Controversy Surrounding Dietary miRNAs

The concept that dietary miRNAs could be therapeutic has been called “compelling, fresh, and revolutionary.” However, the first reports were met with suitable skepticism, which have since evolved into a fierce controversy. Many subsequent attempts at replication failed to unambiguously confirm the initial findings, leaving the medical literature littered with editorials with names like “Diet-derived microRNAs: unicorn or silver bullet?” “Fairy tale or treasure?…”

One study, for instance, found that microRNAs are absorbed in meaningful amounts from even a single cup of milk, but when four people were fed about three cups of broccoli sprouts, they found no bump in common broccoli microRNAs in a blood draw four hours later. Another failed to find fruit microRNAs in the blood of seven collegiate athletes who had eaten cantaloupe the day before. In response, some researchers accuse skeptics of “cherry-picking” these few negative studies and ignoring the larger series of studies reporting positive results. Factors that could account for the negative findings involve using the wrong types of tubes for blood collection and improper storage, both of which can cause the loss of microRNAs. For example, in one study failing to find bovine microRNAs in the blood of milk drinkers, the dry ice used for shipping had largely vaporized in transit. Although micrRNAs can be stable at room temperature, microRNAs can be lost in a freeze/thaw cycle.

A 2021 study claimed to have unequivocally established the presence of dietary plant miRNAs in humans, but that doesn’t necessarily mean they are capable of doing anything. For example, to significantly affect cellular function, there’s thought to be threshold concentration needed, for example at least 100 copies of the microRNA per cell, or maybe even 1,000, or 10,000. Some of the dietary microRNA levels fall well below that, for example 5 copies per cell, compared to up to 50,000 copies for endogenous human microRNAs. One research team calculated that given the concentration of a particular microRNA in cantaloupe, you would have to eat nearly two tons to reach a critical mass in your gut.

Other critics argue that the numbers aren’t just negligible but nonexistent, false positive artifacts of sample contamination, sequencing errors, or instrument failure. There was one broccoli paper that was retracted due to errors in the design of the PCR primers used in the experiment. In terms of accidental cross-contamination, a survey of hundreds of data sets of human tissues alleging xeno-microRNAs found that the majority stem from rodents, common laboratory animals, but a “rare human dietary contribution.” Even many of the plant microRNAs that have been found are not of food species (such as from poplar trees) suggesting the samples were tainted by trace contamination from external sources. Although it continues to be an exciting area, the biological role of dietary plant microRNAs remains far from being firmly established.