity leave. However, the United States is the only country that does not provide paid maternity leave to employed mothers. The benefits of breastfeeding for both the infant and mother are well-documented and include a lower risk of respiratory infections, asthma, diarrhea, food allergies, diabetes, improved cognitive development, and a reduced risk of metabolic disease in adulthood [2, 13, 14].

The Developmental Origins of Health and Disease (DOHaD) theory suggests that breast milk may play a role in epigenetic regulation such as DNA methylation from early stages of life. Changes to the epigenome can lead to long-term development of metabolic disorders, linking external factors like nutrition and environment to the long-term health outcomes of early life phases [2, 15, 16, 17].

2. Metabolic programming

2.1 Epigenetic mechanism

The “first thousand days of life” from conception to age 2 has been the focus of attention for researchers worldwide. This period is considered critical for wellbeing and brain development, as the greatest amount of human growth occurs during this time when cells in the body are being formed and programmed. Studies have shown that insults during the crucial periods of pregnancy and lactation, such as malnutrition, stress, and air pollution exposure, increase the risk of chronic noncommunicable diseases (NCDs) such as obesity, cardiovascular disease, and diabetes throughout life. This leads to metabolic programming, developmental plasticity, and the concept of Developmental Origins of Health and Disease (DOHaD) [2].

The environment has a profound impact on organisms, as per the principle of modern biology. Darwin’s Theory of Evolution suggests that through natural selection, the best DNA alleles are preserved across generations due to genetic variations caused by mutations in the DNA sequence. Currently, it is understood that the environment shapes the organism through epigenetic processes, which do not involve changes in the DNA sequence [18]. The idea of metabolic programming, which involves the impact of prenatal and postnatal metabolic events on adult health, has been established for about 40 years. This theory suggests that these events leave a “mark” in the body (or DNA) and result in cellular memory [9, 10, 11, 14, 19]. These physiological adaptations are possible due to the plasticity of cells, which is temporary in embryonic and fetal stages but persistent in cells like the immune system [20].

Epigenetics result in marks that play a significant role in shaping the risk of metabolic and non-communicable disorders. The DOHaD theory explains the connection between the nutritional and environmental conditions of pregnancy and early childhood, and the development of health and diseases [15, 16, 17, 18]. NCDs usually appear in adulthood, due to the decreasing flexibility of cells and tissues over time. The likelihood of NCDs can be influenced by the body composition and diet of the mother before and during pregnancy, as well as the nutrition of the fetus and infant. Thus, early-life interventions have the potential to reduce later disease risk and affect future generations, while later interventions are expected to have only a minimal impact [16].

The concept of epigenetics refers to modifications that are passed down and affect gene expression, without altering the DNA sequence. These changes in the epigenome are achieved through three processes: DNA methylation, histone modifications, and noncoding RNA expression [2]. During DNA methylation, methyltransferases bind methyl groups to DNA at cytosine sites (CpG islands) during replication or de novo methylation. Methylation in promoter regions of DNA often results in inactive chromatin and silences gene transcription, impacting the expression of key genes for cell stability. Methylation of CpG dinucleotides at the 5′ promoter regions of genes results in stable silencing of transcription. Methylation patterns are established primarily during embryonic development or early postnatal life [2, 7, 20, 21].

The methylation of CpG dinucleotides results in the inactivation of gene transcription by RNA polymerase by making chromatin inaccessible for transcription. This affects the expression of genes crucial for maintaining cell homeostasis [2, 7]. The second mechanism is the modification of histones, which are proteins that help organize DNA by packaging it into nucleosomes. They negatively impact gene transcription by physically obstructing access and blocking the binding of transcription factors, making chromatin less accessible [2]. Histones regulate gene expression by controlling the access of transcription factors (TFs) to the DNA sequence, thereby altering the rate of transcription to messenger RNA (mRNA) [22].

The modification of histones in the amino-terminal region of the histone tails includes processes like acetylation, methylation, sumoylation, phosphorylation and ubiquitination. Acetylation is the most widely recognized modification, carried out by enzymes known as acetyltransferases (HATs) and deacetylases (HDACs). The acetylation of histones leads to the opening of chromatin, thereby enabling the transcription machinery to access the DNA [2].

