Impacts of milk processing and fermentation on microRNA levels in cow’s milk
Year 2025,
Volume: 11 Issue: 2, 127 - 138, 28.03.2025
Dilek Pirim
,
İrem Nur Gözüdok
,
Özden Çobanoğlu
,
Metin Güldaş
,
Ozan Gürbüz
Abstract
Recent evidence suggests that milk-derived microRNAs (miRNAs) are bioactive components of milk that can influence host cells through cross-kingdom miRNA transfer mechanisms. Therefore, it is essential to assess the content and stability of these miRNAs in drinking milk and milk products to explore their potential roles in human health. Here, we examined the small RNAs and microRNA levels in raw and processed milk samples, including plain and prebiotic-rich kefir. Total RNA was isolated from milk samples processed with different heat treatments and fermentation. The effects of milk processing on specific miRNAs were investigated by RT-qPCR, which evaluated the quantities of four miRNAs related to human diseases. We found that miR-21 and miR-125b could resist harsh conditions applied in milk processing plants. However, no detectable amounts of the tested miRNAs were found in kefir samples by qPCR. Our study highlights the miRNA-specific effects of milk processing methods on milk miRNA content. Future studies focusing on total small RNA content in kefir and other milk products may offer valuable insights into the functional role of milk-derived miRNA. Overall, miRNAs in drinking milk warrant further attention for their potential importance for public health.
Ethical Statement
The authors declare that this study does not include experiments with human or animal subjects, so ethics committee approval is not required.
Supporting Institution
Bursa Uludag University Scientific Research Projects Unit
Project Number
FYL-2022-1233 and FGA-2022-820
Thanks
We thank Ms. Özlem Kaner, R&D Coordinator, for her cooperation in obtaining the processed milk samples from the SÜTAŞ dairy processing plants and her contributions to our research (Bursa, Turkey). We also thank our lab members Fatih Atilla Bağcı and Ceren Gümüş for their help in the project management.
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Year 2025,
Volume: 11 Issue: 2, 127 - 138, 28.03.2025
Dilek Pirim
,
İrem Nur Gözüdok
,
Özden Çobanoğlu
,
Metin Güldaş
,
Ozan Gürbüz
Project Number
FYL-2022-1233 and FGA-2022-820
References
- Abou el Qassim, L., Alonso, J., Zhao, K., Le Guillou, S., Diez, J., Vicente, F., … Royo, L.J. (2022). Differences in the microRNAs Levels of Raw Milk from Dairy Cattle Raised under Extensive or Intensive Production Systems. Veterinary Sciences, 9(12), 661. https://doi.org/10.3390/vetsci9120661
- Abou el Qassim, L., Le Guillou, S., & Royo, L.J. (2022). Variation of miRNA content in cow raw milk depends on the dairy production system. International Journal of Molecular Sciences, 23(19), 11681. https://doi.org/10.3390/ijms231911681
- Abou el Qassim, L., Martínez, B., Rodríguez, A., Dávalos, A., López de las Hazas, M.-C., Menéndez Miranda, M., & Royo, L.J. (2023). Effects of cow’s milk processing on microRNA levels. Foods, 12(15), 2950. https://doi.org/10.3390/foods12152950
- Baier, S.R., Nguyen, C., Xie, F., Wood, J.R., & Zempleni, J. (2014). MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers. The Journal of Nutrition, 144(10), 1495–1500. https://doi.org/10.3945/jn.114.196436
- Benmoussa, A., Gotti, C., Bourassa, S., Gilbert, C., & Provost, P. (2019). Identification of protein markers for extracellular vesicle (EV) subsets in cow’s milk. Journal of Proteomics, 192, 78–88. https://doi.org/10.1016/j.jprot.2018.08.010
- Benmoussa, A., Laugier, J., Beauparlant, C.J., Lambert, M., Droit, A., & Provost, P. (2020). Complexity of the microRNA transcriptome of cow milk and milk-derived extracellular vesicles isolated via differential ultracentrifugation. Journal of Dairy Science, 103(1), 16–29. https://doi.org/10.3168/jds.2019-16880
- Benmoussa, A., Lee, C.H.C., Laffont, B., Savard, P., Laugier, J., Boilard, E., … Provost, P. (2016). Commercial dairy cow milk microRNAs resist digestion under simulated gastrointestinal tract conditions. The Journal of Nutrition, 146(11), 2206–2215. https://doi.org/10.3945/jn.116.237651
- Cao, X., Yang, Q., & Yu, Q. (2020). Increased expression of mir-487b is associated with poor prognosis and tumor progression of HBV-related hepatocellular carcinoma. Open Forum Infectious Diseases, 7(12), ofaa498. https://doi.org/10.1093/ofid/ofaa498
- Chen, Q., Zhang, F., Dong, L., Wu, H., Xu, J., Li, H., … Zhang, C.-Y. (2021). SIDT1-dependent absorption in the stomach mediates host uptake of dietary and orally administered microRNAs. Cell Research, 31(3), 247–258.
