a) Composition of Human Milk

Human milk is a complicated biological system that incorporates nutritional and functional factors and interacts to offer the infant the best nutritional and immunological environment. It also has proteins, lipids, carbohydrates, water, vitamins and minerals as well as functional compounds such as enzymes, antibodies, immune molecules, and microRNAs (miRNAs). Studies have shown that this setting is not only physiological and environmental but also genetic determinants which makes one mother different compared to another.

In terms of proteins, human milk has casein, lactoferrin, alpha-lactalbumin, and immune proteins IgA, which are particularly secreted to provide infant immunity in the postnatal environment [5]; [7]; [13]. Lipids are the main source of energy and are essential in the development of the central nervous system, especially the long chain fatty acids like DHA and ARA.

Among the most valuable non-digestible milk compounds are the free carbohydrates, in particular the human milk oligosaccharides (HMOs). They help to develop a healthy gut microbiome and trigger the development of immunity. It has been found that more than 200 forms of HMOs exist, and their ratios among mothers depend on their genetic makeup, specifically on the presence of the gene that regulates the synthesis of functional sugars in the milk, namely, the FUT2 gene [1]; [2]; [14].

Other non-traditional ingredients in milk include cell-free DNA (cfDNA) and miRNAs, which also transferable genetic information that influences immune cell functions in infants and provides immune and neural programming [11]; [12]. Although they were discovered quite recently, these molecules are a progressive edge in the interpretation of the dynamic character of milk composition. The point to note here is that breast milk does not merely constitute a nutritional substance but that it is a responsive molecular environment, which constantly changes in response to genetic, environmental and psychological influences- it is more complex to study than formula or animal milk.

b) Genetics Factors in Human Milk Compositions.

The genetic component is also a basic determinant of human milk composition, when it comes to the composition of fundamental nutritional elements, as well as the presence of finer immunological and functional compounds. Recent genomic findings also show that variations in the rate of gene expression by mothers are among the most significant factors influencing the milk variability, and each mother has a unique genetic fingerprint of milk secretion which interacts with environmental and physiological factors [9].

One of the most powerful genes is the FUT2 that controls the release of the complex HMOs that feed the beneficial gut micro-organisms in infants. The related literature demonstrates that mothers with the secretor genotype have a higher concentration of fucosylated oligosaccharides than non-secretors, which leads to the difference in infant immune responses [1]. The gene, named as the LALBA, is linked with the synthesis of the protein of 2 liters of milk; 2-lactalbumin, which is used in the production of lactose. Its changes in gene expression result in great differences in milk volume and osmotic qualities [2]. Other genes including: CSN2 and LCN2 genes play a role in the structure of the milk protein and antimicrobial value. GWAS studies indicate the genetic variability of the maternal genetic material in these genes, which manifests in immune protein structures and in bacterial and viral infection resistance [4]; [7].

Moreover, miRNA levels in milk have been associated with genes that control miRNA in mammary epithelial cells. These miRNAs have a non-canonical impact on the transmission of regulatory signals in infant cells, which are involved in the formation of the brain and the maturation of the immune [12]; [3]; [15]. These genetic factors do not act alone but rather interact in a complex regulatory system that is determined by diet, stress, mode of delivery and even the sex of the infant - an observation confirmed by RNA sequencing and differential gene expression analyses [11]; [8]. This genetic difference highlights the individuality of human milk and adds to the argument that breastfeeding is not a biological process at all but rather a genetically individualized process that expresses maternal genomic traits and is responsive, in terms of infant genetics, to infant genetics as well.

c) Maternal-Infant Genomic Interaction.

Maternal infant genomic interaction is one of the most significant new ideas that are emerging in the field of molecular biology and functional nutrition. Breast feeding is now being looked upon as a multidirectional genetic interaction as opposed to unidirectional nutrient transfer. This is the interaction between the biochemical markers, regulatory molecules and microbiota, which have a reciprocal response that includes changes in gene expression in both mother and infant.