In contrast, when chromatin is inactive, histone deacetylation reduces the attachment of transcription factors, hindering gene expression [22]. MicroRNAs (miRs), a type of small noncoding RNA, play a role in posttranscriptional regulation by either breaking down mRNA or blocking its translation into protein. These three epigenetic changes, DNA methylation, histone modification and microRNA regulation, shape the expression of multiple genes and drive metabolic programming [2].

3. The impact of breast milk components on metabolic programming

Breastfeeding is recognized to have significant short-term health benefits, and evidence is growing for its long-term consequences [17]. The first 6 months of life is a crucial period for the development of adiposity [23]. The composition of the nutritional environment during this time can contribute to the risk of certain diseases in adulthood, often through epigenetic changes. There is evidence to suggest that certain components of breast milk may directly impact epigenetic modifications [24, 25].

The composition of breast milk includes both macronutrients and micronutrients, and it changes regularly based on various factors such as the health of the mother and baby, maternal diet, environment, and genetics. These changes ensure that breast milk can adapt to the changing nutritional requirements of the growing infant [26, 27].

Moreover, breast milk has a distinct advantage in that it provides newborns with the necessary macronutrients and micronutrients through factors such as enzymes, immune components, and adipokines. Leptin, ghrelin, adiponectin, resistin, and obestatin are some of the most well-known adipokines. Adiponectin and leptin, in particular, are potent and widely studied appetite regulators that are linked to obesity. Research has demonstrated that the leptin present in breast milk helps control appetite and manage calorie intake. This finding has sparked further investigation into the impact of leptin on neonatal development, which was previously an under-researched area [28, 29, 30, 31].

Over the years, numerous studies have explored the connections between breastfeeding and the regulation of infant appetite, as well as its correlation with a decreased risk of obesity and other chronic non-communicable diseases (NCDs). These relationships are due to the synergistic effects of various milk components, maternal characteristics, and breastfeeding patterns [32].

3.1 The role of leptin in the appetite regulation

Leptin, a bioactive compound found in breast milk, has a key impact on metabolic programming. It is generated by white adipose tissue based on the body’s fat content, and it moves from adipose tissue into the bloodstream, where it binds to receptors in the hypothalamus and crosses the blood-brain barrier. Upon binding to the receptors, leptin influences the release of appetite-suppressing peptides, resulting in lower food intake and increased energy expenditure. With higher levels of leptin, energy expenditure is boosted through reduced food intake and increased heat production, while lower levels of leptin boost the growth of fat cells [30].

As a result, the amount of leptin in breast milk varies among infants, as it is dependent on the maternal adiposity and BMI (Body Mass Index). Mothers with low fat levels and low plasma concentrations of leptin produce milk with a low amount of leptin, resembling infant formulas (IFs), while obese mothers provide higher doses of leptin [25, 30].

Recently, it was discovered that leptin is produced not only by white adipose tissue, but also by the placenta and breast epithelium and secreted into breast milk [25, 30]. However, the contribution of each source to the total amount of leptin in breast milk is still unclear. A study on rats showed that gastric leptin is not fully functional during most of the lactation period due to immature stomachs. Additionally, leptin mRNA levels tend to be low during the first days of life and only start increasing after the fifteenth day of life [25].

Çağiran Yilmaz F et al., in cross-sectional study, assessed the relationship between the anthropometric measurements of the mothers (body weights and BMI) and leptin levels in breast milk and maternal serum, both were positively correlating in all months. The relationship between anthropometric measurements of infants, and the leptin levels in breast milk and maternal serum determined that the body weights of the infants and the breast milk leptin level in the assessed months were negatively correlated. In contrast, the length of the infants and leptin levels in breast milk and maternal serum were positive correlated [30].

Another similar study found that during the lactation period, breast milk leptin concentration correlated positively with maternal plasma leptin concentration and with maternal BMI. Breast milk leptin concentration at 1 month of lactation was negatively correlated with infant BMI at 18 and 24 months of age. When lactation occurred for a longer period (1 and at 3 months) was found a better negative correlation among milk leptin concentration and infant BMI at 12–24 months of age. It is concluded that infant body weight during the first 2 years may be influenced by milk leptin concentration during the first stages of lactation. These results seem to point out that milk leptin is an important factor that might explain, the major risk of obesity of formula-fed infants with respect to breast-fed infants [31].

