Dietary delivery of small RNAs: Has the worm turned?

from Biology Fortified by Kendal Hirschi

“You are what you eat,” as the saying goes, which serves for some as a guide to healthy eating. Even the field of nutrition appreciates the literal nature of this adage: as our bodies renew aging cells, our diets provide the necessary building blocks to repair and maintain them. We need basic nutrients, vitamins, and minerals for proper development and to maintain our health, but what about small RNA molecules? There is a growing interest in small RNAs because they regulate the expression of genes in living organisms, and are not only present in our food to begin with but are also being tested in genetically engineered crops to create useful traits. While experimental biologists have used dietary small RNAs to exert regulatory changes in worms for decades, few scientists would recognize small RNAs as nutrients. Several recent reports by Baier et al. and Zhou et al. (see references 1, 2 below), suggest that small RNAs from milk and honeysuckle could have a biological impact on people. Many other researchers have failed to show such impacts (3-5), but in light of these two studies, should we reconsider the “pervading negativity” of the field? Has the “worm turned” for small RNAs?

“To whom do lions cast their gentle looks? Not to the beast that would usurp their den. The smallest worm will turn being trodden on, And doves will peck in safeguard of their brood.” – Lord Clifford, Henry VI, Part 3, William Shakespeare.

Our diets contain hundreds of different small RNAs including microRNAs (miRNAs) that are 19-24 nucleotides long (6). Within the plant or animal of origin, these tiny pieces of genetic information attach to specific mRNAs and modify translation. By interrupting the normal flow of information from DNA to mRNA to protein, small RNAs can “silence” genes within the same organism. Several years ago, a report challenged multiple paradigms, suggesting that ingested miRNAs are transferred to blood, accumulate in tissues, and regulate transcripts within the consuming animal (7). These authors had the bravado to suggest food-derived exogenous miRNA may qualify as a novel nutrient. The scientific community sought to authenticate this claim; however, several high-profile studies failed to validate this initial observation (4,5,8). Despite these negative reports, a small dietary RNA hermeneutic circle formed (9-11). Here I review four recent studies that further demonstrate the potential for dietary delivery of small RNAs (1,2).

Milk: an exosomal miRNA transmitter

Mammalian milk appears to serve as an effective vehicle to deliver dietary animal miRNAs since in milk miRNAs are encapsulated in exosomes and maybe more recalcitrant to degradation and receptive for absorption (1). Bovine milk given to volunteers showed a dose dependent response for milk-based miRNAs, while no change was noted in an endogenous miRNA. Mice fed milk diets contained 61% more plasma of a putative bovine miRNA, than mice fed a milk miRNA-depleted diet. Because the content of the nutrients other than miRNAs was identical, the 61% decrease in this plasma miRNA in the depleted group was explained as an insufficient supply of exogenous dietary miRNAs. The compelling message from this milk feeding study is that dietary milk based microsomes appear to provide a mechanism for oral delivery into healthy consumers (1,12).

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