Formidable challenges to the notion of biologically important roles for dietary small RNAs in ingesting mammals.

The notion of uptake of active diet-derived small RNAs (sRNAs) in recipient organisms could have significant implications for our understanding of oral therapeutics and nutrition, for the safe use of RNA interference (RNAi) in agricultural biotechnology, and for ecological relationships. Yet, the transfer and subsequent regulation of gene activity by diet-derived sRNAs in ingesting mammals are still heavily debated. Here, we synthesize current information based on multiple independent studies of mammals, invertebrates, and plants. Rigorous assessment of these data emphasize that uptake of active dietary sRNAs is neither a robust nor a prevalent mechanism to maintain steady-state levels in higher organisms. While disagreement still continues regarding whether such transfer may occur in specialized contexts, concerns about technical difficulties and a lack of consensus on appropriate methods have led to questions regarding the reproducibility and biologic significance of some seemingly positive results. For any continuing investigations, concerted efforts should be made to establish a strong mechanistic basis for potential effects of dietary sRNAs and to agree on methodological guidelines for realizing such proof. Such processes would ensure proper interpretation of studies aiming to prove dietary sRNA activity in mammals and inform potential for application in therapeutics and agriculture.