[PDF][PDF] RNA sensing by gut Piezo1 is essential for systemic serotonin synthesis

E Sugisawa, Y Takayama, N Takemura, T Kondo… - Cell, 2020 - cell.com
E Sugisawa, Y Takayama, N Takemura, T Kondo, S Hatakeyama, Y Kumagai, M Sunagawa…
Cell, 2020cell.com
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 …
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.
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