RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis
RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis
复制标题
DOI：
10.1016/j.cell.2020.06.022
复制
发表时间：
2020-08-06
期刊：
影响因子：
64.5
通讯作者：
Maruyama, Kenta
中科院分区：
文献类型：
--
作者：
Sugisawa, Erika;Takayama, Yasunori;Maruyama, Kenta
胃肠道嗜铬细胞通过5-羟色胺（5-HT）的产生来调节骨和肠道的稳态。最近的一份报告表明，肠道微生物调节5-HT水平;然而，精确的潜在分子机制尚未探索。在这里，我们揭示了肠道中的阳离子通道Piezo 1作为控制5-HT产生的单链RNA（ssRNA）的传感器。肠上皮特异性缺失小鼠Piezo 1严重干扰肠道蠕动，阻碍实验性结肠炎，并抑制血清5-HT水平。由于系统性5-HT缺乏，Piezo 1的条件性敲除增加了骨形成。值得注意的是，粪便ssRNA被鉴定为天然Piezo 1配体，并且ssRNA刺激的肠道5-HT合成以MyD 88/TRIF非依赖性方式被诱发。RNA酶A的结肠输注抑制了肠道运动并增加了骨量。这些发现表明肠道ssRNA是全身5-HT水平的主要决定因素，表明ssRNA-Piezo 1轴是治疗骨骼和肠道疾病的潜在预防靶点。
Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders.