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.

饮食中的 microRNA 已被证明可以被哺乳动物吸收并调节宿主基因的表达，但吸收机制仍然未知。在这里，我们表明在胃的胃小坑细胞上表达的 SIDT1 是吸收膳食 microRNA 所必需的。SIDT1 缺陷小鼠表现出基础水平降低和膳食 microRNA 动态吸收受损。值得注意的是，我们将胃确定为膳食 microRNA 吸收的主要部位，这在 SIDT1 缺陷小鼠的胃中显着减弱。机制分析表明，胃小坑细胞对外源性 microRNA 的摄取是 SIDT1 和低 pH 依赖性的。此外，口服植物来源的 miR2911 可延缓肝纤维化，这种保护作用在 SIDT1 缺陷小鼠中被消除。