Eating microRNAs: pharmacological opportunities for cross-kingdom regulation and implications in host gene and gut microbiota modulation

Cross-kingdom communication via non-coding RNAs is a recent discovery. Exogenous microRNAs (exog-miRNAs) mainly enter the host via the diet. Generally considered unstable in the gastrointestinal tract, some exogenous RNAs may resist these conditions, especially if transported in extracellular vesicles. They could then reach the intestines and more probably exert a regulatory effect. We give an overview of recent discoveries concerning dietary miRNAs, possible ways of enhancing their resistance to food processing and gut conditions, their transport in extracellular vesicles (animal- and plant-origin) and possible biological effects on recipient cells after ingestion. We critically focus on what we believe are the most relevant data for future pharmacological development of dietary miRNAs as therapeutic agents. Finally, we discuss the miRNA-mediated cross-kingdom regulation between diet, host and the gut microbiota. We conclude that, despite many obstacles and challenges, extracellular miRNAs are serious candidates to be targeted pharmacologically for development of new therapeutic agents.A.G.-R. acknowledges the Marie Curie AMAROUT-II Europe Program(Grant Agreement No. 291803). This research was funded by grantsfrom the Spanish Agencia Estatal de Investigación and EuropeanFEDER Funds (PID2019-109369RB-I00 to A.D., AGL2018-78922-Rto A.G.R. and M.C.L.H., and AGL2017-90623-REDT to A.D. and A.M.).Also supported by the Fundación Ramón Areces (CIVP18A3888) toA.D