Other appetite-regulating hormones, such as ghrelin and Peptide YY (PYY), are produced in the gastrointestinal tract. Ghrelin stimulates food intake, while PYY and leptin suppress appetite and increase metabolism. In addition, the ghrelin/PYY ratio is a more meaningful indicator of orexigenic drive, rather than ghrelin and PYY levels separately. Rapid weight gain in the early stages of life has been linked to a higher risk of adulthood obesity and cardiovascular disease [23].

The study by Fluiter, Kirsten S et al. aimed to investigate the impact of other appetite-regulating hormones (ARH) such as ghrelin, PYY, and leptin on the programming of adiposity. 297 term-born infants had their ghrelin, PYY, and leptin concentrations measured in their blood samples at 3 and 6 months of age, along with a measurement of their fat mass percentage. The results showed that ghrelin levels increased from age 3 to 6 months, while PYY levels decreased, leading to an increase in the ghrelin/PYY ratio over time. Meanwhile, leptin levels decreased from 3 to 6 months. Leptin levels at age 3 and 6 months were found to be related with the fat mass percentage at those same ages, as well as the gain in fat mass percentage from 1 to 6 months. Ghrelin at age 3 months correlated only with fat mass percentage at 6 months, while PYY and ghrelin/PYY ratio did not correlate. Among breastfeeding infants, both ghrelin and the ghrelin/PYY ratio at 3 months correlated with the increase in body fat percentage from 1 to 6 months. At 3 months, exclusively breastfeeding infants had lower levels of ghrelin and higher levels of PYY compared to those who were formula-fed. The increasing ghrelin/PYY ratio suggests a growing orexigenic drive, the ghrelin and leptin, but not PYY, correlated with more fat mass development during the first 6 months, suggesting that they might be involved in adiposity programming [23].

In another study, it was suggested that pre and neonatal overfeeding may affect the DNA methylation patterns in promoter regions of genes regulating food intake and body weight in the hypothalamus. When neonatal overfeeding was induced in rats, rapid weight gain was observed in the early stages, leading to a metabolic syndrome phenotype including obesity, hyperleptinemia, hyperglycemia, hyperinsulinemia, and an elevated insulin/glucose ratio. Low methylation levels of neuropeptide Y (NPY) were seen in both the overfed and control groups, while the gene proopiomelanocortin (POMC) showed increased methylation of CpG dinucleotides. The extent of DNA methylation was found to be inversely related to the ratios of POMC expression/leptin and POMC expression/insulin. These results indicate that a nutritionally-induced alteration of methylation patterns is crucial for regulating body weight and that overfeeding may be considered an epigenetic risk factor for obesity programming [25, 33]. These data suggest that the nutritional status affects methylation, and consequently, the regulatory mechanism of a gene promoter. Overfeeding has been identified as an epigenetic risk factor for programming obesity and consequent cardiovascular diseases [33].

Another study, rats were given physiological doses of leptin during lactation after being exposed to a high-fat diet, and it was found that their POMC promoter methylation was reduced. In contrast, the control group fed a high-fat diet and not supplemented with leptin showed increased POMC promoter methylation. There was also a negative correlation between DNA methylation and mRNA levels of POMC. This suggests that early supplementation with leptin can help regulate food intake, preventing excessive weight gain later in life. The findings indicate that gene promoter methylation may be a mechanism by which early life leptin supplementation can promote a healthy phenotype in adulthood [25].

The changes in the methylation status of the LEP gene are linked to perinatal conditions. The Dutch famine of 1944–1945 provides a prime example of this. Children of mothers who experienced undernutrition during the Dutch famine, either during the pre-conception period or late pregnancy, showed greater DNA methylation of the LEP gene. Additionally, LEP gene methylation was linked to the duration of breastfeeding, with a negative correlation between the DNA methylation of the LEP promoter and the length of breastfeeding. This lower methylation of the LEP gene may account for the higher levels of leptin in these infants and could be one of the ways in which breastfeeding helps protect against childhood obesity [25].

