Cell
Volume 182, Issue 3, 6 August 2020, Pages 609-624.e21
Journal home page for Cell

Article
RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis

https://doi.org/10.1016/j.cell.2020.06.022Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Intestinal epithelium-specific Piezo1 deletion disturbs gut and bone homeostasis

  • Fecal ssRNA is a natural ligand of Piezo1

  • Colonic infusion of RNase A suppresses gut motility and increases bone mass

  • Intestinal ssRNA-Piezo1 axis is a critical factor in systemic 5-HT synthesis

Summary

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.

Keywords

Piezo1
5-HT
bone formation
peristalsis
colitis
single-stranded RNA

Cited by (0)

8

These authors contributed equally

9

Lead Contact