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Milk Exosomes and MicroRNAs: Potential Epigenetic Regulators

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  • First Online:
Handbook of Nutrition, Diet, and Epigenetics

Abstract

The scientific perception of the biological functions of milk, mammal’s secretory product of mammary gland epithelial cells during lactation, has dramatically changed in recent years from a simple food for the newborn mammal to a most sophisticated signaling system between the mother and her infant, in addition to nourishment, protection, and development it provides. From the wide range of extracellular vesicles found in milk, this review focuses primarily on milk exosomes and exosome-delivered microRNAs that emerge as an epigenetic regulatory software of milk decreasing genome methylation of the milk recipient. Thus, milk-derived exosomes are regarded as critical signalosomes for mother-to-child transmission of microRNAs that affect epigenetic regulatory circuits of the milk recipient. Evidence accumulates that epigenetic signaling of milk promotes the development of the infant’s gastrointestinal tract, immune system, osteogenesis, myogenesis, adipogenesis, and neurogenesis. According to the functional hypothesis, milk exosomal microRNAs may reach the systemic circulation of the infant and the adult human milk consumer. Human and bovine milk exosomes and their associated microRNAs are found in the fat fraction of milk and in skim milk. microRNAs are also present in large numbers in the cellular fraction of milk, making it a microRNA-rich medium, likely the richest microRNA source of all body fluids in humans. Human milk and commercial cow’s milk provides abundant amounts of microRNA-148a, microRNA-152, microRNA-29b, and microRNA-21, which all target DNA methyltransferases (DNMTs) that potentially affect whole genome DNA methylation patterns. DNA CpG demethylation upregulates the expression of many genes including the m6A RNA demethylase fat mass- and obesity-associated protein (FTO). In this regard, milk exosomal microRNAs may function as potential epigenetic modifiers of DNA- and RNA methylation of the milk recipient, who under physiological conditions is the suckling infant, but also the human consumer of commercial cow’s milk. Whereas milk exosome-driven epigenetic signaling appears to be indispensable for adequate postnatal growth and programming of the infant, this microRNA transmitter is almost absent in artificial formula, potentially leading to faulty or immature epigenetic programming of formula-fed infants. Furthermore, persistent consumption of commercial cow’s milk that still contains bioactive microRNAs, some of which exhibit high complementarity to human milk microRNAs, has currently unknown consequences to human health and may bear a health risk for humans of developed milk-consuming civilizations.

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Abbreviations

AGO2:

Argonaute 2

AKT:

V-AKT murine thymoma viral oncogene homolog

CMA:

Cow’s milk allergy

D2R:

Dopamine receptor type 2

DNMT:

DNA methyltransferase

EV:

Extracellular vesicle

FoxP3:

Forkhead box P3

FTO:

Fat mass- and obesity-associated gene

GLUT1:

Glucose transporter 1

IEC:

Intestinal epithelial cell

IgE:

Immunoglobulin E

IGF-1:

Insulin-like growth factor-1

IGF1R:

Insulin-like growth factor-1 receptor

IL:

Interleukin

ILV:

Intralumial vesicle

IκBα:

Nuclear factor κB inhibitor α

KO:

Knockout

LCT:

Lactase gene

m6A:

N6-methyladenosine

MEC:

Mammary epithelial cell

MEF:

Mouse embryonic fibroblast

MFG:

Milk fat globule

MFGM:

Milk fat globule membrane

microRNA:

Micro-ribonucleic acid

mTORC1:

Mechanistic target of rapamycin complex 1

MVB:

Multi-vesicular body

NEC:

Necrotizing enterocolitis

NFKBI:

Nuclear factor of κ light chain gene enhancer in B cells inhibitor α

NF-κB:

Nuclear factor κB

NR4A3:

Nuclear receptor subfamily 4, group A, member 3

NRF2:

Nuclear factor erythroid 2-related factor 2

p53:

Transformation-related protein 53

PBMCs:

Peripheral blood mononuclear cells

PGC1α:

PPAR-γ coactivator 1-α

PI3K:

Phosphatidylinositol 3-kinase

PPARγ:

Peroxisome proliferator-activated receptor-γ

RASGRP1:

Ras guanyl nucleotide-releasing protein-1

RISC:

RNA silencing complex

RNA:

Ribonucleic acid

ROCK1:

Rho-associated coiled-coil containing protein kinase 1

RUNX1T1:

Runt-related transcription factor 1, translocated to, 1

S6 K1:

Ribosomal protein S6 kinase

SIDT1:

Systemic RNA interference-defective-1 transmembrane family member 1

SNP:

Single nucleotide polymorphisms

SREBP-1:

Sterol regulatory element-binding protein 1

SRSF2:

Serine/arginine-rich splicing factor-2

TCR:

T cell receptor

TGFβ:

Transforming growth factor-β

TNF:

Tumor necrosis factor

TSDR:

Treg-specific demethylated region

UTR:

Untranslated region

VEC:

Vascular endothelial cell

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Authors and Affiliations

  1. Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Osnabrück, Germany

    Bodo C. Melnik

  2. School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, Australia

    Foteini Kakulas

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  1. Bodo C. Melnik
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  2. Foteini Kakulas
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Correspondence to Bodo C. Melnik .

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Editors and Affiliations

  1. School of Life Sciences, University of Westminster, London, UK

    Vinood B. Patel

  2. Diabetes and Nutritional Sciences Research Division, Faculty of Life Sciences and Medicine, King’s College London, London, UK

    Victor R. Preedy

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Melnik, B.C., Kakulas, F. (2019). Milk Exosomes and MicroRNAs: Potential Epigenetic Regulators. In: Patel, V., Preedy, V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-55530-0_86

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  • DOI: https://doi.org/10.1007/978-3-319-55530-0_86

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-55529-4

  • Online ISBN: 978-3-319-55530-0

  • eBook Packages: MedicineReference Module Medicine

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