Grant: Project Grant

MicroRNAs modulate ~60% of our genes and are important to our health, as deregulation of microRNA levels has been associated with a panoply of major human diseases, including cancer. Intriguingly, all the plant and animal species composing our diet contain "dietary" microRNAs that we ingest on a daily basis. A long-standing belief is that microRNAs contained in foods do not resist the chemical and biochemical conditions of digestion, and are readily degraded. This dogma, however, was shaken by a provocative study suggesting that a plant microRNA could be absorbed orally and detected in the circulation and organs of mice. Subsequent studies and analyses failed to appease this controversy, due mainly to intrinsic limitations related to the conservation of microRNA sequences between species. Seven years later, whether microRNAs can be transferred orally remains highly debated and controversial. To address most of these limitations, we established a partnership with a major biotechnology firm to set up a unique experimental approach based on the use of milk produced by transgenic (TG) cows. This milk contains endogenously expressed, TG microRNA sequences inexistent in the species under study. Its comparison to the milk of wild-type (WT) cows of the same lineage will allow us to fully assess cow's milk microRNA bioavailability with little to no bias. Preliminary analyses of TG cow's milk revealed the abundance of TG microRNAs and their association with extracellular vesicles formed of a lipid bilayer, coated with proteins and containing the microRNA effector protein Argonaute 2. This unique packaging, offering "triple" protection, may explain that 7-14% of TG microRNAs resisted simulated human digestion and could reach the colon of mice fed by gavage. Our proposal is expected to settle the controversy surrounding the oral transfer of dietary microRNAs and establish the basis for the formulation of a safe and reliable vehicle for the delivery of therapeutic RNAs.