SIDT1-dependent absorption in the stomach mediates host uptake of dietary and orally administered microRNAs

  • Cell Res. 2021 Mar;31(3):247-258. doi: 10.1038/s41422-020-0389-3.
Qun Chen   #  1 ,  Fan Zhang   #  1 ,  Lei Dong   #  1 ,  Huimin Wu   #  2 ,  Jie Xu   #  1 ,  Hanqin Li   #  1 ,  Jin Wang  1 ,  Zhen Zhou  1 ,  Chunyan Liu  1 ,  Yanbo Wang  1 ,  Yuyan Liu  1 ,  Liangsheng Lu  1 ,  Chen Wang  1 ,  Minghui Liu  1 ,  Xi Chen  1 ,  Cheng Wang  3 ,  Chunni Zhang  3 ,  Dangsheng Li  4 ,  Ke Zen  1 ,  Fangyu Wang  5 ,  Qipeng Zhang  6 ,  Chen-Yu Zhang  7
Affiliations
  • 1. Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China.
  • 2. Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.
  • 3. Department of Clinical Laboratory, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, 210002, China.
  • 4. Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 5. Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China. [email protected].
  • 6. Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China. [email protected].
  • 7. Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), NJU Institute of AI Biomedicine and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China. [email protected].
  • # Contributed equally.
PMID: 32801357 DOI: 10.1038/s41422-020-0389-3
Abstract

Dietary MicroRNAs have been shown to be absorbed by mammals and regulate host gene expression, but the absorption mechanism remains unknown. Here, we show that SIDT1 expressed on gastric pit cells in the stomach is required for the absorption of dietary MicroRNAs. SIDT1-deficient mice show reduced basal levels and impaired dynamic absorption of dietary MicroRNAs. Notably, we identified the stomach as the primary site for dietary MicroRNA absorption, which is dramatically attenuated in the stomachs of SIDT1-deficient mice. Mechanistic analyses revealed that the uptake of exogenous MicroRNAs by gastric pit cells is SIDT1 and low-pH dependent. Furthermore, oral administration of plant-derived miR2911 retards liver fibrosis, and this protective effect was abolished in SIDT1-deficient mice. Our findings reveal a major mechanism underlying the absorption of dietary MicroRNAs, uncover an unexpected role of the stomach and shed light on developing small RNA therapeutics by oral delivery.

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