MicroRNAs in Breastmilk and the Lactating Breast: Potential Immunoprotectors and Developmental Regulators for the Infant and the Mother

Abstract

Human milk (HM) is the optimal source of nutrition, protection and developmental programming for infants. It is species-specific and consists of various bioactive components, including microRNAs, small non-coding RNAs regulating gene expression at the post-transcriptional level. microRNAs are both intra- and extra-cellular and are present in body fluids of humans and animals. Of these body fluids, HM appears to be one of the richest sources of microRNA, which are highly conserved in its different fractions, with milk cells containing more microRNAs than milk lipids, followed by skim milk. Potential effects of exogenous food-derived microRNAs on gene expression have been demonstrated, together with the stability of milk-derived microRNAs in the gastrointestinal tract. Taken together, these strongly support the notion that milk microRNAs enter the systemic circulation of the HM fed infant and exert tissue-specific immunoprotective and developmental functions. This has initiated intensive research on the origin, fate and functional significance of milk microRNAs. Importantly, recent studies have provided evidence of endogenous synthesis of HM microRNA within the human lactating mammary epithelium. These findings will now form the basis for investigations of the role of microRNA in the epigenetic control of normal and aberrant mammary development, and particularly lactation performance.

Roles of MicroRNA across Prenatal and Postnatal Periods

“…Breast milk contains the highest concentration of total RNA of the 12 body fluids tested, more than 80 times the concentration found in amniotic fluid [4]. More than 1400 mature miRNAs are expressed in human milk [71]. These miRNAs are thought to originate from mammary gland epithelial cells [72].…”

“…Importantly, miRNAs are thought to either have a functional role or a nutritional role. The functional hypothesis suggests that milk miRNAs are absorbed by the suckling baby to imply specific actions: for example, to modulate and shape the immune system [85,88] by regulating T-cells, inducing B-cell differentiation [71,77], and preventing the development of allergies [89]. The nutritional hypothesis suggests miRNAs simply provide nutrition and refutes the transfer and the absorption of milk miRNA into the systemic circulation of offspring [85].…”

“…Interestingly, breast milk is rich with immune-related miRNAs [71,77,88] and miRNAs are implicated in multiple physiological processes [75], including cellular differentiation and proliferation, tissue identity, metabolism, and developmental programming [72]. Some miRNAs present in milk are involved in nervous system pathways and may mediate brain development.…”

Potential relevance of microRNAs in inter-species epigenetic communication, and implications for disease pathogenesis

“…17,38 Milk miRNAs are secreted in exosomes and they are extremely stable under different conditions such as very low and high pH, repeated cycles of freezing and thawing or even extended storage. 39,40 The largest amount of milk miRNAs is derived from the lactating mammary epithelium.…”

The Ubiquitous Existence of MicroRNA in Body Fluids

“…In addition to their possible biomarker applications, circulating miRNAs have been shown to possess specific biological activities that may have a clinically significant impact on human health (1 ). For example, miRNA in breast milk has been implicated in the health and development of infants (2 ). In 2008, Lawrie et al first reported the detection of miRNA in serum from patients with diffuse large B-cell lymphoma, and the concentrations of specific miRNAs correlated with the disease condition (3 ).…”