https://doi.org/10.1038/s41422-020-0389-3
- Fabris, L., & Calin, G.A. (2016). Circulating free xeno-microRNAs—The new kids on the block. Molecular Oncology, 10(3), 503–508. https://doi.org/10.1016/j.molonc.2016.01.005
- Fox, P.F., Cogan, T.M., & Guinee, T.P. (2017). Chapter 25—Factors That Affect the Quality of Cheese. In P.L.H. McSweeney, P.F. Fox, P.D. Cotter, & D.W. Everett (Eds.), Cheese (Fourth Edition) (pp. 617–641). San Diego: Academic Press. https://doi.org/10.1016/B978-0-12-417012-4.00025-9
- Golan-Gerstl, R., Elbaum Shiff, Y., Moshayoff, V., Schecter, D., Leshkowitz, D., & Reif, S. (2017). Characterization and biological function of milk-derived miRNAs. Molecular Nutrition & Food Research, 61(10), 1700009. https://doi.org/10.1002/mnfr.201700009
- Herwijnen, M.J.C. van, Driedonks, T.A.P., Snoek, B.L., Kroon, A.M.T., Kleinjan, M., Jorritsma, R., … Wauben, M. H.M. (2018). Abundantly present mirnas in milk-derived extracellular vesicles are conserved between mammals. Frontiers in Nutrition, 5.
- Howard, K.M., Jati Kusuma, R., Baier, S.R., Friemel, T., Markham, L., Vanamala, J., & Zempleni, J. (2015). Loss of miRNAs during processing and storage of cow’s (Bos taurus) milk. Journal of Agricultural and Food Chemistry, 63(2), 588–592. https://doi.org/10.1021/jf505526w
- 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. Journal of Dairy Science, 95(9), 4831–4841. https://doi.org/10.3168/jds.2012-5489
- Izumi, Hirohisa, Tsuda, M., Sato, Y., Kosaka, N., Ochiya, T., Iwamoto, H., … Takeda, Y. (2015). Bovine milk exosomes contain microRNA and mRNA and are taken up by human macrophages. Journal of Dairy Science, 98(5), 2920–2933. https://doi.org/10.3168/jds.2014-9076
- Jonas, S., & Izaurralde, E. (2015). Towards a molecular understanding of microRNA-mediated gene silencing. Nature Reviews. Genetics, 16(7), 421–433. https://doi.org/10.1038/nrg3965
- Kirchner, B., Pfaffl, M.W., Dumpler, J., von Mutius, E., & Ege, M.J. (2016). microRNA in native and processed cow’s milk and its implication for the farm milk effect on asthma. The Journal of Allergy and Clinical Immunology, 137(6), 1893-1895.e13. https://doi.org/10.1016/j.jaci.2015.10.028
- Larrue, R., Fellah, S., Van der Hauwaert, C., Hennino, M.-F., Perrais, M., Lionet, A., … Cauffiez, C. (2022). The Versatile role of miR-21 in renal homeostasis and diseases. Cells, 11(21), 3525. https://doi.org/10.3390/cells11213525
- Le, T.T., Van de Wiele, T., Do, T.N.H., Debyser, G., Struijs, K., Devreese, B., … Van Camp, J. (2012). Stability of milk fat globule membrane proteins toward human enzymatic gastrointestinal digestion. Journal of Dairy Science, 95(5), 2307–2318. https://doi.org/10.3168/jds.2011-4947
- Li, J., Lei, L., Ye, F., Zhou, Y., Chang, H., & Zhao, G. (2019). Nutritive implications of dietary microRNAs: Facts, controversies, and perspectives. Food & Function, 10(6), 3044–3056. https://doi.org/10.1039/c9fo00216b
- Li, R., Dudemaine, P.-L., Zhao, X., Lei, C., & Ibeagha-Awemu, E.M. (2016). Comparative Analysis of the miRNome of Bovine Milk Fat, Whey and Cells. PLOS ONE, 11(4), e0154129. https://doi.org/10.1371/journal.pone.0154129
- Liao, Y., Du, X., Li, J., & Lönnerdal, B. (2017). Human milk exosomes and their microRNAs survive digestion in vitro and are taken up by human intestinal cells. Molecular Nutrition & Food Research, 61(11). https://doi.org/10.1002/mnfr.201700082
