An Apple a Day? The Hypothesis of Cross-Kingdom Gene Regulation by Plant miRNAs in Mammals and Its Controversies

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. In plants, miRNAs are involved in environmental responses and can be transferred to other species to mediate cross-kingdom regulation of gene expression. This mechanism has recently been proposed in mammals, yet evidence remains scarce and inconsistent. Multiple studies have shown that a fraction of plant-derived miRNAs (pmiRNAs) present in food resist processing, cooking, and digestion. Evidence suggests that dietary-derived pmiRNAs might be absorbed in the gastrointestinal tract and enter circulation, predominantly packaged in extracellular vesicles, and reach different tissues, where they might exert cross-kingdom gene expression regulation. Nonetheless, several attempts to reproduce or confirm the above results have failed, raising questions about the reliability of studies supporting the hypothesis of cross-kingdom gene regulation by pmiRNAs. In this review, we recapitulate the state-of-the-art knowledge in the field, addressing both supporting and opposing evidence, as well as the main analytical challenges that need to be taken into consideration, in an effort to provide a comprehensive framework on the controversial evidence collected so far and support the use of best practices for future research.