3.2 The role of adiponectin in the appetite regulation

Adipokines are secretory factors produced by adipocytes that play a role in regulating various metabolic processes, including lipid and glucose metabolism and energy homeostasis, as well as having anti-inflammatory effects [28, 29]. Adiponectin, in particular, is present in human milk at much higher concentrations than other appetite regulators, being forty times more abundant than leptin [29]. The levels of adiponectin in breast milk are positively correlated with those in the mother’s bloodstream, and the mother’s serum adiponectin levels are inversely linked to her body weight and BMI [29].

During pregnancy maternal serum adiponectin and breast milk adiponectin show an inverse relationship with infant adiposity, probably due the changes in maternal metabolism and adipose tissue deposition [28].

The impact of adiponectin on reducing childhood obesity is still a topic of debate. However, numerous studies have shown a negative correlation between maternal serum and breast milk adiponectin levels during pregnancy and infant adiposity development in the first year of life. Recently, adiponectin has gained attention as a potential clinical biomarker for obesity and related diseases in therapeutic approaches. Keeping in mind that adiponectin is not routinely measured, future studies are needed to verify which indicator - whether pre-pregnancy, early, mid- or late pregnancy weight status, or body fat - can be considered the best surrogate for adiponectin. Additionally, further human trials are needed in order to translate the observational research on the use of adiponectin as a clinical biomarker into therapeutic strategies in the future [28].

3.3 Macronutrients

The way an infant is fed (exclusive breastfeeding, milk formula or mixed feeding), the composition of their milk, and the amount they consume are crucial elements in ensuring optimal growth and development during the first 6 months of life, leading to long-term health benefits. Quick weight gain during the first 6 months can be a significant predictor of adverse metabolic outcomes in adulthood, such as a higher risk of obesity, central adiposity, and insulin resistance. However, it remains unclear if slow weight gain in breastfed infants is due to low caloric intake or the nutrient composition of breast milk (macronutrients) [34].

A cohort study tested the hypothesis that differential breast milk total calorie content or macronutrient contents may be associated with infancy growth. It was concluded breast milk of mothers exclusively breast feeding was more calorific with higher percentage fat, lower percentage carbohydrate and lower percentage protein. The higher breast milk total calorie content was associated with lower 12 months BMI/adiposity, and lower 3–12 months gains in weight/BMI. Breast milk percentage fat was inversely related to 3–12 months gains in weight, BMI and adiposity, whereas percentage carbohydrate was positively related to these measures. Breast milk percentage protein was positively related to 12-months BMI [34].

Infants who are fed breast milk tend to have lower levels of adiposity, suggesting that the composition of breast milk is optimal for their healthy growth. Breast milk has a higher proportion of lipids and a lower proportion of proteins and carbohydrates. Thus, infants fed breast milk with a lower percentage of fat felt less satiated and drank larger volumes of milk, hence gaining more weight [34].

3.3.1 Breast milk oligosaccharides

Lactose is the main sugar found in breast milk. Its high concentration, 6.7 g/100 ml, is higher than that of other species, reflecting the high nutritional needs of the human brain [35]. The unique nutritional value of breast milk is largely attributed to human milk oligosaccharides (HMOs), which are the third most abundant component after lactose and lipids. HMOs are complex sugars with diverse structures that are indigestible by infants [36].

HMOs are bioactive molecules that play a crucial role in infant health, with levels ranging from 1 to 10 g/l in mature milk and 15–23 g/l in colostrum [35, 37]. In mature milk, 35–50% of HMOs are fucosylated, 12–14% are sialylated, and 42–55% are non-fucosylated and neutral, respectively. The structures of oligosaccharides vary based on the presence of specific transferase enzymes expressed in the lactocytes. It has been hypothesized that the variation in HMO composition among mothers may enhance human survival, as pathogens exhibit different binding affinities according to specific structures of oligosaccharides [35]. HMOs also act as prebiotics, promoting the growth of beneficial bacteria such as Bifidobacteria and Bacteroides species [35, 36].

