Intestinal permeability, digestive stability and oral bioavailability of dietary small RNAs

Authors: YANG, JIAN - Children'S Nutrition Research Center (CNRC); ELBAZ-YOUNES, ISMAIL - University Of Illinois; PRIMO, CECILIA - Children'S Nutrition Research Center (CNRC); MURUNGI, DANNA - Children'S Nutrition Research Center (CNRC); HIRSCHI, KENDAL - Children'S Nutrition Research Center (CNRC)

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/19/2018
Publication Date: 7/6/2018
Citation: Yang, J., Elbaz-Younes, I., Primo, C., Murungi, D., Hirschi, K. 2018. Intestinal permeability, digestive stability and oral bioavailability of dietary small RNAs. Scientific Reports. http://doi.org/10.1038/s41598-018-28207-1.
DOI: https://doi.org/10.1038/s41598-018-28207-1

Interpretive Summary: A strong correlation exists between the consumption of plant-based diets and health and disease prevention; however, for the most part, the components within the plant that make the greatest difference for health have remained elusive. Plant foods contain numerous small pieces of nucleotides (the building blocks of DNA) that maybe the elusive "missing health ingredient". Here we test how the health status of the consuming mouse alters the uptake of the plant-based nucleotides. When the lining of the small intestine becomes damaged, it causes undigested food particles to "leak" through the intestines and flood the blood stream. This condition did not appear to alter the amount of plant-nucleotides found in circulation and suggests that most of the plant dietary nucleotides were degraded during the process of digestion. We then tested a variety of different nucleotide pieces for digestive stability, the ability to withstand the gut environment. We found that the most stable nucleotide pieces were also the most abundant in the consumer's circulation. These findings suggest that if nucleic acids from plants are the missing health ingredient and that we can alter their digestive stability to improve their biological activity. These findings could be used to create more nutritious foods and develop alternative nutritional therapies.

Technical Abstract: Impactful dietary RNA delivery requires improving uptake and enhancing digestive stability. In mice feeding regimes, we have demonstrated that a plant-based ribosomal RNA (rRNA), MIR2911, is more bioavailable than synthetic MIR2911 or canonical microRNAs (miRNAs). Here mutagenesis was used to discern if MIR2911 has a distinctive sequence that aids stability and uptake. Various mutations had modest impacts while one scrambled sequence displayed significantly enhanced digestive stability, serum stability, and bioavailability. To assess if small RNA (sRNA) bioavailability in mice could be improved by increasing gut permeability, various diets, genetic backgrounds and pharmacological methods were surveyed. An intraperitoneal injection of anti-CD3 antibody enhanced gut permeability and correlated with improved uptake of the digestively stable scrambled MIR2911 variant. However, the bioavailability of canonical miRNAs was not enhanced. Similarly, interleukin-10 (IL-10)–deficient mice and mice treated with aspirin displayed enhanced gut permeability that did not enhance uptake of most plant-based sRNAs. This work supports a model where dietary RNAs are vulnerable to digestion and altering gut permeability alone will not impact apparent bioavailability. We suggest that some dietary sRNA may be more digestively stable and methods to broadly increase sRNA uptake requires delivery vehicles to optimize gut and serum stability in the consumer.