Further characterization of cellular and extracellular RNAs of milk may be useful and needed. However, the hypothesis that milk miRNAs are taken up and function in the ingesting organism has not yet been nearly as well established as is suggested in this article. I am concerned by several selective and misleading citations. Take the following passage as an example:

"Accumulating evidence is suggesting that, similar to plant food-derived miRNA [20, 21], bovine milk miRNA survive the gastrointestinal tract, enter the bloodstream, and exert tissue-specific regulatory functions in the adult [17, 22–24]. These effects are thought to be mediated by the packaging of milk miRNA in exosomes as well as in milk cells and other microvesicles, which protect them from degradation and facilitate their cellular absorption [7, 25–29]."

Regarding uptake of plant miRNAs, citation 20 has been widely questioned by numerous negative studies (see Snow, et al, RNA Biology, 2013; Dickinson, et al, Nat Biotech, 2013; Witwer, et al, RNA Biology, 2013) and the especially important finding that the initial profiling results were likely due to contamination (Tosar, et al, RNA, 2014). Citation 21 suggests that gut damage promotes uptake of gut contents, including prominently, a ribosomal RNA fragment of plants that was temporarily and erroneously identified as a microRNA (miR2911). Although both positive and negative studies can be found surrounding the hypothesis, the consensus in the field is that even if low levels of uptake of plant xenomiRs were to be confirmed in more rigorous studies, they could have no biological meaning in the context of canonical miRNA-mediated regulation.

Moving on to bovine milk miRNAs in the GI tract entering the bloodstream and functioning, citation 17 addresses movement of milk cells in to circulation of animals in which gut closure has not occurred; it contains no information on vesicles or microRNAs. Citation 22 reports upregulation of 2 miRNAs following milk ingestion, but cannot distinguish between exogenous and endogenous sources; my group could not confirm these results using the same samples or analyzing sequencing data from the original study (http://f1000research.com/...). Citation 23 does not address survival, bloodstream entry, or function of milk miRNAs. Citation 24 is a nonphysiologic in vitro study...nicely done as far as showing transfer of lipid dyes from vesicles to cells, but irrelevant to concentrations of milk EVs in the human gut. Not cited were rigorous and definitive studies that used mouse models, finding that milk xenomiR uptake was undetectable and irrelevant to regulation (Laubier, et al, RNA Biology, 2015, and Title, et al, JBC, 2015).

On milk extracellular vesicles protecting and and transferring miRNAs to cells, citation 25 is a physics paper that has nothing to do with milk or miRNAs (surely a mistake?). The authors of citation 26 voice appropriate doubt about milk miRNA uptake, show only that milk itself contains several miRNAs, and they state that more studies would be needed. Citation 27 is a hypothesis paper. Citation 28 reports protection of miRNAs, but not uptake. Citation 29 does not concern milk.

In the end, these citations have been offered in a highly selective manner to support a hypothesis that has gathered little evidence after years of speculation.