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.

胃肠道肠嗜铬细胞通过5-羟色胺（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，肠道微生物可调节5-HT水平。然而，确切的潜在分子机制尚待探索。在这里，我们揭示了肠道中的阳离子通道Piezo1充当控制5-HT产生的单链RNA（ssRNA）的传感器。小鼠Piezo1的肠上皮特异性缺失极大地干扰了肠道蠕动，阻碍了实验性结肠炎，并抑制了血清5-HT水平。由于全身5-HT缺乏，Piezo1的条件性敲除骨形成增加。值得注意的是，粪便中的ssRNA被鉴定为天然的Piezo1配体，并且以独立于MyD88 / TRIF的方式诱发了肠道中ssRNA刺激的5-HT合成。结肠灌注RNase A可抑制肠蠕动并增加骨量。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轴是骨和肠道疾病治疗的潜在预防目标。