Throughout human life, the abundance of bifidobacteria decreases, going to 90% of the total colonic microbiota in breastfed infants to just 5% in adults, and declining even further in the elderly. A low abundance of bifidobacteria has been associated with gastrointestinal disorders such as irritable bowel syndrome. Supplementing with HMOs may be an effective strategy for modulating the gut microbiota and promoting the growth of beneficial bifidobacteria in adults [38].

HMOs have an anti-pathogenic effect against bacterium, virus, fungus and protozoan parasite. This is because HMOs can bind to pathogens and prevent pathogens from binding to receptors on the surface of epithelial cells and passing through the gastrointestinal tract, causing disease [36].

The impact of HMOs on gut barrier function has been largely underexplored. The intestinal epithelium the small intestine and colon are considered a key part of the innate immunity, serving as a physical barrier [36, 38].

The intestinal barrier is composed of a mucus layer that covers a single layer of intestinal epithelial cells, which separates bacteria from the underlying submucosa and is critical to maintaining gut homeostasis [38]. The intercellular junctional complexes regulate the passage of luminal nutrients, ions, and water and restrict bacterial entry, thereby controlling the barrier function of the epithelium. Microbes can indirectly affect epithelial permeability through their impact on host immune cells and the release of cytokines, either reducing or enhancing the barrier function. HMOs can influence the expression of intercellular junction proteins, reducing permeability and strengthening the barrier function of the epithelium [36, 38].

Currently, HMOs have been synthesized artificially as additives in infant milk formula for the infants who cannot be fed with breast milk. Thus, supporting the growth and providing protection against different diseases in early years life [36].

The HMOs that showed positive results were 2′-fucosylactose (2’-FL) and lacto-N-neo-tetraose (LNnT). A clinical study showed that IFs just with 2’-FL inhibited inflammatory cytokine production. IFs with 2′-FL and LNnT kept infants healthy whose parents had respiratory tract infections and bronchitis. Recently, it was found that the addition of 2′-FL and LNnT to IF could change the microbiota towards a similar microbiota of breastfed infants, by increasing the quantity of Bifidobacteria and decreasing the number of Clostridium difficile [36, 38].

Clinical studies have been conducted to investigate the impact of pre-pregnancy and postpartum maternal BMI on the composition of HMOs and its effect on infant growth [39, 40].

Results showed that maternal obesity was associated with lower levels of fucosylated and sialylated HMOs. Infants born to obese mothers had lower intake of these HMOs. Specific HMOs, including 3-fucosylactose, 3-sialylactose, 6-sialylactose, disyallylacto-N-tetraose, disyallylacto-N-hexaose, and total acidic HMOs, were positively related to infant growth during the first 6 months of life. This suggests that maternal obesity is linked to changes in HMO concentrations, which in turn may affect childhood adiposity [37, 41].

3.3.2 Breast milk lipids

Lipids, in the form of fat globules, are the main source of energy in breast milk, accounting for 44% of the total energy provided. They are produced in the endoplasmic reticulum of mammary epithelial cells and are surrounded by an outer membrane rich in bioactive compounds such as glycerophospholipids, sphingolipids, sphingomyelin, glycolipids, cholesterol, and glycosylated proteins. When these components are added to IFs, they have been linked to improved neurocognitive development and immune function [35].

The content of lipids, including long chain polyunsaturated fatty acids (LC-PUFAs), in breast milk is heavily influenced by the mother’s diet. LC-PUFAs have several key biological effects, particularly on membrane functions, growth, immune response, and the functional development of the retina and cerebral cortex. This suggests that developing countries should consider supplementing IFs with alpha-linoleic and docosahexaenoic acid (DHA). Medium-chain monoglycerides have the ability to inactivate various pathogens in vitro, such as group B Streptococcus [34, 35].

The majority of breast milk arachidonic acid derives from maternal reserves, but the content of DHA depends on the maternal nutrition. For a daily DHA supply of 100 mg in exclusively breastfeeding infants, the mother should consume at least 200 mg/day of DHA [35].

