Study led by Zhang Chen-Yu from the Nanjing University School of Life Sciences, China finds the molecular mechanism of SIDT1 in mediating the uptake of dietary and orally administered microRNAs (miRNA).
Past research by the same research group found that intact plant miRNA in foods can be absorbed through the mammalian digestive system. This discovery brings new light to the potential use of oral administration of miRNA therapeutic drugs. Despite evidence demonstrating the presence of intact dietary miRNAs within mammalian hosts, the molecular mechanism by which these miRNAs are absorbed in the gastrointestinal tract remain a mystery.
In the study by Zhang Chen-Yu’s research group, they were able to find that SID-1 transmembrane family member 1 (SIDT1), mammalian homolog of SID-1 expressed on gastric pit cells in the stomach is required for the absorption of dietary miRNAs. The team removed SIDT1 in mice and found reduced basal levels and impaired dynamic absorption of dietary miRNAs. Most significantly, they were able to identify the stomach as a primary site for absorption and showed to drop drastically in the stomachs of SIDT1-deficient mice.
Further analysis into the molecular mechanism and microenvironment found that the uptake of exogenous miRNAs by gastric pit cells is SIDT1 and low-pH dependent. Particularly, oral administration of plant-derived miR2911 retards liver fibrosis, and the protective effect was eliminated in SIDT1-deficient mice.
The researchers explained that the study is crucial for a number of reasons. First, it discovers that the stomach senses and takes up functional dietary miRNAs, providing a unique new understanding of digestion physiology. The low-pH conditions required for efficient uptake of exogenous miRNA via SIDT1 revealed an evolutionary explanation for functional dietary miRNA absorption, in which the stability of dietary miRNAs is granted in stomach, where RNase activity is largely absent in this low-physiological-pH gastric environment. Finally, as shown from the study that orally administered plant-derived miR2911 is absorbed through SIDT1 was able to alleviate liver fibrosis in mice. This shows potential for a new therapeutic strategy using small-RNA-based treatments, harnessing the physiological mammalian absorption pathway of dietary miRNA.
Overall, this study was able to reveal major molecular mechanisms of dietary miRNA absorption, revealing a new physiological function of the mammalian stomach. It also shows potential for the use of orally delivered small-RNA for therapeutics and drug development.