Non-Coding RNAs in Human Breast Milk: A Systematic Review

Abstract

Breast milk is the primary source of nutrition and hydration for the newborn infant but also plays an important role in the child’s first immune defense. Additionally, several breast milk factors have been implicated in immune-related health outcomes later in life, including immunoglobulins, cytokines, chemokines, growth factors and, more recently, non-coding RNA (ncRNA) species. In this systematic review, we provide a comprehensive summary of the current literature on endogenous ncRNAs found in human breast milk. Thirty (30) relevant studies were identified and, whilst the majority studies focused on microRNAs (miRNAs), there is evidence that breast milk contains high quantities of RNA which also include long-coding RNAs, circular RNAs, as well as other short RNAs and fragmented tRNA and rRNAs. Among studies investigating miRNAs, miR-148a-3p, miR-30a/d-5p, miR-22-3p, miR-146b-5p, miR-200a/c-3p, and the 5p end of the let-7 miRNAs were commonly reported among the top 10 miRNAs in the cell, lipid, and skim milk fractions of breast milk. Methodological difference and small sample sizes limit the possibility of conclusively identifying which maternal and infant characteristics affect the miRNA profile. The highly expressed miRNAs were generally reported to be similar across lactational stage, milk fraction, maternal and infant characteristics, or infant growth and health. All the same, individual studies identify potential differences in miRNA expression levels which should be confirmed by future studies. Stability, uptake, and physiological functions of miRNAs were also considered in several studies. Breast milk miRNAs are relatively resistant to a range of harsh conditions and uptake experiments suggest that extracellular vesicles containing miRNAs and circular RNAs can be taken up by intestinal epithelial cells. Although the evidence regarding the functional effect of breast milk miRNAs is limited, the predicted functions range from metabolic and biosynthetic processes to signaling pathways, cellular adhesion, communication, growth, and differentiation. Finally, this systematic review highlights some of the methodological challenges and knowledge gaps which can help direct future research in this field. In particular, it is important to further investigate the bioavailability of miRNAs in different milk fractions, and to characterize other ncRNAs which are largely unstudied.Systematic Review RegistrationPROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=138989, identifier CRD42020138989.

Influence of the Bioactive Diet Components on the Gene Expression Regulation

“…The qualitative and quantitative composition of miRNA molecules in milk is related to many factors, such as the fraction of milk, the processing method, or, in the case of human milk, the mother's age, health, and her lifestyle [177]. For this reason, it is difficult to establish the exact profile of miRNA in human milk [178][179][180] and thus the exact effect of miRNA from milk on a child's development. It is known, however, that milk-derived exosomal miRNAs that target DNA methyltransferase 1 (DNMT1) (miRNA-148a, miRNA-21) and DNMT3B (miRNA-148a, miRNA-29b) have been suggested to play a fundamental epigenetic role for milk-induced FOXP3 expression and Treg stabilization.…”

Transcriptomic Characterization of Cow, Donkey and Goat Milk Extracellular Vesicles Reveals Their Anti-Inflammatory and Immunomodulatory Potential

“…Concerning miRNAs, the majority of molecules highly expressed and shared between the three species (let-7i, miR-148b, miR-151a, miR-186, miR-191, miR-200b, miR-21, miR-27b, miR-30b, and miR-30d) are known to be enriched in milk [ 20 , 66 , 67 , 68 ] and involved in immunomodulation [ 22 , 63 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. Although several studies have investigated the miRNA content in milk EVs from individual species [ 67 ], very few are about EV-associated miRNAs among different species [ 68 ]. Interestingly, in all studies, several abundant miRNAs were shared between species and are coherent with our results.…”

“…MiR-148 regulates DNA methyl-transferase 1 (DNMT1), suggesting that milk consumption might affect the epigenome signatures [ 40 , 67 ] through mEVs uptake. Interestingly, milk miR-148a-3p and miR-29a-3p can also downregulate DNMT3B [ 77 ], a protein responsible for Forkhead box P3 (FOXP3) epigenetic inhibition [ 78 ].…”

“…Regarding other common mEV miRNAs, let-7 together with miR-148, regulate transcription factor NF-κB in vivo, with the immune response suppression as an outcome [ 67 , 68 ]. Moreover, miR-30b and miR-200, along with miR-148, have been designated as major immune-related miRNAs [ 81 ] and are highly represented in milk [ 82 ] and also present in our core molecules in mEVs ( Table 1 ).…”

The Exposome Approach in Allergies and Lung Diseases: Is It Time to Define a Preconception Exposome?

“…The T cells were identified as specific for antigens against these pathogens [ 96 ]. Several studies suggest that the transfer of noncoding RNA (ncRNAs) through breastmilk is plausible [ 97 ]. There are indications that such transfer, on the other hand, could predispose offspring to enhanced allergic inflammation under certain conditions [ 98 , 99 ].…”