A recent study reported an inverse association between fat intake at 2 years of age and body fat, assessed by bioelectrical impedance analysis at 20 years, also suggesting that early diet containing greater fat may benefit later body composition. It is believed that the content of omega 6 fatty acids and linoleic acid may explain this relationship [34].

Results of a recent systematic review showed a positive association between maternal BMI and the amount of fat in breast milk in term-born infants between 1 and 6 months postpartum. For each increase of 1 kg/m² in maternal BMI the concentration of fat in milk increased by 0.56 g/l [42].

The link between breastfeeding and obesity is well-established, but the mechanisms involved are unclear. Some studies have attempted to define some of the breast milk lipidome, identifying 300 lipid species and 700 lipid characteristics. However, more specific details on maternal genetics, health and diet are lacking from literature. Future research should to collat more maternal data, including dietary information as to understand the impact of the breast milk lipidome and it is consequences on infant health [43].

3.3.3 Breast milk proteins

Proteins are the third most important component in breast milk for the healthy growth and development of infants, providing not only nutrition but also performing several bioactive functions. Proteins act as carriers for other nutrients, such as lactoferrin, haptocorrin, alpha-lactalbumin, and beta-casein, and help promote intestinal development and nutrient absorption. The quantity and quality of protein in human milk are crucial in influencing infant growth and body composition. In fact, a high protein intake in infancy has been associated with increased weight gain and a higher risk of developing obesity later [35].

Breastfed infants’ protein intake has served as a model for estimating protein needs in the first year of life. The protein content of breast milk depends on the stage of lactation and time since partum, with a high protein concentration during the first few weeks of lactation and a gradual decrease throughout the first year. Proteins are made up of amino acids that are linked together by peptide bonds. During digestion, proteins are broken down into simple amino acids and then absorbed. These absorbed amino acids are then used to build new proteins. The amount of protein intake may not accurately reflect the amount of amino acids used to synthesize new proteins because some breast milk proteins remain intact in the infant’s feces. Despite a decrease in protein concentration during lactation, the nutritional value of breast milk remains constant to meet the growing infant’s needs [44].

There is evidence to suggest a correlation between the presence of branched-chain amino acids (leucine, isoleucine, and valine) and aromatic amino acids (phenylalanine and tyrosine) in breast milk and an increased risk of childhood obesity. The maternal body mass index (BMI) is positively correlated with the amount of isoleucine, leucine, and aromatic amino acids consumed by infants. Infants who consume the highest amounts of these amino acids also show a positive association with their body composition [39].

4. Breastfeeding vs formula-fed infants

Breast milk has been shown to be the ideal source of nutrition for infants. However, most infants are fed human-milk substitutes. Cow’s milk proteins are the unique source of proteins in most IFs but have a lower quality compared with breast milk, partly because of differences in their amino acid contents [41].

IFs have been designed to imitate the nutritional benefits of breast milk for infants unable to be breastfed. The aim is to provide similar outcomes for optimal growth, development, maturation of the immune system and programming of the metabolism system. Despite the ongoing improvement of IFs, the growth patterns and development of body composition still differ from those of breastfed infants and may result in a higher risk of obesity for formula-fed infants [41, 45].

The mechanism behind the protective effect of breastfeeding is not fully understood. Several mechanisms may account such as differences in appetite regulation, early growth patterns, circulating leptin, and the gut microbiome [44, 45].

The first few months of life are a crucial time for avoiding metabolic, cardiovascular, and obesity issues in the future. Infant growth and weight gain during the first half-year of life is a more accurate predictor of adolescent body composition compared to weight gain from 6 months to 2 years old. Early patterns of body fat also indicate future obesity, as obese adults tend to experience an earlier rise in body fat compared to non-obese adults [41].

Breastfed infants generally have a slower weight gain in the first year of life compared to formula-fed infants. Formula-fed newborns have a 22% higher risk of developing childhood obesity compared to breastfed infants. Breastfeeding has been shown to be associated with a 13% reduction in childhood overweight or obesity, which is strongly linked to adult obesity, despite declining rates of breastfeeding. Exclusive breastfeeding is more effective in preventing childhood obesity than the combination of breastfeeding and IFs (mixed feeding), and the mixed feeding is more effective than exclusive formula feeding [41].