The rising evidence indicates that when breastfeeding, infant saliva contains chemical substances and microbial elements which activate the receptors in the mammary epithelial cells. It provokes instant changes in the composition of milk, especially the increase in antibodies, including IgA and other immune factors [7]; [4]. Analyses of the differential gene expression demonstrate that such responses entail transient transcriptional alterations in the tissues of the mammary glands. On the other hand, infant genes, in particular, immune-functional genes and gut microbiome genes influence the reception and use of milk components. The reaction of infants with certain genetic forms of HMOs or miRNAs may be different, which means that there can be genetic compatibility or mismatch that affects the efficiency of breastfeeding [9]; [3].

The miRNAs and the cfDNA have been reported in human milk, and they are absorbed into the infant gastrointestinal tract and enter circulation, where they perform regulatory functions on immune and neural gene expression [11]; [12]. This implies that milk does not only convey biological knowledge in the mother to the infant but could be described as a genetic messenger that programs infant gene expression. Interaction with the environment Genomic interaction can also be extended to environmental-genetic responses such as the microbiome shared by the mother and infant. When comparing the microbial genomes of the infant and those found in maternal milk, metagenomic sequencing shows that bacterial strains in maternal milk are similar to those present in the infant microbiota, meaning that there is a directed transfer of microorganisms based on the genomic profiles of both the mother and the infant [7]; [5]. In practical terms, the knowledge of this two-way genetic interaction could be used to form the basis of genetically customized feeding systems, as supplements or formula could be designed to be of a specific fit to maternal and infant genotype.

d) Gene Expression, miRNAs, and cfDNA of Human Milk.

The latest findings that have shown the existence of active genetic molecules in human milk, specifically miRNAs and cfDNA have radically changed the perception of milk as an active biological system instead of a passive nutritional one. Human milk is currently becoming a conceptualized molecularly enriched biofluid that is able to relay regulatory cues that will affect cellular development, immune development, and gene transcription events in the infant.

The studies of gene expression show that mammary epithelial cells actively release miRNAs that are embedded in extracellular vesicles (exosomes in particular). The phosphatidylinositol vesicles are exceptionally stable to enzymatic degradation within the infant gastrointestinal tract and are therefore taken up by infant tissues where they are involved in post-transcriptional gene regulation [12]; [3] [15]. Milk-derived miRNAs have been demonstrated to regulate neurodevelopment, inflammatory regulation, and immune cell differentiation pathways and have a functional role in realizing their potential as a central epigenetic programming mechanism through a process served by breastfeeding.

Another genetic component of human milk that has been recently discovered is cell-free DNA (cfDNA). Majority of the cfDNA fragments are derived mainly out of the mammary epithelial cells and they are indicated to appear in quantifiable amounts and in greater association with immunological and regulatory functions. There is some new data indicating that milk cfDNA can be used as a biomarker in future to monitor the health of the mammary gland and lactational status and can also act as a transient maternal-infant genetic signaling [11]. Interestingly, the profiles of the cfDNA in human milk have proven to be sensitive to the health conditions of the mother and lactation, as well as the sex of the infant, which is why it represents a highly sensitive and adaptable biological operation.

Correspondingly, the level of gene expression in the mammary gland itself is a constantly modulated process in changes to hormonal, environmental and genetic stimuli. RNA-sequencing (RNA-seq) studies show that there are dynamic changes in transcription of immune protein production, oligosaccharide production genes and hormonal regulation genes. Such types of transcription vary greatly between mothers and seem to be highly dependent on personal genetic histories [1]; [2]. The interaction with the microbiome of the milk and the skin is what makes these molecular components even more unique and puts another dimension of complexity to the genetic communication between mothers and newborns. These interactions further develop the concept of human milk as a highly responsive system developing integration of genetic, microbial and environmental cues in a timely fashion. Together, these results validate that breastfeeding enables the passage of biologically significant molecular data and has the potential to define the genetic expression pattern, as well as functional maturation of the infant.