- López de Las Hazas, M.-C., Del Pozo-Acebo, L., Hansen, M. S., Gil-Zamorano, J., Mantilla-Escalante, D.C., Gómez-Coronado, D., … Dávalos, A. (2022). Dietary bovine milk miRNAs transported in extracellular vesicles are partially stable during GI digestion, are bioavailable and reach target tissues but need a minimum dose to impact on gene expression. European Journal of Nutrition, 61(2), 1043–1056. https://doi.org/10.1007/s00394-021-02720-y
- Manca, S., Upadhyaya, B., Mutai, E., Desaulniers, A.T., Cederberg, R.A., White, B.R., & Zempleni, J. (2018). Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns. Scientific Reports, 8(1), 11321. https://doi.org/10.1038/s41598-018-29780-1
- Melnik, B.C., Kakulas, F., Geddes, D.T., Hartmann, P.E., John, S.M., Carrera-Bastos, P., … Schmitz, G. (2016). Milk miRNAs: Simple nutrients or systemic functional regulators? Nutrition & Metabolism, 13(1), 42. https://doi.org/10.1186/s12986-016-0101-2
- Melnik, B.C., & Schmitz, G. (2019). Exosomes of pasteurized milk: Potential pathogens of Western diseases. Journal of Translational Medicine, 17(1), 3. https://doi.org/10.1186/s12967-018-1760-8
- Myrzabekova, M., Labeit, S., Niyazova, R., Akimniyazova, A., & Ivashchenko, A. (2021). Identification of Bovine miRNAs with the Potential to Affect Human Gene Expression. Frontiers in Genetics, 12, 705350. https://doi.org/10.3389/fgene.2021.705350
- O’Brien, J., Hayder, H., Zayed, Y., & Peng, C. (2018). Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Frontiers in Endocrinology, 9.
- Oh, S., Park, M.R., Son, S.J., & Kim, Y. (2015). Comparison of total RNA isolation methods for analysis of immune-related microRNAs in market Milks. Korean Journal for Food Science of Animal Resources, 35(4), 459–465. https://doi.org/10.5851/kosfa.2015.35.4.459
- Shandilya, S., Rani, P., Onteru, S.K., & Singh, D. (2017). Small Interfering RNA in Milk Exosomes Is Resistant to Digestion and Crosses the Intestinal Barrier In Vitro. Journal of Agricultural and Food Chemistry, 65(43), 9506–9513. https://doi.org/10.1021/acs.jafc.7b03123
- Shome, S., Jernigan, R.L., Beitz, D.C., Clark, S., & Testroet, E.D. (2021). Non-coding RNA in raw and commercially processed milk and putative targets related to growth and immune-response. BMC Genomics, 22(1), 749. https://doi.org/10.1186/s12864-021-07964-w
- Sohel, M.H. (2016). Extracellular/Circulating MicroRNAs: Release Mechanisms, Functions and Challenges. Achievements in the Life Sciences, 10(2), 175–186. https://doi.org/10.1016/j.als.2016.11.007
- Torrez Lamberti, M.F., Parker, L.A., Gonzalez, C.F., & Lorca, G.L. (2023). Pasteurization of human milk affects the miRNA cargo of EVs decreasing its immunomodulatory activity. Scientific Reports, 13(1), 10057. https://doi.org/10.1038/s41598-023-37310-x
- Wang, F., Ye, B.-G., Liu, J.-Z., & Kong, D.-L. (2020). miR-487b and TRAK2 that form an axis to regulate the aggressiveness of osteosarcoma, are potential therapeutic targets and prognostic biomarkers. Journal of Biochemical and Molecular Toxicology, 34(8), e22511. https://doi.org/10.1002/jbt.22511
- Wang, Y., Zeng, G., & Jiang, Y. (2020). The emerging roles of miR-125b in cancers. Cancer Management and Research, 12, 1079–1088. https://doi.org/10.2147/CMAR.S232388
- Weber, J.A., Baxter, D.H., Zhang, S., Huang, D.Y., Huang, K.H., Lee, M.J., … Wang, K. (2010). The microRNA spectrum in 12 body fluids. Clinical Chemistry, 56(11), 1733–1741. https://doi.org/10.1373/clinchem.2010.147405
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