Breast milk protein concentration decreases over the weeks of lactation, while the protein concentration in IFs remains constant. Research has demonstrated that formula-fed infants consume 66–70% more protein compared to breastfed infants in the first 6 months of life. The lower protein content in breast milk is believed to affect infants’ growth, and reduced protein intake may prevent childhood obesity [44, 45].

Kouwenhoven et al. studied the short-term and long-term effects of a low-protein IFs (with 20% reduced protein content) on growth and body composition. Despite the lower protein levels, differences in growth, weight gain, and body composition still existed between formula-fed and breastfed infants. Formula-fed infants had significantly higher total fat mass, total fat-free mass, and fat-free mass index (FFMI) compared to breastfed infants up to 6 months of age. At 2 years old, significant differences in body composition were observed between the low-protein formula group and the breastfed reference group. Further research is necessary to examine the potential impact of higher protein intake on growth and body composition [45].

The exact mechanisms behind the impact of higher protein intake on growth and body composition are not yet understood. However, it is known that the anabolic hormones insulin and IGF-1 respond to changes in protein intake. No short-term correlations between insulin, glucose, the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and body composition have been observed in the first year of life. However, these associations were evident at 2 years of age, indicating that decreased insulin sensitivity early in life may affect body composition later in life, rather than the other way around [32, 45].

The differences in growth and body composition between infants fed low-protein formula and those who are breastfed suggest the use of formula with even lower protein content than 1.7 g/100 kcal. A recent study showed that a formula containing only 1.43 g protein per 100 kcal resulted in a significantly lower weight gain rate compared to formulas with 1.9 g or 2.18 g protein/100 kcal during the first 4 months of life [45]. Although the investigators reported adequate growth, it was not possible to determine the safety of such a low-protein formula. Thus, further research is required to determine the safety and effectiveness of reducing protein intake to levels closer to that found in human milk [45].

The fat matrix of IFs changed in the early 20th century. Previously it was composed of cow’s milk fat, later being constituted of a blend of vegetable oils.

This allows for a better mimicry of the mono- and polyunsaturated fatty acid (PUFA) profile found in breast milk. Formula is usually supplemented with higher levels of LC-PUFAs from the omega 3 and omega 6 families. The omega 3 LC-PUFAs have been linked to improved insulin sensitivity, reduced weight gain and adiposity, and improved lipid profiles. Postnatal supplementation with omega 3 PUFAs has been shown to reduce body fat deposition in adulthood and improve plasma lipid profile and glucose homeostasis. Similar benefits were observed with a low-omega-6 PUFA diet [41].

The main source of carbohydrates in standard IFs is lactose. Animal studies have shown that a high intake of carbohydrates in early life can have negative long-term effects, such as chronic hyperinsulinemia and adult-onset obesity [41].

Thus, although the mixture of HMOs found in breast milk cannot be replicated in IFs, adding prebiotics is a step towards mimicking their benefits. Currently, the prebiotics used in IFs mainly consist of a 9:1 mixture of short-chain galactooligosaccharides (scGOS) and long-chain fructooligosaccharides (lcFOS). However, the prebiotics commonly added to IFs have much simpler structures than HMOs and cannot reproduce all their benefits [41].

Recently, the availability of 2′FL and lacto-N-neotetraose (LNnT), has provided opportunities for the development of IFs that are similar to breast milk. Supplementation with these two HMOs did not result in any differences in weight, length, or BMI compared to non-supplemented IFs. However, it did result in a similar gut microbiota and metabolic programming to that of breastfed infants at 3 months of age [41].

Recently, it has been acknowledged that breast milk is a source of viable commensal and potentially probiotic bacteria such as Staphylococcus, Streptococcus, Bifidobacterium, and Lactobacillus. The composition of the breast milk microbiome is influenced by factors such as the maternal nutrition, gestational age and health status. The prevailing theory is that the bacteria reach the mammary gland through the lymphatic and circulatory systems, providing the infant with 107–108 bacterial cells per day through the consumption of approximately 800 ml of breast milk [41].

