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MicroRNAs in Milk

    3D view of a molecule of a microRNA (miRNA) molecule

    Written by: Peter Williamson, Ph.D. | Issue # 11 | 2013

    • MicroRNAs control levels of protein produced by milk-making cells.
    • MicroRNAs are a biological component of milk.
    • MicroRNAs survive strong acidic conditions and milk processing.
    • The biological activity of milk microRNAs may potentially be transferred to gut cells.

    Small things remain invisible unless one knows to look for them. Case in point: tiny RNAs. What are they? Why are they in milk? Are they good for the consumer?

    Proteins are a fundamental nutritional and bioactive component of milk. These proteins are primarily produced by cells in the mammary gland. Gene activation dictates the amount of protein produced, and critical to this process is something called messenger RNA. Messenger RNA, or mRNA, is a molecule that serves as an intermediary between gene and protein. In other words, gene activation leads to the production of mRNA, which then leads to the synthesis of proteins, including those in milk. Genes beget mRNA; mRNA begets proteins.

    Although we’ve known about mRNA for decades, just twenty years ago, scientists discovered a new class of RNA molecules that have turned out to play a crucial role in affecting the rate of protein synthesis. Prior to this groundbreaking finding, we believed the speed at which proteins were produced was controlled by the amount of mRNA present that coded for the protein or perhaps the stability of that mRNA. Now we know that these new RNA molecules, called microRNA, or miRNA (discovered in worms, no less!), function as the brake pedal in protein synthesis. That is, their natural function is to retard the rate of production of proteins in cells by disrupting the molecular machinery required for translating those mRNA strands to proteins. In short, microRNAs slow protein production.

    Is miRNA found in human milk?

    In 2010, the results of a fundamental collaborative research project between the Nutritional Science Laboratory of the Morinaga Milk Industry in Kanagawa, Japan, and the National Cancer Center Research Institute in Tokyo were published, demonstrating the presence of miRNA in breast milk (2). The study focused on miRNA species that were previously implicated in downregulating levels of immune-related proteins. The study also reported that these miRNAs were relatively resistant to low acid pH levels similar to those found in the human stomach.

    A study just published online in BMC Genomics (December 2012)(1) is the latest in a series of articles dealing with miRNA and lactation. Because miRNAs are molecules that help regulate the levels of proteins that are involved in biological processes, their presence in milk could mean they contribute to the regulation of developmental and physiological functions. This latest study shows that miRNA differs in the lactating and non-lactating mammary gland. This is similar to the difference in patterns of gene expression that are observed when the mammary gland begins to make milk.

    What about bovine milk and commercial milk products?

    Now that scientists are discovering miRNAs in human milk, it’s important to know if the same, different, or any miRNAs are found in other milk sources, such as bovine milk and commercial milk products. A few studies have shown that miRNA is found in raw and processed bovine milk (3-5). The miRNA found by individual investigators varied between the different reports, although this was undoubtedly influenced by study design. Colostrum and milk show differences in the absolute number of each miRNA found, and there is a greater variety in colostrum. Not surprisingly, different stages of milk storage and processing show considerable variation in the levels of most miRNA molecules in milk. Additionally, in infant formula, some miRNA molecules are found at one-tenth the level at which they exist in unprocessed milk. Seven miRNA molecules were identified as relatively stable in raw milk, and these may be useful as indicators of milk processing effects or spoilage. Although miRNA is relatively resistant to milk processing, they seem to undergo a considerable loss in concentration during the process, perhaps due to disruption of small bubble-like compartments that contain the majority of miRNA molecules. Whether this is of any significance to the consumer remains to be seen.

    Does milk-derived miRNA have a biological function?

    The evidence strongly supports that miRNA are delivered to the infant via milk, and because of their remarkable resilience to degradation, they would transit through the stomach. The resistance to degradation may be attributed to the fact that miRNA is predominantly found in exosomes.

    Exosomes are very small bubble-like compartments that form inside cells and are secreted into the fluid surrounding these cells. Milk-producing cells secrete exosomes into milk. Exosomes contain not only miRNA, but also other biomolecules, including proteins. There is convincing evidence that exosomes can fuse into the cell membrane of target cells and release their contents, including miRNA. When exosomes are put together with cells in the laboratory, they have been shown to modify the cellular responses of their target cells, including the release of immune modulatory molecules (4, 6). However, clear evidence that miRNA is delivered in this way and affects receiving cells is still lacking. Furthermore, extrapolating from the laboratory into an entire person or animal has drawbacks, and so it is unknown whether ingested miRNAs are functional in the recipient.

    However, one intriguing finding published recently showed the presence of plant-derived miRNAs in the bloodstream of adults who had eaten rice (7). The researchers showed that a miRNA from rice slows the production of a liver protein in a mouse! This study demonstrated for the first time that a plant food component potentially regulates mammalian cells. It should be even easier for a mammalian food (milk) to regulate mammalian cells.

    There are still a lot of questions to be answered, but we do know that miRNA are highly conserved between species, so if these molecules do have biological activity, it is likely that bovine-derived miRNA will have similar effects as human miRNA. Do miRNAs in milk affect the health of the consumer? In a word: maybe.

    References

    1. Li Z, Liu H, Jin X, Lo L, & Liu J (2012) Expression profiles of microRNAs from lactating and non-lactating bovine mammary glands and identification of miRNA related to lactation. (Translated from Eng) BMC Genomics 13:731 (in Eng).

    2. Kosaka N, Izumi H, Sekine K, & Ochiya T (2010) microRNA as a new immune-regulatory agent in breast milk. (Translated from eng) Silence 1:7 (in Eng).

    3. Chen X, Gao C, Li H, Huang L, Sun Q, Dong Y, Tian C et al. (2010) Identification and characterization of microRNAs in raw milk during different periods of lactation, commercial fluid, and powdered milk products. (Translated from Eng) Cell Res 20:1128-1137 (in Eng).

    4. Hata T, Murakami K, Nakatani H, Tamamoto Y, Matsuda T, Aoki N. (2010) Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. (Translated from Eng) Biochem Biophys Res Commun 396:528-533 (in Eng).

    5. Izumi H, Kosaka N, Shimizu T, Sekine K, Ochiya T, Takase M. (2012) Bovine milk contains microRNA and messenger RNA that are stable under degradative conditions. (Translated from Eng) J Dairy Sci 95:4831-4841 (in Eng).

    6. Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, Norman M, Neve EP et al.(2007) Exosomes with immune modulatory features are present in human breast milk. (Translated from Eng) J Immunol179:1969-1978 (in Eng).

    7. Zhang L, Hou D, Chen X, Li D, Zhu L, Zhang Y, Li J et al. (2012) Exogenous plant MIR168a specifically targets mammalian LDLRAP1: Evidence of cross-kingdom regulation by microRNA. (Translated from Eng) Cell Res 22:107-126 (in Eng).

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