Li Ting, Liu Yueyue, Duan Tianchi, Guo Chao, Liu Bin, Fu Xiuqiong, Wang Lu, Wang Xiaoyuan, Dong Xinyue, Wang Chennan, Lu Yalong, Wang Yu, Shi Lin, Tian Honglei, Yang Xingbin
College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China.
College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China.
Cell Metab. 2025 Feb 4;37(2):345-360.e6. doi: 10.1016/j.cmet.2024.10.012. Epub 2024 Nov 18.
Oligosaccharides are conventionally recognized as "passersby" in the small intestine. However, our research has reframed this understanding by uncovering a new function of oligosaccharide stachyose, which binds hydrophobic residues of membranous HSP90β on small intestinal epithelial cells, thus reprograming the exosomal miRNA profile. CRISPR-Cas9-mediated HSP90β knockout abolished the accumulation of stachyose on cell membrane and its regulatory effects on these miRNAs. Notably, stachyose's regulation on these miRNAs is independent of its prebiotic role, as evidenced by the observation of stachyose-altered fecal miRNAs in pseudo-germ-free mice. These stachyose-altered miRNAs further shaped colonic microbiome, especially harboring Lactobacillus in mice. Thereinto, miR-30a-5p that was downregulated (LogFC < -2) in both mice and human feces following stachyose treatment could specifically suppress the growth of Lactobacillus reuteri. These findings build a new regulatory axis of stachyose-intestinal miRNAs-gut microbiota and unveil a previously unknown mechanism underlying the direct "talk" of oligosaccharides to intestine epithelium via membranous HSP90β.
传统上，寡糖在小肠中被视为“过客”。然而，我们的研究通过揭示水苏糖的新功能，重新构建了这一认知。水苏糖能与小肠上皮细胞上膜性HSP90β的疏水残基结合，从而重新编程外泌体miRNA谱。CRISPR-Cas9介导的HSP90β基因敲除消除了水苏糖在细胞膜上的积累及其对这些miRNA的调控作用。值得注意的是，水苏糖对这些miRNA的调控与其益生元作用无关，这在无菌小鼠粪便中观察到水苏糖改变的miRNA得到了证实。这些水苏糖改变的miRNA进一步塑造了结肠微生物群，尤其是在小鼠中富集了乳酸杆菌。其中，水苏糖处理后在小鼠和人类粪便中均下调（LogFC < -2）的miR-30a-5p可特异性抑制罗伊氏乳杆菌的生长。这些发现建立了水苏糖-肠道miRNA-肠道微生物群的新调控轴，并揭示了寡糖通过膜性HSP90β与肠上皮直接“对话”的潜在机制。