Probiotics are defined as ‘live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host’. The most commonly probiotics used in infant nutrition are strains of Bifidobacterium and Lactobacillus. The long-term impact of early consumption of probiotics on growth has been studied, with no effect observed from supplementation with Lactobacillus rhamnosus or Lactobacillus fermentum in the first months of life on growth at 2, 3, 5, and 13 years. Contrarily, the use of maternal probiotic supplementation with L. rhamnosus was seen to have an impact on the weight development of children. This was indicated by a slower rate of weight gain until the age of 2 to 4 years, particularly among children who became overweight later. This led to a lower body mass index until 7 years of age. The ESPGHAN Committee on Nutrition concluded in 2011 that supplementing healthy infants with currently evaluated probiotic formulas does not raise safety concerns regarding growth and adverse effects. However, due to high variability in responses, the relevance of supplementing IFs with probiotics remains unclear and the routine use of probiotic supplemented IFs is not currently mandatory [41].

Breastfeeding has been linked to a decreased risk of obesity, metabolic disorders such as diabetes, hypertension, and cardiovascular disease, as well as a lower likelihood of being overweight or obese in adulthood [25]. On the other hand, formula-fed infants have a higher risk of developing insulin resistance and type-2 diabetes later in life. They have been found to have higher levels of insulin secretion, indicated by higher concentrations of urinary C-peptide, as well as higher pre- and post-meal blood glucose levels. These elevated insulin levels may contribute to a greater buildup of subcutaneous fat. In comparison, breastfed infants have 3% lower insulin levels in adulthood than those who were formula-fed [41].

Early nutrition may also have an impact on cardiovascular risk factors and atherosclerosis in adulthood. Formula-fed infants may have higher blood pressure levels and an increased risk of atherosclerosis compared to breastfed infants. A prospective study of Mexican children found that exclusive and prolonged breastfeeding had a positive effect on later cardiovascular health, with lower levels of total cholesterol, LDL cholesterol, and triglycerides at age 4. However, at 4 and 8 weeks, formula-fed infants had lower levels of serum cholesterol, triglycerides, and transaminase (ALAT, ASAT, γGT) compared to breastfed infants. Despite these findings, the long-term impact of breastfeeding on the prevention of cardiovascular disease is still a matter of debate and more research is needed to fully understand the issue [41].

5. Conclusion

More and more evidence is showing that breast feeding confers protection to the infant against a range of diseases such as obesity, hypertension, dyslipidemia and cardiovascular disease.

This seems to be a result of early metabolic programming that we can find in the developmental origins of the health and disease hypothesis (DOHaD) theory. This DOHaD theory clarifies how the early life environment can impact the risk of chronic diseases from childhood to adulthood and witch the mechanisms epigenetics involved. Thus, there is a relationship between the Nutritional and environmental challenges prior to and during gestation, lactation, and early life and the health development of the infant. One where breast milk plays a key role. It is widely recognized that the mothers health and lifestyle has a big impact on offspring. The support and promotion of breastfeeding by healthcare professionals have the potential to increase breastfeeding prevalence before, during and after childbirth.

For the infants who need IF is possible adjust and further improve IF. However, is difficult to mimic breast milk or the art of breastfeeding because of its complexity and its effect on infant physiology.

Improving the functional effects of IF to reduce the gap between breastfed and formula-fed infants is crucial and has been the topic of great research over the past years. However, it is still under study which components should be added to IF and in which quantity.

Regarding metabolic health of infants, an improved IFs would consist in modulating all macronutrients. Decrease the quantity and improve their quality of the proteins, add lipids with size, structure and composition of the fat globule and balanced omega 3: omega 6 LC-PUFA ratio and to supplement with prebiotics, probiotics or synbiotics. The impact of breastfeeding on public’s health is big as it will help with obesity and DNTs prevention and ensuring improvement of quality of life and sustainable living for current and future generations.

Acknowledgments

The author would like to acknowledge the editorial support, namely the constructive review of the manuscript and raised comments. The author also would like to acknowledge to Isabel Caçoilo e Joana Matos Silva for critical review of the manuscript.

Conflict of interest

The authors declare no conflict of interest.