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

Stephen Y Chan, Jonathan W Snow, Stephen Y Chan, Jonathan W Snow

Abstract

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.

Keywords: Agriculture; Biotechnology; Cross-kingdom; Diet; Ecology; Genetically engineered; Invertebrate; Plant; miRNA; sRNA.

Figures

Fig. 1
Fig. 1
Model for uptake of dietary sRNA from the digestive tract. To carry RNAi regulatory activity on gene expression in an ingesting organism, a sRNAs from the diet (potentially packaged in (1) ribonucleoprotein (RNP) complexes or (2) in vesicles) should cross the epithelial cell (white) barrier via transcellular or paracellular mechanisms or via conveyance by immune cells (gray). They should then be taken up by proximal cells, such as stromal cells (brown) or must gain access to the circulatory (red) or lymphatic system (light gray) for systemic dissemination. b Subsequently, after exit from the circulatory system (red), uptake of sRNAs would ensue by cells of various tissues and organs (gray, brown, and yellow). None of these putative steps are understood at the level of molecular mechanism
Fig. 2
Fig. 2
Critical steps for successful alteration gene expression of an ingesting organism by dietary sRNA (adapted from [64]). (1) Sufficient levels of bio-available sRNA in the diet (potentially packaged (a) in ribonucleoprotein (RNP) complexes or (b) in vesicles); (2) crossing the digestive tract barrier; (3) systemic dissemination; (4) cellular uptake; and (5) alteration of post-transcriptional expression of specific target genes by the RNA-induced silencing complex (RISC, green)

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