WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan.
Department of Physiology, Showa University School of Medicine, Showa University, Tokyo 142-8555, Japan.
Cell. 2020 Aug 6;182(3):609-624.e21. doi: 10.1016/j.cell.2020.06.022. Epub 2020 Jul 7.
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.
肠道肠嗜铬细胞通过 5-羟色胺（5-HT）的产生来调节骨骼和肠道的稳态。最近的一份报告表明，肠道微生物调节 5-HT 水平；然而，确切的潜在分子机制尚不清楚。在这里，我们揭示了肠道中的阳离子通道 Piezo1 作为单链 RNA（ssRNA）的传感器，调节 5-HT 的产生。小鼠肠道上皮细胞特异性敲除 Piezo1 会严重扰乱肠道蠕动，阻碍实验性结肠炎，并抑制血清 5-HT 水平。由于全身 5-HT 缺乏，Piezo1 的条件性敲除增加了骨形成。值得注意的是，粪便 ssRNA 被鉴定为天然的 Piezo1 配体，并且 ssRNA 刺激肠道中 5-HT 的合成是通过 MyD88/TRIF 非依赖性方式触发的。结肠输注核糖核酸酶 A 可抑制肠道蠕动并增加骨量。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-Piezo1 轴可能是治疗骨骼和肠道疾病的潜在预防靶点。
